Absolute Neutrophil Count Nadir Research Articles

Irradiation of Anatomically Defined Pelvic Bone Marrow Subsites and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation

Irradiation of pelvic bone marrow (PBM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. Multiple studies have suggested that irradiation of the lumbosacral spine (LSBM) may be the primary cause of HT. We hypothesized that irradiation of the LSBM may be a superior predictor of absolute neutrophil count (ANC) nadir than the PBM or other anatomically-defined subsites. The cohort included 45 patients with non-metastatic anal cancer who were treated with definitive chemoradiation with mitomycin-C and 5-fluorouracil. PBM was defined as the external contour of the pelvic bones from the top of the L5 vertebral body to the bottom of the ischial tuberosity. PBM was divided into three subsites: LSBM included the entire sacrum and L5 vertebral body, iliac subsite (IBM) extended from the iliac crests to the superior border of the femoral head, and lower pelvis (LPBM) included the pubic bones, ischia, acetabula, and proximal femora. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2 weeks of completion of treatment. Generalized linear modeling was used to analyze the correlation between the equivalent uniform doses (EUD) with “a” value of 0.5 to the PBM, LSBM, IBM, and LPBM structures and the ANC. Age, BMI, sex, baseline ANC count, immunosuppression were analyzed as potential covariates. Mean ANC nadir was 0.77 x 109/L (standard deviation: 0.66 x 109/L). Grade 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. Baseline ANC was the only significant covariate and was included in all models. EUD of PBM, LSBM and IBM were significantly associated with ANC nadir (Table). Model performance (R2) was not superior for the LSBM compared to the IBM and PBM models. Grade 4 ANC toxicity was significantly associated with the EUD of PBM (odds ratio per Gy (OR)): 1.04; P = 0.038), LSBM (OR: 1.02; P = 0.029), and IBM (OR: 1.04; P = 0.035). The LSBM model was not superior to the PBM model, likely because of the functional importance of the IBM region. Our results support further investigation of techniques designed to reduce irradiation of both the LSBM and IBM subsites. Whether the LPBM should be considered functionally important for avoidance of HT requires further study.Abstract 2487; Table 1.Modelß95% Confidence IntervalP-valueAdjusted R2PBM-0.065-0.109 to -0.0200.0070.226LSBM-0.031-0.059 to -0.0130.0130.206IBM-0.066-0.107 to -0.0240.0040.249LPBM-0.029-0.078 to 0.0200.2520.106 Open table in a new tab

1433O - Phase 3 efficacy and safety trial of proposed pegfilgrastim biosimilar MYL-1401H vs EU-neulasta® in the prophylaxis of chemotherapy-induced neutropenia

MYL-1401H is a proposed pegfilgrastim biosimilar to the reference product EU-Neulasta®, based on physicochemical characterization, in vitro bioassays, toxicokinetics (TK), pharmacokinetics (PK), and pharmacodynamics (PD) studies. This is a phase 3, multicenter, randomized, double-blind, parallel-group trial of MYL-1401H vs EU-Neulasta®. Chemotherapy and radiotherapy naïve patients with newly diagnosed Stage II/III breast cancer were eligible to receive docetaxel, doxorubicin, and cyclophosphamide anti-cancer chemotherapy planned every 3 weeks for 6 chemotherapy cycles. A total of 194 patients were randomized in a 2:1 ratio to receive 6 mg/0.6 mL of either MYL-1401H or EU-Neulasta® on Day 2 of each cycle. The primary efficacy endpoint was the duration of severe neutropenia (DSN) in Cycle 1, defined as days with absolute neutrophil count (ANC) < 0.5 × 109/L in the per protocol population. The sample size to provide 90% power to declare that MYL-1401H is comparable to Neulasta® in the analysis of duration of severe neutropenia (DSN) in cycle 1. Equivalence is declared if the two-sided 95% confidence interval (CI) of the least squares means difference between the DSNs falls wholly within an equivalence region defined as [-1, +1 day]. A sensitivity analysis in the intent-to-treat population was also carried out. The mean ± SD DSN in the MYL-1401H and EU-Neulasta® groups were 1.2 ± 0.93 and 1.2 ± 1.10, respectively. The 95% CI of least squares means difference [-0.285 day, 0.298 day] was within [-1 day, +1 day] range, that was also corroborated by the sensitivity analysis. Other endpoints of the study including Grade 3-4 neutropenia, time to ANC nadir, and duration of post-nadir recovery were comparable too. The overall safety profile of MYL-1401H was similar to EU-Neulasta® with bone pain, an expected AE, as the most frequently reported treatment related TEAE. MYL-1401H demonstrated equivalent efficacy to EU-Neulasta® in the prophylaxis of chemotherapy induced neutropenia in patients with breast cancer. MYL-1401H was generally well tolerated and there were no particular safety concerns identified with overall safety profile being similar to EU-Neulasta®.

