Incidence Of Severe Neutropenia Research Articles

Efbemalenograstim alfa not inferior to pegfilgrastim in providing neutrophil support in women with breast cancer undergoing myelotoxic chemotherapy: results of a phase 2 randomized, multicenter, open-label trial

PurposeEvaluate the safety and efficacy of efbemalenograstim alfa for neutrophil support in breast cancer patients undergoing myelosuppressive chemotherapy in a phase 2, dose-finding, open-label study (NCT01648322, ClinicalTrials.gov, 2012–07-19).Methods232 patients received up to 4 cycles of chemotherapy, 141 patients with docetaxel + cyclophosphamide (TC) and 91 patients with docetaxel + doxorubicin + cyclophosphamide (TAC). Patients were randomized to efbemalenograstim alfa (80, 240, or 320 µg/kg [TC]; 240 or 320 µg/kg [TAC]) or pegfilgrastim (6 mg) on Day 2 of each cycle.ResultsEfbemalenograstim alfa was non-inferior to pegfilgrastim in duration of moderate and severe neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L) in TAC Cycle 1 (mean [SD] of 2.1 [1.58] and 2.1 [1.46] days for 240 µg/kg and 320 µg/kg efbemalenograstim alfa, respectively, and 1.8 [1.28] days for pegfilgrastim), with a difference (95% CI) of 0.3 (-0.4, 1.1) days. ANC nadir occurred between Days 7–8 of TAC Cycle 1, with mean [SD] of 0.68 [1.064], 0.86 [1.407] and 0.78[1.283] × 109/L for 240 µg/kg, 320 µg/kg efbemalenograstim alfa and pegfilgrastim, respectively. Time to ANC recovery post nadir (defined as an ANC > 2.0 × 109/L after the expected ANC nadir) was 2.0–2.4 and 1.9 days for TAC patients treated with efbemalenograstim alfa and pegfilgrastim, respectively. No significant difference was found between any dose of efbemalenograstim alfa and pegfilgrastim in TAC Cycle 1 for incidence of moderate to severe neutropenia (76%-77% of patients) or incidence of severe neutropenia (ANC < 0.5 × 109/L; 63%-72%). Efbemalenograstim alfa exhibited similar safety profile to pegfilgrastim. Febrile neutropenia occurred in 4 (1.8%) patients, 2 patients each for 320 µg/kg efbemalenograstim alfa and pegfilgrastim, with no event considered related to study drug.ConclusionEfbemalenograstim alfa was comparable to pegfilgrastim in efficacy and safety.ClinicalTrials.gov identifierNCT01648322.

Incidence and Risk Factors for Neutropenia After Intra-Arterial Chemotherapy for Retinoblastoma

