The Utility of Granulocyte Colony Stimulating Factor in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy with Axicabtagene Ciloleucel

Background: Infection during the period of neutropenia following chemotherapy represents a major cause of morbidity and mortality in patients with malignancy.(Freifeld, et al, 2011, Baden LR, et al, 2012) Several guidelines recommend granulocyte colony stimulating factor (GCSF) to reduce the duration and severity of chemotherapy-induced neutropenia and abate infection risk.(Lyman, et al 2018, Aapro, et al, 2011, Smith, et al, 2015). Optimal GCSF administration following chimeric antigen receptor (CAR) T-cell therapy remains undefined and requires characterization. Methods: The Mayo Institutional Review Board approved this retrospective, single-center study. Electronic medical records for patients prescribed axicabtagene ciloleucel were reviewed until disease relapse, death, or a maximum of 60 days after infusion. Baseline characteristics and laboratory values were abstracted prior to lymphodepleting chemotherapy. GCSF support was originally prescribed when the absolute neutrophil count (ANC) declined below 500 cells/mm3 and discontinued when the ANC exceeded 1000 cells/mm3 (neutropenia) for 2 consecutive days. A practice change was made where GCSF was recommended only in those with febrile neutropenia and an increased concern for infection. The primary endpoint was the difference in the total days of neutropenia for patients receiving and not receiving GCSF. Secondary outcomes compared total days of severe neutropenia, number of neutropenia episodes, infection rates by GCSF use, and outcomes by protocol change. Neutropenia and severe neutropenia were defined as an ANC below 500 cells/mm3 and 100 cells/mm3, respectively. Updated data with more patients will be presented at the conference. Results: The 60 included patients had a median age of 59 (IQR: 44, 63) years, 38 (63%) were male and 53 (88%) were Caucasian. Significantly fewer patients were prescribed GCSF according to infection-related concerns compared to ANC-based indication, 18% vs. 94%, p<0.001. Because only 3 subjects received GCSF based on infection-related concerns, results based on GCSF use versus no use is shown here. GCSF was prescribed to 35 (58%) patients for a median of 8 (IQR: 6, 12) doses with a median cumulative dosage of 3840 mcg (IQR 2100-5400) and median time to first dose of 3 days (IQR: 1, 4) post CAR T-cell infusion. Table 1 displays additional baseline characteristics and laboratory parameters according to GCSF support utilization. GCSF prescribed: Table 2 displays outcomes by GCSF use. Total days of neutropenia were similar between groups (13 vs. 16, p=0.52) with a trend towards significantly fewer days of severe neutropenia when prescribed GCSF (6 vs. 9, p=0.129). Patients prescribed GCSF were more likely to experience multiple episodes of neutropenia (83% vs. 43% p=0.002) with a significantly greater median number of episodes (3 vs. 1, p=0.002) when compared to those not prescribed GCSF. GCSF use significantly decreased the median days of the first neutropenia episode (6 vs. 12, p=0.001). There was a trend for decreased median days of severe neutropenia in the first episode with GCSF (5.0 vs. 8.0, p=0.236). Figure 1 displays a trend towards a lower overall risk of infection (HR 0.55, 95%CI: 0.16-1.87, p=0.34) and lower risk of bacterial infection (HR: 0.49, 95% CI: 0.18-1.31, p=0.15); however, these were not statistically significant. Conclusion: Patients prescribed GCSF according to ANC-based indication were significantly more likely to experience multiple neutropenia episodes; however, duration of first neutropenic episode and days of severe neutropenia during the first neutropenic episode were significantly reduced. Interestingly, the total days of neutropenia and severe neutropenia were similar between groups. It is possible that using the parameter of ANC more than 1000 cells/mm3 for 2 consecutive days is not the optimal criteria for stopping GCSF. Risk of overall and bacterial infection was lower with ANC-based initiation of GCSF, although non-significant likely due to small sample size. The potential benefit for using CSF and the optimal timing after CAR T-cell infusion requires further, rigorous, prospective investigation. Disclosures Ansell: ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding. Bennani:Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding.