Dosimetric predictors of acute haematological toxicity in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy.

Haematological toxicity (HT) is common in patients with oesophageal cancer (EC) treated with chemoradiotherapy (CRT). The Quantitative Analysis of Normal Tissue Effects in the Clinic guidelines provide no dose constraints for the bone marrow (BM) to avoid HT. We aimed to determine dosimetric factors associated with HT during CRT for EC. 41 patients with EC treated with neoadjuvant cisplatin and 5-fluorouracil-based CRT were retrospectively reviewed. Associations between the dose-volume histogram parameters of thoracic bones and blood cell count changes during CRT were assessed using logistic regression analyses. Receiver-operating characteristic curves were used to derive optimal dosimetric planning constraints. Vx indicates the total organ volume percentage exceeding a radiation dose of x (Gy). Greater thoracic vertebrae and rib irradiation doses, including mean vertebral dose (MVD), thoracic vertebrae V5-30 (TVV5-30), mean rib dose and rib V5-20, were associated with increased leukopenia (grade ≥ 3) risk. Additional BM sites (sternum, scapulae and clavicles) did not influence HT. White blood cell and absolute neutrophil count nadirs were associated with increased irradiation doses to the thoracic vertebrae, ribs and sternum. Chemotherapy cycle number was not significantly associated with severe neutropenia or leukopenia. Cut-off values with the highest likelihood of avoiding leukopenia were MVD < 25.9 Gy, TVV20 < 70% and TVV10 < 77%. Thoracic bone irradiation dose was significantly associated with HT after adjusting for chemotherapy effects. Efforts to maintain MVD < 25.9 Gy, TVV10 < 77% and TVV20 < 70% could reduce HT. This is the first study addressing issues concerning HT in patients with neoadjuvant CRT-treated EC.

Dose to specific subregions of pelvic bone marrow defined with FDG-PET as a predictor of hematologic nadirs during concomitant chemoradiation in anal cancer patients.

To test the hypothesis that irradiated volume of specific subregions of pelvic active bone marrow as detected by (18)FDG-PET may be a predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation, we analyzed 44 patients submitted to IMRT and concurrent chemotherapy. Several bony structures were defined: pelvic and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. Active BM was characterized employing (18)FDG-PET and characterized in all subregions as the volume having standard uptake values (SUVs) higher than SUVmean. All other regions were defined as inactive BM. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hb) and platelet (Plt) nadirs. Generalized linear modeling was used to find correlations between dosimetric variables and blood cells nadirs. WBC nadir was significantly correlated with LSBM mean dose (β=-1.852; 95% CI -3.205/-0.500; p=0.009), V10 (β=-2.153; 95% CI -4.263/-0.721; p=0.002), V20 (β=-2.081; 95% CI -4.880/-0.112; p=0.003), V30 (β=-1.971; 95% CI -4.748/-0.090; p=0.023) and IBM V10 (β=-0.073; 95% CI -0.106/-0.023; p=0.016). ANC nadir found to be significantly associated with LSBM V10 (β=-1.878; 95% CI -4.799/-0.643; p=0.025), V20 (β=-1.765; 95% CI -4.050/-0.613; p=0.030) and IBM V10 (β=-0.039; 95% CI -0.066/-0.010; p=0.027). Borderline significance was found for correlation between Plt nadir and LSBM V30 (β=-0.056; 95% CI -2.748/-0.187; p=0.060), V40 (β=-0.059; 95% CI -3.112/-0.150; p=0.060) and IBM V30 (β=-0.028; 95% CI -0.074/-0.023; p=0.056). No inactive BM subsites were found to be correlated with any blood cell nadir. (18)FDG-PET is able to define active bone marrow within pelvic osseous structures. LSBM is the strongest predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation.

A Phase II prospective nonrandomized trial of magnetic resonance imaging-guided hematopoietic bone marrow-sparing radiotherapy for gastric cancer patients with concurrent chemotherapy.