Intra-arterial chemotherapy (IAC) has quickly gained popularity as a mainstay of treatment for retinoblastoma. Intra-arterial chemotherapy has been described as having several advantages over systemic chemotherapy, including reducing systemic toxicity and neutropenia; however, studies on the risk of neutropenia after IAC remain limited. To estimate the incidence of neutropenia after IAC, as well as identify risk factors associated with the development of neutropenia. This case series included pediatric patients with unilateral or bilateral retinoblastoma who were treated with IAC at a single quaternary care center from July 13, 2013, to January 6, 2023. All patients were treated with IAC and underwent multiple IAC cycles depending on treatment response. The primary chemotherapy agent used was melphalan, but topotecan or carboplatin could be used along with melphalan. Melphalan doses were kept to 0.4 mg/kg or less per cycle. After each IAC cycle, complete blood cell counts were obtained within 10 to 12 days and repeated until the absolute neutrophil count (ANC) was greater than or equal to 1000/μL. The primary outcome was the minimum ANC after each IAC cycle. The secondary outcome was the development of severe (grade 3 or 4) neutropenia (ANC <1000/μL). Regression analyses were used to identify associations between variables and outcomes. Receiver operating characteristic curves were used to calculate threshold dose for each chemotherapy agent potentially associated with the development of severe neutropenia. A total of 64 eyes of 49 patients (mean [SD] age, 1.7 [1.2] years; 25 females [51.0%]) with retinoblastoma were treated with 171 cycles of IAC. The mean (SD) nadir ANC was 1325.3 (890.7)/μL and occurred a median (IQR) of 10 (10-14) days (range, 6-28 days) after IAC administration. The frequency distribution of post-IAC neutropenia grades 0, 1, 2, 3, 4, and missing was 31 (18.1% of cycles), 25 (14.6%), 40 (23.4%), 37 (21.6%), 26 (15.2%), and 12 (7.0%), respectively. Factors weakly correlated with a lower ANC were higher melphalan dose (β = -2356 [95% CI, -4120.6 to -611.2]; adjusted R2 = 0.251; P = .01) and higher topotecan dose (β = -4056 [95% CI, -7003.6 to -1344.5]; adjusted R2 = 0.251; P = .006). In this case series of patients with retinoblastoma, the incidence of severe neutropenia after IAC was nearly 40%, which is higher than previously reported. Extended laboratory monitoring may aid in capturing previously overlooked cases of neutropenia. Topotecan may be associated with the development of neutropenia; limiting topotecan doses, especially in the setting of a high melphalan dose, may be beneficial in reducing the risk of neutropenia.

Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study.

To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust. To investigate the impact of this temporary policy change on clinical and safety outcomes. All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined. Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02-28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection. There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.

Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer

Although FOLFIRINOX (l-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27–111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18–7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

Prophylaxis of chemotherapy-induced neutropenia with lipegfilgrastim in patients with lung cancer: final results from the non-interventional study NADIR

Objective Real-world evidence on the application of the granulocyte colony-stimulating factor lipegfilgrastim for the reduction of chemotherapy-induced neutropenia and febrile neutropenia (FN) is limited. The NADIR study aimed to evaluate effectiveness and safety of lipegfilgrastim as primary or secondary prophylaxis in patients with lung cancer undergoing chemotherapy in routine clinical practice. Methods The non-interventional study NADIR (German Clinical Trials Register (DRKS) Number DRKS00005711) enrolled 156 patients with small-cell lung cancer (SCLC) and 145 patients with non-small-cell lung cancer (NSCLC), who received lipegfilgrastim during chemotherapy. Primary endpoint was the incidence of severe neutropenia (CTCAE grade 3/4) and FN. The analysis was stratified for age groups (≤65 years vs. >65 years). Results Approximately half of the patients were aged >65 years (SCLC 54.5%; NSCLC 46.9%). Intention of antineoplastic treatment was mostly palliative (SCLC 89.1%; NSCLC 73.1%). Patients with high FN risk (SCLC 44.9%; NSCLC 28.3%) mostly received lipegfilgrastim for primary prophylaxis (SCLC 81.4%; NSCLC 70.7%). FN was reported in 1.9% SCLC and 1.4% NSCLC patients. At least one severe neutropenia was documented in 30.1% SCLC and 17.9% NSCLC patients. For NSCLC patients aged >65 years, less severe neutropenia was reported as compared to younger patients (14.7% vs. 20.8%). Lipegfilgrastim-related adverse events were reported in 10.3% SCLC and 7.7% NSCLC patients. Conclusion Lipegfilgrastim in routine clinical practice of patients with lung cancer showed similar effectiveness and safety as compared to the pivotal trial. Interestingly, in older patients severe neutropenia was reported less frequently. While most patients with high FN risk received lipegfilgrastim for primary prophylaxis as recommended, there are still 20–30% of patients at high FN risk without primary prophylaxis who could benefit from better adherence to guidelines.