Secondary infections after cytotoxic chemotherapy in patient with hematological malignancies

Introduction: This study was initiated to investigate the risk factors of secondary infections in febrile neutropenic patients following chemotherapy, and to evaluate the clinical, microbiological, and mortality outcomes of these infections. Methodology: An evaluation was done on all patients with hematological malignancy who developed a febrile neutropenic episode (FNE) after cytotoxic chemotherapy in the Department of Hematology, Akdeniz University Faculty of Medicine, between January 2007 and December 2008. Results: A total of 294 primary FNEs that responded to the initial empirical or targeted treatment were included in the study, and secondary infections developed after 72 (24.5%) of 294 primary FNEs. Risk factors for secondary infections were determined as acute leukemia as the underlying disease, salvage chemotherapy for refractory/relapse diseases, prolonged neutropenia (10 days and over), Multinational Association of Supportive Care in Cancer (MASSC) score < 21, and fungal infection during the primary episode. The mortality rate of patients who developed secondary infections was significantly higher compared to patients without secondary infections (27.8% and 5.4%, respectively; p = 0.001). Conclusions: The development of secondary infections in patients with hematological malignancy was not very rare. Greater concern should be shown for these infections to increase patient survival rates.

Influence of Febrile Neutropenia Period on Plasma Viscosity at Malignancy

Cancer, chemotherapy, and infections all together make changes in blood rheology and may affect the defense mechanisms by changing the thrombocyte function and endothelial cell. We have examined changes of blood rheology on plasma viscosity to put on probable following criteria for starting the treatment of febrile neutropenia immediately. A total of 27 postchemotherapy patients (16 males and 11 females) with febrile neutropenia diagnosed according to international guidelines have been included into the study. The plasma viscosity of the patients whose febrile neutropenia has been successfully treated was also measured to assess the impact of the duration of neutropenia on viscosity. The plasma viscosities of the patients were significantly higher during neutropenic episode than in nonneutropenic state () except for alkaline phosphatase. All study parameters, particularly acute phase reactants, were statistically similar during both states. In the correlation of analysis with study parameters and stages, significant correlation was not observed between plasma viscosity alteration and leukocyte-neutrophil alteration, also other study parameters. We have demonstrated significantly elevated plasma viscosity in our patients during febrile neutropenic episode. Despite normal values of various parameters known to trigger plasma viscosity, particularly fibrinogen, it can be easily argued that the main mechanism may be the endothelial injury during infectious process and immune response mediated microcirculatory blood flow alterations.

Anaerobiospirillum succiniciproducens bacteraemia in a patient with acute lymphoblastic leukaemia

A 17-year-old man with acute lymphoblastic leukaemia had fever and diarrhoea during a febrile neutropenic episode. A spiral-shaped, Gram-negative anaerobic bacterium was isolated from blood, and confirmed as Anaerobiospirillum succiniciproducens by 16S rRNA sequencing. The patient responded to imipenem.

Outpatient Oral Antibiotics for Febrile Neutropenic Cancer Patients Using a Score Predictive for Complications

Purpose Since febrile neutropenic patients were recognized to constitute a heterogeneous population, several models have been developed for predicting the risk of serious medical complications. The Multinational Association for Supportive Care in Cancer score and its derived clinical prediction rules have been validated, but thus far there were no data about its use for simplifying therapy in predicted low-risk patients. Patients and Methods In a single institution, we followed all episodes of febrile neutropenia between January 1999 and November 2003. Those patients predicted at low risk for complications, who were not receiving antibacterials at fever onset and were eligible for treatment with oral antibiotics, were treated with ciprofloxacin and amoxicillin-clavulanate and were discharged if they were clinically stable or improving after an initial observation period. The primary end point of the study was the rate of resolution of the febrile neutropenic episode without complications, among these early discharged patients. Results Of 383 first febrile neutropenic episodes predicted at low risk of omplication, 178 patients (33 men and 145 women, mainly with solid tumors) were treated orally; they constituted the basis of our analysis. Seventy-nine patients (44%) were discharged early (with a median time to discharge of 26 hours); no complications occurred among them but three patients had to be readmitted, resulting in a success rate of 96% (95% CI, 92% to 100%). Conclusion Our study shows that oral therapy followed by early discharge was feasible in a small but significant proportion of patients selected by a strategy combining predicted low risk and medical and nonmedical criteria.