PurposeThis study aimed to spare hematopoietical bone marrow (BM) identified by magnetic resonance (MR) radiation in order to alleviate acute hematologic toxicity (HT) for gastric cancer patients treated with postoperative chemoradiotherapy (CRT).MethodsA prospective, open-label, single-arm Phase II study (Clinicaltrials.gov; NCT 01863420) was conducted in 25 patients with gastric cancer who were eligible for postoperative concurrent CRT. The MR images of vertebral body T8-L4 were fused with images of simulating computed tomography. Hematopoietical BM was contoured according to the MR and spared in radiotherapy plan. The CRT regimen consisted of daily capecitabine (1600 mg/m2/d) and 45 Gy of radiation at 1.8 Gy per day. Primary endpoints were grade ≥3 HT that occurred within 2 months of initiation of CRT. The relationship between HT and dose–volume of BM was estimated by multivariable linear regression model.ResultsTwenty four patients (96%) had T3–4 disease and 22 (88%) had disease with node positive. The median age was 53 years (range, 28–73 years). Before concurrent CRT, adjuvant chemotherapy was administered with a mean cycle of 4.3±0.5. Only five patients (20%) developed grade 3–4 HT during treatment, among whom two (8.0%) patients experienced grade 3–4 leucopenia, two (8.0%) experienced neutropenia, and two (8.0%) experienced thrombocytopenia, respectively. None of the patients showed grade 3–4 anemia. Multivariable linear regression revealed increased BM-V5 (P=0.03) and BM-V20 (P=0.002) were found to be significantly associated with decreased white blood cells nadirs in multivariable regression; increased BM-V20 (P<0.001) with decreased absolute neutrophil count nadirs, increased BM-V30 (P=0.002) and volume of BM (P=0.001) with decreased platelet count nadirs.ConclusionIrradiation of active BM identified by MR is associated with HTs. Techniques to limit low-dose radiation, especially V20, to BM could reduce HT in gastric cancer patients.

Abstract P1-10-01: A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1)

Abstract Background: An abbreviated pathway for biological products shown to be biosimilar to the reference product exists in Europe and the US. The randomized PROTECT1 trial compared the efficacy and safety of the proposed biosimilar pegfilgrastim with reference pegfilgrastim. Methods: In this multinational, prospective, double-blind trial, chemotherapy-naïve women aged ≥18 years with histologically proven breast cancer received up to 6 cycles of (neo)-adjuvant TAC chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2). Patients were randomized to a single 6 mg SC injection of the proposed biosimilar pegfilgrastim (LA-EP2006) or the reference (Neulasta®) on day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) during Cycle 1, defined as number of consecutive days with an absolute neutrophil count (ANC) &amp;lt;0.5 x 109/L. The study was powered at 90% and had a hierarchical testing procedure utilizing a ±1 day margin to test for equivalence (2-sided 95% confidence interval [CI]) and a subsequent −0.6 day non-inferiority margin (1-sided 97.5% CI) for DSN during Cycle 1. DSN was analyzed with an ANCOVA model adjusted for treatment, chemotherapy, region and baseline ANC. Secondary efficacy assessments were: time to ANC recovery, ANC nadir, incidence of febrile neutropenia, number of days of fever, frequency of infections and mortality due to infection. Safety was assessed at 4 weeks and 6 months after the last pegfilgrastim administration. Immunogenicity was assessed by testing for neutralizing anti-pegfilgrastim antibodies. Results: A total of 316 patients were randomized and included in the full analysis set (LA-EP2006: n=159; reference: n=157). Baseline demographics were similar in both groups (mean±SD age: LA-EP2006 49.9±9.53, reference 50.5±10.87 years; breast cancer stage II-III: LA-EP2006 n=155 [97.5%], reference n=151 [96.2%]). Mean±SD DSN in Cycle 1 was 0.75±0.88 days with LA-EP2006 and 0.83±0.90 days with reference, with a treatment difference of 0.07 days (95% CI: −0.12, 0.26); LA-EP2006 was both equivalent and non-inferior to the reference. There were no clinically meaningful differences between LA-EP2006 and reference in incidence of febrile neutropenia (3.8% vs 7.0% in Cycle 1, 5.7% vs 7.6% across all cycles), days with fever, depth of ANC nadir in Cycle 1, time to ANC recovery in Cycle 1, or frequency of infections in Cycle 1 and across all cycles. Treatment-emergent adverse events (TEAEs) were similar across groups and consistent with the known safety profile of pegfilgrastim. Most frequently reported TEAEs related to treatment were musculoskeletal and connective tissue disorders (LA-EP2006 4.4%, reference 5.7%). Serious TEAEs were reported in 10.1% of LA-EP2006 and 13.4% of reference patients. No neutralizing anti-pegfilgrastim antibodies were detected. Conclusions: Proposed biosimilar pegfilgrastim (LA-EP2006) met the primary endpoint demonstrating both equivalence and non-inferiority to the reference. LA-EP2006 and the reference are similar with no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving (neo)-adjuvant myelosuppressive chemotherapy. Citation Format: Harbeck N, Zbarskaya I, Lipatov O, Frolova M, Udovitsa D, Topuzov E, Ganea-Motan DE, Nakov R, Singh P, Rudy A, Blackwell K. A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-01.