A retrospective study of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia during definitive concurrent chemoradiotherapy in patients with esophageal squamous carcinoma

ObjectiveTo compare the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for preventive or delayed treatment in neutropenia, completion rate of concurrent chemoradiotherapy and hospitalization rate in patients with esophageal squamous carcinoma during definitive concurrent chemoradiotherapy. MethodsA total of 70 patients with esophageal squamous carcinoma in Peking University Cancer Hospital from January 2019 to December 2020, who received PEG-rhG-CSF during concurrent chemoradiotherapy, were enrolled in this retrospective analysis. There were 32 patients in the preventive group, and 38 patients in the delayed group. The incidence of neutropenia, completion rate of concurrent chemoradiotherapy and neutropenia-related hospitalization rate were compared between PEG-rhG-CSF preventive group and delayed group. ResultsThe incidence of severe neutropenia (Grades 3–4) in all patients was 31.4%. Comparison between preventive group and delayed group showed that the incidence of severe neutropenia was 6.3% and 39.4% (χ2 ​= ​10.428, P ​= ​0.001), respectively. In preventive group, the incidence of severe neutropenia was 3.7% and 20.0%, respectively, for primary prevention and secondary prevention of PEG-rhG-CSF (χ2 ​= ​12.321, P ​= ​0.001). The completion rate of concurrent chemoradiotherapy was 93.8% in the preventive group and 63.2% in the delayed group (χ2 ​= ​9.220, P ​= ​0.002). The incidence of treatment interruption was 25.7% in the whole group, 12.5% in the preventive group and 36.8% in the delayed group (χ2 ​= ​5.389, P ​= ​0.020). Seven patients (7/70, 10.0%) were hospitalized and treated with intravenous antibiotics for neutropenia, including 1 in the preventive group and 6 in the delayed group (P ​= ​0.078). ConclusionsProphylactic use of PEG-rhG-CSF during concurrent chemoradiotherapy for patients with esophageal squamous carcinoma can effectively reduce the incidence of neutropenia, ensure the safety of treatment, and improve the completion rate of concurrent chemoradiotherapy.

Biosimilar Versus Originator Pegfilgrastim for Preventing Chemotherapy-Induced Neutropenia: A Phase III Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

PURPOSEThis study evaluated the efficacy, safety, and immunogenicity of biosimilar pegfilgrastim (PegFilBS) and originator pegfilgrastim (PegFilOR) in patients with stage 2-4 breast cancer.METHODSThis phase III randomized, multicenter, evaluator-blinded, noninferiority study recruited women with stage 2-4 breast cancer in Argentina who were scheduled to receive chemotherapy. Stratification was based on the breast cancer stage. The primary end point was the duration of severe neutropenia (DSN, noninferiority margin: 1 day) in the first chemotherapy cycle. Secondary end points assessed were incidence of severe neutropenia, grade 3 neutropenia, febrile neutropenia, infections, postchemotherapy hospitalization and duration, and the incidence of adverse drug reactions (ADRs).RESULTSA total of 120 patients were randomly assigned to receive PegFilBS (58 patients) or PegFilOR (62 patients). Severe neutropenia occurred in 52 of 283 cycles (18.4%) for 27 patients who received PegFilBS and in 48 of 297 cycles (16.2%) for 20 patients who received PegFilOR (P = .48). During the first cycle, severe neutropenia occurred in 16 patients who received PegFilBS (DSN: 0.78 ± 1.53 days) and in 11 patients who received PegFilOR (DSN: 0.53 ± 1.25 days; 95% CI, –0.26 to 0.76 days). In the intention-to-treat analysis, the mean DSN values were 0.90 ± 1.79 days for the PegFilBS group and 0.50 ± 1.21 for the PegFilOR group (95% CI, –0.15 to 0.95 days). No significant differences were observed for the secondary efficacy end points. Three patients experienced seven ADRs in the PegFilBS group while 10 patients experienced 31 ADRs in the PegFilOR group. The most common ADR was myalgia.CONCLUSIONRelative to PegFilOR, PegFilBS provided noninferior efficacy outcomes in Argentinian women with stage 2-4 breast cancer who were treated using myelosuppressive chemotherapy.