Abstract OT3-02-13: Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study)

Abstract Background: SPI-2012 is a distinct biologic that uses the innovative, proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™) to enhance the activity of G-CSF. SPI-2012 consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, more potent, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors. The primary endpoint of this Phase 3 study is to compare the efficacy of a single dose of SPI-2012 with pegfilgrastim in patients with early-stage breast cancer (ESBC) receiving TC chemotherapy, as measured by the Duration of Severe Neutropenia (DSN) in Cycle 1. Key secondary objectives include the comparison of SPI-2012 with pegfilgrastim during Cycle 1 in: Time to Absolute Neutrophil Count (ANC) Recovery; Depth of ANC Nadir and Incidence of Febrile Neutropenia. Safety and pharmacokinetics will also be assessed. Trial Design: This is a randomized, open-label, active-controlled, multicenter study comparing the efficacy and safety of SPI-2012 to pegfilgrastim. Patients (n=506) will be randomized in a 1:1 ratio to receive either SPI-2012 (equivalent to 3.6 mg G-CSF) or pegfilgrastim (equivalent to 6.0 mg G-CSF) once per chemotherapy cycle (up to 4 cycles), approximately 24 hrs after chemotherapy. Eligibility Criteria: This study will enroll histologically confirmed ESBC patients who are eligible to receive adjuvant or neoadjuvant TC chemotherapy and at least 18 years of age, with adequate hematologic, renal and hepatic function. Patients will be excluded if they have active concurrent malignancy or life-threatening disease; a known sensitivity or previous reaction to E. coli derived products or any of the products to be administered during study participation; concurrent adjuvant cancer therapy; locally recurrent/metastatic or contralateral breast cancer; previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development prior to the administration of study drug; bone marrow or hematopoietic stem cell transplant or radiation therapy prior to enrollment or are pregnant or breast-feeding. Statistical Methods: The goal of the study is to demonstrate non-inferiority of SPI-2012 to pegfilgrastim. For the Primary Efficacy Analysis, the mean DSN in Cycle 1 will be compared between the SPI-2012 and pegfilgrastim treatment arms. A 2-sided 95% confidence interval (CI) of the difference between the mean DSN of the SPI-2012 arm and the mean DSN of the pegfilgrastim arm will be calculated using bootstrap resampling with treatment as the only stratification factor. For the Secondary Efficacy Analyses, the results will each be summarized by treatment arm and Cycle. The two-sided 95% CI for the difference between the treatment arms will be calculated. Target Accrual: Approximately 506 pts. Citation Format: Schwartzberg L, Vacirca JL, Hager SJ, Adoo CS, Ibrahim EN, Bhat G, Choi MR, Allen LF, Tedesco KL, Agajanian R. Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-13.

Irradiation of FDG-PET–Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation

Irradiation of pelvic bone marrow (BM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. We hypothesized that irradiation of hematologically active bone marrow (ABM) subregions defined by fluorodeoxyglucose (FDG) positron emission tomography (PET) is a principal cause of radiation-associated HT. The cohort included 45 patients with nonmetastatic anal cancer who underwent FDG-PET imaging prior to definitive chemoradiation with mitomycin-C and 5-fluorouracil. Total bone marrow (TBM) was defined as the external contour of the pelvic bones from the top of lumbar 5 (L5) to the bottom of the ischial tuberosity. Standardized uptake values (SUV) for all voxels within the TBM were quantified and normalized by comparison to normal liver SUV. Subvolumes of the TBM that exhibited the highest and lowest 50% of the SUVs were designated ABM50 and IBM50, respectively. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2weeks of completion of treatment. Multivariate linear modeling was used to analyze the correlation between the equivalent uniform doses (EUD) with an a value of 0.5, 1 (equivalent to mean dose), 3, 7, and 12 to the BM structures and the ANC. Mean±SD ANC nadir was 0.77×10(9)/L (±0.66×10(9)/L). Grades 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. The EUD a parameter of 0.5 was optimal for all BM models indicating high radiation sensitivity. EUD of TBM and ABM50 and IBM50 were all significantly associated with ANC nadir. However, model performance for ABM50 was not superior to that of the TBM and IBM50 models. Irradiation of pelvic BM was associated with HT. However, FDG-PET-defined ABM models failed to improve model performance compared to the TBM model.

Proposed Biosimilar Pegfilgrastim (LA-EP2006) and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients with Breast Cancer: A Randomized, Double-Blind Trial. Protect 2: Pegfilgrastim Randomized Oncology (supportive care) Trial to Evaluate Comparative Treatment Results

Background: Approval of a biosimilar is based on it being highly similar with regard to safety, purity, and potency and with no clinically meaningful differences when compared with a reference product.The first biosimilar, filgrastim (EP-2006), was recently approved in US.LA-EP2006 is a proposed biosimilar to the reference product pegfilgrastim (Neulasta®).Methods: This was a prospective, randomized, double-blind trial conducted in the US, Latin America, Asia and Europe. Patients with histologically proven breast cancer receiving (neo)-adjuvant TAC chemotherapy (docetaxel 75mg/m2, doxorubicin 50mg/m2, cyclophosphamide 500mg/m2) over six cycles were treated with a single 6mg SC injection of LA-EP2006 or reference pegfilgrastim on day 2 of each cycle. Primary endpoint was the duration of severe neutropenia (DSN) during Cycle 1 defined as number of consecutive days with an absolute neutrophil count (ANC) <0.5 x 109/L. The study was powered at 90% and had a hierarchical testing procedure utilizing a ±1 day margin to test for equivalence (two-sided 95% confidence interval [CI]) and then a -0.6 day non-inferiority margin (one-sided 97.5% CI) for DSN during Cycle 1. DSN was analyzed with an ANCOVA model adjusted for treatment, chemotherapy, region and baseline ANC. Secondary efficacy assessments were: time to ANC recovery, depth of ANC nadir, incidence of febrile neutropenia, number of days of fever, infection frequency and mortality due to infection. Safety and immunogenicity were assessed until 4 weeks after last study drug administration.Results: A total of 308 patients were randomized and included in the full analysis set (LA-EP2006: n=155; reference: n=153). Baseline characteristics were similar in both groups (mean±SD age: LA-EP2006 48.8±10.50, reference 49.1±10.07 years; breast cancer stage II-III: LA-EP2006 n=148 (95.5%), reference n=139 (90.8%). Mean±SD DSN in Cycle 1 was 1.36 ± 1.13 days in the LA-EP2006 group versus 1.19 ± 0.98 days in the reference group (treatment difference −0.16 days; 95% CI: −0.40, 0.08). LA-EP2006 was thus both equivalent and non-inferior to reference pegfilgrastim as the 95% CI was within the defined margin of ±1 day and the lower bound of the 95% CI was entirely above −0.6 days. There were no clinically meaningful differences between LA-EP2006 and reference in incidence of febrile neutropenia (7.7% vs 9.8% in Cycle 1, 10.3% vs 13.1% across all cycles), days with fever, depth of ANC nadir in Cycle 1, time to ANC recovery in Cycle 1, or frequency of infections. Treatment-emergent adverse events (TEAEs) were similar across groups and consistent with the known safety profile of pegfilgrastim. The most frequent TEAEs related to treatment were musculoskeletal and connective tissue disorders (LA-EP2006 16.1%, reference 13.7%). Serious TEAEs were reported in: LA-EP2006 18.7%, reference 20.9%). No neutralizing anti-pegfilgrastim antibodies were detected.Conclusions: Proposed biosimilar pegfilgrastim (LA-EP2006) met the primary endpoint demonstrating it to be both equivalent and non-inferior to the reference. LA-EP2006 and the reference are similar with no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving (neo)-adjuvant myelosuppressive chemotherapy.Acknowledgment: The authors acknowledge the other investigators who participated in the PROTECT2 study. DisclosuresBlackwell:Celgene: Consultancy, Research Funding; GE Healthcare: Consultancy; Genentech: Consultancy, Research Funding; Hospira: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Roche: Consultancy; Sandoz: Consultancy; Pfizer: Research Funding; Genomic Health: Speakers Bureau; Boehringer Ingelheim: Consultancy; Amgen: Consultancy. Nakov:Sandoz: Employment. Singh:Sandoz: Employment. Schaffer:Sandoz: Employment. Gascon:Sandoz: Honoraria, Speakers Bureau. Harbeck:Sandoz: Other: Chair of Data and Safety Monitoring Board (DSMB) on trials sponsored by Sandoz.

The Effect of Radiation Dose and Variation in Neupogen® Initiation Schedule on the Mitigation of Myelosuppression during the Concomitant GI-ARS and H-ARS in a Nonhuman Primate Model of High-dose Exposure with Marrow Sparing.