Abstract CT177: A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC)

Abstract Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

Effect of 3 mg versus 6 mg pegfilgrastim on the prevention of febrile neutropenia in breast cancer patients receiving docetaxel and cyclophosphamide: a retrospective study.

An ECCOPG (Eastern China Cooperative Oncology Pharmacy Group) funded study was designed to compare the effect of 3 versus 6 mg pegfilgrastim for primary prevention of febrile neutropenia (FN) in Chinese breast cancer patients retrospectively. Patients undergoing a docetaxel and cyclophosphamide chemotherapy regimen, followed by pegfilgrastim, for primary prevention during 2018 and 2020 were retrospectively enrolled in the present study. The patients were divided into 2 groups according to the dose of pegfilgrastim. The incidence of severe neutropenia (absolute neutrophil count <0.5×109/L), incidence of FN, and recovery time were calculated to compare the efficacy of different groups. P<0.05 was considered statistically significant. A total of 295 patients were enrolled, 150 in the 3 mg pegfilgrastim group and 145 in the 6 mg pegfilgrastim group. No significant differences were found in the incidence of severe neutropenia (3 vs. 6 mg, 39.3% vs. 34.5%, P=0.401) and the incidence of FN (3 vs. 6 mg, 7.3% vs. 8.3%, P=0.830). Median recovery time was 2 days for both groups (P=0.485). 3 mg pegfilgrastim may be effective and safe for Chinese breast cancer patients as the primary prevention for FN. Prospective studies are needed to further confirm the prophylactic effect of 3 mg pegfilgrastim.

Real-world effectiveness of the pegfilgrastim on-body injector in preventing severe neutropenia

Granulocyte colony-stimulating factors are used in medical oncology for the prevention of neutropenia. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the clinic, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real-world. Women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a granulocyte colony-stimulating factor were retrospectively identified from the medical records of Henry Ford Hospital. The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤ 1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN. A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher baseline ANC, and were more often white. The incidences of SN, neutropenic fever and neutropenia were not different between groups. Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. AC (doxorubicin and cyclophosphamide) was the most commonly used chemotherapy regimen (38% of total cycles). There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever and neutropenia.

Identification of Predictive Markers of Severe and Prolonged Neutropenia after CD19-Specific CAR T-Cell Treatment in Patients with Relapsed/Refractory B-Cell Malignancies