A nonhuman primate (NHP) model of acute high-dose, partial-body irradiation with 5% bone marrow (PBI/BM5) sparing was used to assess the effect of Neupogen® [granulocyte colony stimulating factor (G-CSF)] to mitigate the associated myelosuppression when administered at an increasing interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neupogen® on the mortality or morbidity of the hematopoietic (H)- acute radiation syndrome (ARS) and concurrent acute gastrointestinal radiation syndrome (GI-ARS). NHP were exposed to 10.0 or 11.0 Gy with 6 MV LINAC-derived photons at approximately 0.80 Gy min. All NHP received medical management. NHP were dosed daily with control article (5% dextrose in water) initiated on day 1 post-exposure or Neupogen® (10 μg kg) initiated on day 1, day 3, or day 5 until recovery [absolute neutrophil count (ANC) ≥ 1,000 cells μL for three consecutive days]. Mortality in both the 10.0 Gy and 11.0 Gy cohorts suggested that early administration of Neupogen® at day 1 post exposure may affect acute GI-ARS mortality, while Neupogen® appeared to mitigate mortality due to the H-ARS. However, the study was not powered to detect statistically significant differences in survival. The ability of Neupogen® to stimulate granulopoiesis was assessed by evaluating key parameters for ANC recovery: the depth of nadir, duration of neutropenia (ANC < 500 cells μL) and recovery time to ANC ≥ 1,000 cells μL. Following 10.0 Gy PBI/BM5, the mean duration of neutropenia was 11.6 d in the control cohort vs. 3.5 d and 4.6 d in the day 1 and day 3 Neupogen® cohorts, respectively. The respective ANC nadirs were 94 cells μL, 220 cells μL, and 243 cells μL for the control and day 1 and day 3 Neupogen® cohorts. Following 11.0 Gy PBI/BM5, the duration of neutropenia was 10.9 d in the control cohort vs. 2.8 d, 3.8 d, and 4.5 d in the day 1, day 3, and day 5 Neupogen® cohorts, respectively. The respective ANC nadirs for the control and day 1, day 3, and day 5 Neupogen® cohorts were 131 cells μL, 292 cells μL, 236 cells μL, and 217 cells μL, respectively. Therefore, the acceleration of granulopoiesis by Neupogen® in this model is independent of the time interval between radiation exposure and treatment initiation up to 5 d post-exposure. The PBI/BM5 model can be used to assess medical countermeasure efficacy in the context of the concurrent GI- and H-ARS.

Neutropenia Associated with Long-Term Ceftaroline Use.

Ceftaroline is a fifth-generation cephalosporin with potent antimicrobial activity against Gram-positive and Gram-negative pathogens. Neutropenia is a rare serious adverse event for the class of cephalosporins; however, we observed several cases of severe neutropenia in our outpatient infectious disease practice believed to be associated with ceftaroline use. The aim of this study was to determine the incidence of neutropenia among patients receiving ceftaroline therapy for more than 7 days. We conducted a retrospective cohort analysis of patients admitted to an 800-bed regional medical center between June 2012 and December 2014 who received ceftaroline for more than 7 days to assess the incidence of developing clinically significant neutropenia. Demographic and patient care data points as well as underlying admitting and chronic diagnoses were retrospectively collected from the medical record. Clinically significant neutropenia was defined as an absolute neutrophil count (ANC) less than 1,500 cells/mm(3). Analysis was performed to determine the incidence, severity, and outcome of neutropenia following ceftaroline administration. A total of 39 patients were included in the cohort. The median duration of therapy was 27 days. Seven patients (18%) developed neutropenia while on ceftaroline therapy. Four (10%) of the neutropenic patients had an ANC of <500 cells/mm(3). The median first neutropenic day was day 17, with the median ANC nadir of 432 cells/mm(3) on day 24. We determined that extended ceftaroline infusion is associated with the development of neutropenia. We recommend obtaining a complete blood count (CBC) with differential at the onset of therapy and weekly thereafter. Should the ANC fall below 2,500 cells/mm(3), then twice-weekly CBCs should be monitored for the duration of ceftaroline therapy, and therapy should be discontinued if the ANC falls to 1,500 cells/mm(3) or less.

Irradiation of FDG-PET Defined-Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation

Irradiation of FDG-PET Defined-Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation

Predictors of outcome and severity in adult filipino patients with febrile neutropenia

Aim. The study aimed to describe the profile of Filipino febrile neutropenia patients and to determine parameters associated with severe outcomes. Methods. This is a retrospective study of Filipino febrile neutropenia patients admitted to the Philippine General Hospital. Patients were described in terms of clinical presentation and stratified according to the presence or absence of severe outcomes. Prognostic factors were then identified using regression analysis. Results. 115 febrile episodes in 102 patients were identified. Regression analysis yielded prolonged fever >7 days prior to admission (OR 2.43; 95% CI, 0.77–7.74), isolation of a pathogen on cultures (OR 2.69; 95% CI, 1.04–6.98), and nadir absolute neutrophil count (ANC) 7 days prior to admission, positive pathogen on cultures, and nadir ANC < 100 during admission predicted severe outcomes, whereas G-CSF use and complete antibiotic therapy were associated with better outcomes. These prognostic variables might be useful in identifying patients that need more intensive treatment and monitoring.