Introduction: Genetically engineered CD19-specific CAR T-lymphocytes have emerged as a powerful new class of immunotherapeutic agents in relapsed/refractory B-cell malignancies. However, their utility is hampered by unique toxicities including prolonged cytopenias that can predispose for severe infectious complications. Here, we evaluate predictive markers of hematotoxicity in patients treated in the real-world setting. Methods: To define the incidence and nature of CAR T-cell associated hematotoxicity, we performed a retrospective chart review across three German academic hospitals (LMU Munich, Tübingen, Hamburg-Eppendorf). Between January 2019 and June 2020, a total of 69 patients (58 r/r B-NHL, 11 BCP-ALL) were studied following treatment with the commercial CD19-specific CAR T-cell products Axi-cel (n=43) or Tisa-cel (n=26). The relative impact of baseline (=prior to lymphodepletion) demographic, laboratory and clinical characteristics on hematotoxicity was analyzed by uni- &amp; multivariate analysis using the following primary endpoint: duration of clinically significant neutropenia - defined as an ANC &amp;lt;500/µl - between days 0-60. Results: In this heavily pre-treated cohort, the incidence of severe neutropenia (ANC &amp;lt;500/µl) was 97% with a median duration of 12 days (95% CI: 10-15). Neutropenia followed a bimodal temporal curve with intermittent hematopoietic recovery upon G-CSF support. Profound, protracted (ANC &amp;lt;100/µl for ≥7 days) and prolonged (ANC &amp;lt;1000/µl after day 21) neutropenia was common, occurring in 36% and 78% of patients respectively. The incidence of severe anemia (Hb &amp;lt;7 g/dl or requiring pRBC transfusion) and severe thrombocytopenia (PLT count &amp;lt;50 G/l) was 68% and 71% respectively. Of note, a total of 12 patients (17 %) observed severe, G-CSF-refractory bone marrow aplasia with an ANC &amp;lt; 500/µl greater than 30 days. The following baseline clinical markers were significantly correlated with the duration of neutropenia by univariate or logistic regression analysis (Figure 1): Platelet Count (r = -0.45, P=0.0001), Hemoglobin (r = - 0.33, P=0.006), ANC (r = - 0.28, P=0.02), C-reactive Protein (r = +0.35, P=0.004), Ferritin (r = +0.52, P= &amp;lt;0.0001), and BM Infiltration for lymphoma (LR=6.7, P=0.0096). Interestingly, the following baseline factors were not significantly correlated: LDH, age, prior lines of cytotoxic therapy, and eGFR. On stepwise multivariate analysis using a binary logistic regression for the outcome severe neutropenia ≥ 14 days, baseline ferritin, hemoglobin and platelet count retained significance. In terms of dynamic clinical variables, both peak IL-6 and peak CRP were not associated with increased hematotoxicity, though peak IL-6 exhibited a trend towards significance (r = +0.22, P= 0.077). While peak ferritin was associated with a longer duration of neutropenia (r = +0.37, P=0.025), the peak value was less predictive than the baseline value. Moreover, we observed no nested dependency between hematotoxicity and CRS/ICANS. CRS grade in particular was not associated with prolonged neutropenia in our study cohort. Furthermore, the application of G-CSF was not associated with an increased rate or severity of neurotoxicity. When comparing the duration of neutropenia by CAR product (Axi-cel vs. Tisa-cel) and disease entity (DLBCL vs. BCP-ALL), no statistically significant difference was observed. Conclusions: Profound and prolonged neutropenia was common in our study cohort. This included cases of severe, G-CSF-refractory bone marrow aplasia. The identified predictive markers point toward a multifactorial model of pathogenesis for CAR T-cell associated hematotoxicity. They include markers of impaired hematopoietic reserve (e.g. low baseline PLT count, Hemoglobin, ANC), inflammatory state (e.g. hyperferritinemia, elevated CRP), and tumor microenvironment (e.g. BM infiltration). These findings carry important implications for both risk-stratification and the development of predictive clinical tools. The identified factors are currently being validated in an independent patient cohort and prospective validation is ongoing. Figure 1 Disclosures Blumenberg: Novartis: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Research Funding. Buecklein:Celgene: Research Funding; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Subklewe:Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding.

Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study

BackgroundLipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia.Patient and methodsOne hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21.ResultsLipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was − 0.3 days (95% confidence interval, − 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease.ConclusionsThis study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile.Trial registration numberClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23

MM-390: Pegfilgrastim vs. Filgrastim in the Supportive Care of Heavily Pre-Treated Multiple Myeloma in Treatment with Pomalidomide-Dexamethasone

Context: Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends its half-life and allows for once-per-cycle dosing, requiring less frequent dosing than non-pegylated G-CSF. Objective: The objective of this study was to compare the efficacy and safety of pegfilgrastim in heavily pre-treated MM treated with pomalidomide-dexamethasone. Design: Real-world analysis. Setting: Supportive care in rrMM. Patients: We enrolled 57 patients (31 M and 26 F) with a median age at diagnosis of 69 years (r. 52–84) and a median age at start of treatment of 76 years (r.56–90) who were treated with several lines of treatments (median 7, r. 2–12), were refractory to all drugs previously received, and had received Pomalidomide-Dexamethasone (P 4 mg for 21 days, D 40 mg on days 1, 8, 15, 22, pegfilgrastim day +8) every 28 days until progression. Interventions: Pegfilgrastim in rrMM. Main outcome measures: Results were evaluated according to IMWG criteria. Results: Since first course, which was received in domestic setting, patients had blood counts performed once weekly and received, from day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after the first cycle, filgrastim (5 μg/kg/day for 3 days) was given if the neutrophil count was Conclusions: In patients affected by heavily pre-treated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility of maintaining the scheduled time of treatment.

Pegfilgrastim on-body injector: Post-market performance analysis.

e19226 Background: Granulocyte colony-stimulating factors (G-CSF) are widely used in medical oncology for the prevention of neutropenia and its complications. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the oncology clinic the day after chemotherapy, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real world. Methods: Adult women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a G-CSF were retrospectively identified from the medical records of Henry Ford Hospital (Detroit, MI, USA). The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN. Results: A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher ANC, were more often black, had worse performance status, and were more often smokers. The incidences of SN, neutropenic fever and neutropenia were not different between groups (Table). Mortality was not different between groups when adjusted for confounding variables (OR 1.8, 95% CI 0.9-3.6, p=0.09). Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. TAC (docetaxel, doxorubicin and cyclophosphamide combined) carried the highest risk for SN among the chemotherapy regimens used. Conclusions: There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever, neutropenia, and death. Independent predictors of SN included the chemotherapy regimen used, baseline ANC and ethnicity. [Table: see text]

Do irinotecan (IRI) dose reductions driven by UGT1A1*28 genotyping prevent IRI-related severe neutropenia? A real-world study.

e16116 Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.

Pegfilgrastim versus filgrastim in the supportive care of heavily pretreated multiple myeloma in treatment with pomalidomide-dexamethasone.

e20514 Background: Pegfilgrastim is a pegylated long-acting recombinant form of G-CSF that extends the half-life and allows for once-per-cycle dosing, requiring less frequent dosing than nonpegylated G-CSF. The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic usage and hospedalization duration. Methods: We enrolled 57 patients (31 M, 26 F) median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-12), every refractory to all the drugs previously received, received Pomalidomide-Dexamethasone (P 4 mg for 21 days, D 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. Results: Since first course, received in domestic setting, with a very good compliance, patients performed blood counts once weekly and received, day +8 to day +19, prophylactic oral chinolonic antibiotics and anti-fungal drugs. During neutropenia after first cycle, Filgrastim (5 μgr/kg/day for 3 d) was given if neutrophils count was &lt; 1500 x 10^9 cells/L. Median number of filgrastim administrations was 4.6 (r. 3-6); nadir neutropenia was registered after a median of 10.4 days (r. 7-14); median of nadir neutrophil count was 1.13 x 10^9 cells/L (r.0.3–1.5), with maximum duration of 14 days. From the second course, all patients switched to pegfilgrastim (6 mg), injected subcutaneously with a single administration on day +3 independently from the neutrophil count at that time. During pegfilgrastim, neutropenia was never longer than 8 days, with a consequent reduction of neutropenia-related infections. Median nadir neutrophil count, evaluated for every patients for at least three courses of therapy (r. 3-6) registered at day +11, was 1.28 (r.0.9-2.2). Only 4 patients needed a supplement of 3 administrations of filgrastim. Pegfilgrastim was well tolerated in all patients: main side effects were mild fever and bone pain (21.2%). Conclusions: In conclusions, in patients affected by heavily pretreated MM treated with pomalidomide-dexamethasone, pegfilgrastim seems to reduce the incidence of severe neutropenia and infections and may increase the possibility to maintain the scheduled time of treatment.