Modeling early haematologic adverse events in conformal and intensity-modulated pelvic radiotherapy in anal cancer

Background and purposeTo 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 materialsTwo 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 5–25Gy were tested for statistical significance. Regression models were used to test for correlation to blood counts. NTCP modeling was also performed. ResultsPMB 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). ConclusionWhilst 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.

Monocyte nadir is a possible indicator for neutrophil nadir during lung cancer chemotherapy.

No previous study clearly demonstrated the association between the absolute neutrophil count (ANC) nadir and the absolute monocyte count (AMC) nadir among patients undergoing chemotherapy. We retrospectively reviewed patients with an incurable lung cancer in two university hospital who were treated with platinum doublet or triplet. In this study, the nadir was defined as the lowest value during days 1-22. We observed 75 patients: 61 men (81%) and 14 women (19%), median age of 69 years. The number of days that elapsed between the first day of chemotherapy and the median ANC nadir of 12 days was longer than that for AMC nadir of 6 (Wilcoxon signed rank test: P < 0.001). The number of days that elapsed between the first day of chemotherapy and the AMC nadir was the only factor that had a significant correlation with that for ANC nadir (Spearman's rank correlation: r = 0.34, P = 0.003). Among 75 patients, 23 (31%) had an ANC at nadir <1000/μL. AMC at nadir of 100/μL predicted an ANC at nadir <1000/μL with a sensitivity of 83% and a specificity of 56%. Both neutrophils and monocytes are differentiated from a common progenitor, a granulocyte macrophage colony forming cell, which can provide good explanation for the association between ANC and AMC nadirs. We would like to recommend physicians to observe the AMC nadir to predict the timing and severity of the ANC nadir.

Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy

Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen(®), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC). A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1. The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments. This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment. NCT01519700.

Phase III, randomized, double-blind, placebo-controlled, multicenter study of lipegfilgrastim in patients with non-small cell lung cancer receiving myelosuppressive therapy.

PurposeThe aim of this study was to demonstrate lipegfilgrastim superiority versus placebo in adults with non-small cell lung cancer receiving myelosuppressive chemotherapy.MethodsThis phase III, double-blind study randomized chemotherapy-naive patients to receive cisplatin and etoposide with either lipegfilgrastim 6 mg or placebo. Because of the placebo control, patients at individual high risk for febrile neutropenia (FN; ≥20%) were excluded. Study drug was administered on day 4 (24 h after chemotherapy) of a 21-day cycle for ≤4 cycles. Primary efficacy measure was FN incidence in cycle 1. Secondary assessments included duration of severe neutropenia (DSN), absolute neutrophil count (ANC) profile, and adverse events (AEs).ResultsThe study included 375 patients (lipegfilgrastim, n = 250; placebo, n = 125). Lipegfilgrastim superiority for FN incidence in cycle 1 was not achieved but incidence was lower (2.4%) versus placebo (5.6%). Cycle 1 mean DSN was significantly shorter for lipegfilgrastim (0.6 ± 1.1 days) versus placebo (2.3 ± 0.5 days; p < 0.0001). Incidence of severe neutropenia was significantly lower for lipegfilgrastim versus placebo overall and in each cycle (all, p < 0.0001). Mean ANC nadir was lowest in cycle 1 but significantly higher for lipegfilgrastim (1.60 ± 1.64) than placebo (0.67 ± 0.85; p < 0.0001). Mean time to ANC recovery was shorter with lipegfilgrastim in each cycle. Treatment-emergent AEs were similar between treatment groups.ConclusionsLipegfilgrastim was not statistically superior to placebo for incidence of FN in cycle 1, but was more effective in reducing incidence of severe neutropenia, DSN, and time to ANC recovery, with an acceptable safety profile.Controlled-trials.com identifier: ISRCTN55761467.

Abstract P3-12-07: A multicenter randomized double-blind phase III clinical trial to evaluate the efficacy and safety of GCPGC, a novel pegylated G-CSF in patients receiving DA or TAC chemotherapy for breast cancer compared to peg-filgrastim

Abstract Introduction Treatment with cytotoxic chemotherapy is known to be associated with a significant risk of febrile neutropenia. GCPGC(Green Cross Co., Korea) is a novel long acting recombinant human granulocyte colony-stimulating factor (G-CSF) analog that reduces the severity and duration of neutropenia. We conducted a phase III trial to evaluate the efficacy and safety of GCPGC compared to pegfilgrastim. Methods A total of 117 patients were enrolled in this multicenter, phase III, double-blind randomized trial between Feb 2012 and May 2013. They were randomly assigned to receive either GCPGC or pegfilgrastim during the maximal 6 cycles of chemotherapy which consisted of DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide). Based on the results of the phase II dose-finding study for GCPGC, the dose of 6 mg was selected. Both medications were administered 24 hours after the completion of each cycle of chemotherapy. The primary efficacy endpoint of this study was the duration of grade 4 neutropenia (Absolute Neutrophil Count (ANC) &amp;lt;500/mm3) during the first cycle of chemotherapy. Secondary endpoints included the time to ANC recovery during the first cycle of chemotherapy, which was defined as the number of days required for neutrophil counts to exceed 2,000/mm3, the rate of febrile neutropenia, the rate of severe neutropenia which persisted for more than three days during first cycle of chemotherapy, the depth of ANC nadir, the ANC level on day 7 after each cycle of chemotherapy, the frequency of dose reduction or delay, the number of hospitalization related to febrile neutropenia after the first cycle of chemotherapy, and the number of treatment with intravenous antibiotics. Results A total of 116 patients were evaluable for safety and 115 patients were evaluable for efficacy. The intention-to-treat analysis showed that there was no statistical difference between GCPGC and pegfilgrastim in terms of the duration (days) of grade 4 neutropenia in chemotherapy cycle 1 (1.64±1.18 vs 1.80±1.05; difference -0.15±1.11 [97.5% C.I. -, 0.26]; the pre-specified non-inferiority margin of 1.0). Notably, patients treated with GCPGC had a statistically significant reduction in the time to recovery from neutropenia (ANC &amp;gt;2,000/mm3), one of the secondary endpoints of the study, compared to those treated with pegfilgrastim (8.85 ± 1.45 vs. 9.83 ± 1.20 days; p &amp;lt;0.0001). There was no difference between groups regarding the other secondary endpoints. In addition, no significant differences were observed between the safety profiles of the two groups. Conclusion Collectively, GCPGC is not inferior to peg-filgrastim and represents an effective alternative for reducing the duration of neutropenia in breast cancer patients receiving TAC or DA chemotherapy. Citation Format: Joo Han Lim, Ki-Hyeong Lee, Keon-Uk Park, In-Hae Park, Eun Kyung Cho, Moon Hee Lee, So-Young Yoon, Jee-Hyun Kim, In-Sil Choi, Jae-Hoo Park, Young-Jin Choi, Hee-Jun Kim, Kyung Hae Jung, Si-Young Kim, Do-Youn Oh, Seock-Ah Im. A multicenter randomized double-blind phase III clinical trial to evaluate the efficacy and safety of GCPGC, a novel pegylated G-CSF in patients receiving DA or TAC chemotherapy for breast cancer compared to peg-filgrastim [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-07.

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study

The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

Predictors of Outcome and Severity in Adult Filipino Patients with Febrile Neutropenia.

Aim. The study aimed to describe the profile of Filipino febrile neutropenia patients and to determine parameters associated with severe outcomes. Methods. This is a retrospective study of Filipino febrile neutropenia patients admitted to the Philippine General Hospital. Patients were described in terms of clinical presentation and stratified according to the presence or absence of severe outcomes. Prognostic factors were then identified using regression analysis. Results. 115 febrile episodes in 102 patients were identified. Regression analysis yielded prolonged fever >7 days prior to admission (OR 2.43; 95% CI, 0.77–7.74), isolation of a pathogen on cultures (OR 2.69; 95% CI, 1.04–6.98), and nadir absolute neutrophil count (ANC) < 100 during admission (OR 1.96; 95% CI, 0.75–5.12) as significant predictors of poor outcome. Factors that significantly correlated with better outcome were granulocyte colony-stimulating factor (G-CSF) use (OR 0.31; 95% CI, 0.11–0.85) and completeness of antibiotic therapy (OR 0.26; 95% CI, 0.10–0.67). Conclusion. Prolonged fever >7 days prior to admission, positive pathogen on cultures, and nadir ANC < 100 during admission predicted severe outcomes, whereas G-CSF use and complete antibiotic therapy were associated with better outcomes. These prognostic variables might be useful in identifying patients that need more intensive treatment and monitoring.