Neutropenia in Myelosuppressed Cancer Patients Treated with Recombinant Human Erythropoietin (EPO)

Recombinant human erythropoietin (EPO) has been used extensively for 3 decades to treat various forms of anemia, including anemia associated with cancer treatment. Multiple randomized, placebo controlled clinical trials conducted since the late 1980's found that EPO treatment ameliorated anemia, reduced transfusion requirements, and improved quality of life measures in cancer patients receiving myelosuppressive chemotherapy. However, results of several of these trials suggested that EPO treatment might also exacerbate neutropenia in these patients. This possible side effect had been anticipated by a pre-clinical observation that neutrophil production in long-term marrow cultures was suppressed by EPO. However, chemotherapy-induced neutropenia was expected in these clinical trials and not studied, nor reported, in detail. Recently, primary data from 5 prospective randomized, placebo controlled clinical trials of EPO treatment in cancer patients undergoing myelosuppressive chemotherapy, sponsored by Johnson &amp; Johnson, became available through the Yale Open Data Access (YODA) project*. These data allowed us to compare serial neutrophil counts (ANCs) from 1650 study subjects with various forms of cancer who participated in these 5 clinical trials and were randomly assigned to either EPO or placebo treatment. Individual clinical trial sample sizes varied from 71 to 922 (Table below). ANC values were recorded weekly in 2 trials but less frequently in the other 3. In our analysis we determined the percent of study subjects with recorded ANC values &lt;1500/mm3, &lt;500/mm3, and &lt;200/mm3 during the initial 12 weeks of each trial for individuals assigned either to placebo or to EPO treatment. Mantel-Haenszel odds ratios were used as measures of differences between treatment groups. In addition, Poisson regression was used to assess differences in the total numbers of ANC measurements &lt;500/mm3 per study subject per 12 weeks on study that had been recorded in each treatment group. In each trial more study subjects assigned to EPO than to placebo treatment were found to have had at least one ANC &lt;500/mm3 reflecting severe neutropenia (Table). Study-specific odds ratios for this difference ranged from 1.24 to 2.08 and the Mantel-Haenszel odds ratio for the combined studies was 1.48 with a 95% Confidence Interval (CI) of 1.08 - 2.03, p =0.014. A statistically significant odds ratio was also found for ANC values of &lt;200/mm3 (1.73, 1.10-2.70, p=0.016), but not for neutropenic ANC values overall, i.e. &lt;1500/mm3 (1.18, 0.93-1.50, p=0.17). Total numbers of recorded ANC values &lt;500/mm3 per study subject per 12 weeks on study were also significantly different - 0.66 (95% CI, 0.57-0.76) in the EPO treatment group vs. 0.49 (0.42-0.60) in the placebo group, p=0.0075. This analysis of 5 randomized placebo controlled clinical trials carried out from 1988 to 2002 finds that EPO treatment of individuals undergoing myelosuppressive chemotherapy was associated with statistically significant increases in the incidence of severe neutropenia and suggests that competition between the erythroid and myeloid lineages may occur in the setting of suppressed hematopoietic reserves when the erythroid lineage is pharmacologically amplified. *This study, carried out under YODA Project 2017-2486, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH &amp; DEVELOPMENT, L.L.C.. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH &amp; DEVELOPMENT, L.L.C.. Table Disclosures No relevant conflicts of interest to declare.

GX-G3, a long-acting G-CSF, compared with pegfilgrastim in reducing duration of severe neutropenia after chemotherapy for non-Hodgkin’s lymphoma.

e19065 Background: G-CSF is used in patients at significant risk for developing severe neutropenia (neutrophil count &lt; 0.5 × 109/L or grade 4 neutropenia) following myelosuppresive chemotherapy. GX-G3, human G-CSF fused to hyFc is a proposed alternative to Neulasta. Methods: An open-label, randomized, phase II study was designed to compare the effects of subcutaneous (SC) injection of GX-G3 (a long-acting G-CSF) at doses of 150, 250 and 350 μg/kg with Neulasta 6 mg administered SC in patients receiving R-CHOP for advanced NHL (n = 65). The primary objective was to assess the duration of severe neutropenia after 1st cycle of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). The following parameters were also assessed: duration of severe neutropenia after 2nd cycle of chemotherapy, optimal time for GX-G3 intervention (two GX-G3 250 μg/kg cohorts; administered 24 and 72 hours after R-CHOP), incidence of severe neutropenia and febrile neutropenia post R-CHOP, pharmacokinetics, and safety. Patients were randomly assigned to receive GX-G3 or reference drug, Neulasta, one dose after 1st and 2nd cycle of R-CHOP for a total of 2 doses. Results: The mean duration of severe neutropenia after 1st cycle was shortest in GX-G3 350 μg/kg group [GX-G3 150, 250 (24h, 72h), 350 μg/kg and Neulasta®; 3.2, 2.3, 2.0, 1.3 and 2.4 days, respectively]. The results of all GX-G3 groups and Neulasta were not significantly different for duration of severe neutropenia after 2nd cycle of R-CHOP, incidence of severe neutropenia and febrile neutropenia, or toxicity profile. The elimination half-life of GX-G3 and Neulasta ranged from 29.8 to 66 hours and 19.2 to 76.8 hours, respectively. Conclusions: GX-G3, in all tested dosage regimen, was safe and well tolerated in this patient population. A single injection of GX-G3 per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by Neulasta. GX-G3 administration after 24 hours, compared to 72 hours post R-CHOP treatment resulted in relatively shorter duration of severe neutropenia. Clinical trial information: 2015-002693-20.

A randomized, multicenter clinical trial to determine the efficacy and safety of pegfilgrastim (GEMA BIOTECH) compared to pegfilgrastim (Roche) for prevention of chemotherapy induced neutropenia in patients with breast cancer.

3113 Background: Peg-Neutropine, GEMA BIOTECH SAU biosimilar Peg-Filgrastim, is the first Peg-Filgrastim approved in LATAM for prevention of febrile neutropenia in patients treated with myelosuppressive chemotherapy. Methods: Study population: women with stage 2, 3 or 4 of breast cancer scheduled to receive 4 or 6 cycles of chemotherapy (with Taxane) at 3 weeks interval. Stratification was based on breast cancer stage. Study drug was administered subcutaneously in a 6 mg dose. The study was blind to the assessors. The primary endpoint was Duration of Severe Neutropenia (DSN, Absolute Neutrophil Count-ANC &lt; 500/mm3) in the first cycle of chemotherapy. Secondary endpoints were incidence of severe neutropenia (SN), other efficacy measures, and incidence of ADRs. The non-inferiority margin for DSN was estimated in less than 1 day. Results: A total of 120 subjects were randomized 1:1, 58 were treated with Peg-Neutropine and 62 with Peg-Filgrastim (Roche). Efficacy: SN was developed in 52/283 (18,4%) cycles with Peg-Neutropine in 27 patients and 48/297 (16,2%) cycles with Peg-Filgrastim (Roche) in 20 patients (p=0,4836). In the first cycle, 16 patients with Peg-Neutropine and 11 patients with Peg-Filgrastim (Roche) developed SN. In per protocol analysis mean DNS in the first cycle was 0,78 ± 1,53 days for Peg-Neutropine group and 0,53±1,25 for Peg-Filgrastim (Roche) group (95% IC for the difference -0,26; 0,76). Per ITT analysis the mean DSN was 0,90±1,79 for Peg- Neutropine group and 0,50±1,21 for Peg-Filgrastim (Roche) group , (95% IC for the difference -0,15; 0,95). For all the efficacy secondary endpoints the differences were not statistically significant. Safety: 7 ADRs were developed by 3 subjects with Peg-Neutropine and 31 ADRs were developed by 10 subjects with Peg-Filgrastim (Roche). The most common reaction was myalgia, and other ADRs were arthralgia, asthenia, bone pain and acid sensitive syndrome. Conclusions: Based on the non-inferiority margin established we conclude that Peg-Neutropine is biosimilar to Peg-Filgrastim (Roche). Clinical trial information: NCT03404752.

A retrospective analysis of plasma concentration monitoring of fluorouracil in patients with advanced colorectal cancer

ObjectivesTo analyse the results of fluorouracil (5-FU) plasma concentration monitoring in patients with advanced colorectal cancer after 5-FU treatment, and to provide a reference for the application prospect of 5-FU...