Induced Myelosuppression and Recommendation for Monitoring of Absolute Neutrophil Counts in Patients Treated with Epirubicin and Cyclophosphamide in Early Breast Cancer: Results from a Phase 2a Collaborative Trial of the AGO-B and CESAR Study Groups
Authors: Pleimes Dirk , Möbus Volker , Mayer Frank , Schmidt Marcus , Asang Corinna , Flunkert Kathrin , Mikus Gerd 
Published: October 2019

Abstract
Introduction
Despite much progress in the treatment of patients with malignant disorders, severe neutropenia and infections are frequent adverse events associated with standard chemotherapy regimens.
Due to the low frequency of neutrophil monitoring in most clinical studies, limited insights exist about the time of the nadir, the lowest absolute neutrophil counts (ANCs), and the adequate timing of complete blood counts (CBCs) in clinical practice.
Objective
To analyze the trajectory of ANCs in a patient population undergoing anthracycline and cyclophosphamide treatment with the aim of producing a recommendation for the optimal time to monitor the ANCs.
Methods
The MyeloConcept Study is a randomized, double-blind, placebo-controlled, multi-centre phase 2a study, in which patients received adjuvant or neoadjuvant chemotherapy for the treatment of breast cancer. Patients were either randomized into a placebo group or an imidazolyl ethanamide pentandioic acid (IEPA, Myelo001) treatment group. The study was conducted at 23 sites in Germany between March 2016 and November 2017 (NCT02692742).
This abstract reports on the placebo group of 65 patients who received background treatment with epirubicin (E) 90 mg/m2 BSA (body surface area) + cyclophosphamide (C) 600 mg/m2 BSA q21d. Patients' CBCs were measured in a central and/or local laboratory at least 9 times (on average every three days), throughout the first chemotherapy (CTX) cycle with an increased frequency when ANC decreased < 1.0 × 109 cells/L. Linear interpolation was used to obtain a continuous ANC time curve. The first occurrence and presence of grade 4 neutropenia among subjects who developed a grade 4 neutropenia were assessed on each possible monitoring day. The participating study sites provided data in the form of a questionnaire to assess 'real-life' ANC monitoring practice.
Results
The mean age of the 65 female breast cancer patients was 55.7 years (SD 10.66; median 57.0), ECOG was grade 0 in > 95% of patients (Table 1). The mean time after CTX start to the ANC nadir was 13.8 days (SD 1.31; median 14.0). ANC CTCAE severity grades 3 and 4 were reached in 65 (100%) and 53 (81.5%) subjects, respectively, in the first CTX cycle (Table 2). The mean duration of grade 3 and 4 neutropenia was 7.81 days (SD 2.46; median 7.77) and 5.57 days (SD 2.48; median 5.44), respectively.
Among subjects who developed a grade 4 neutropenia in this study population, the onset of grade 4 neutropenia occurred between day 10 and day 15, and most prominently on days 11 and 12 (32% and 25% of subjects, respectively (Table 3)). The greatest presence of grade 4 neutropenia (i.e. new onset or already existent neutropenia) occurred on days 13, 14 and 15 (79, 85 and 89% respectively).
Based on a questionnaire of the real-life practices of the 23 participating sites, 83% (1 site gave no answer (n.a.)) evaluated CBCs at the beginning of the first cycle of CTX and during the cycle once (26%), twice (48%) or three times (9%), whereas 17% of sites did not monitor CBCs. Blood counts were assessed most frequently on days 7, 8 or 15 and monitoring was commonly (65%, 2 sites n.a.) increased once the neutrophil count fell below a certain ANC threshold, mainly below 0.5 × 109 cells/L.
Conclusions
With all subjects experiencing neutropenia grade ≥ 3 during the first CTX cycle, severe ANC toxicities undergoing q21d anthracycline and cyclophosphamide (EC) treatment were more frequently observed in this study than previously reported (Smith et al., 2006). This finding may be due to the considerably higher frequency ANC monitoring compared to prior clinical studies.
In contrast to the existing 'real-life' practice reported, in-cycle ANC monitoring may be most informative if measured on day 11 or day 12 to assess the first occurrence (incidence) and on days 13 to 15 for the presence of grade 4 neutropenia (prevalence). A reliable and early detection system for grade 4 neutropenia offers an opportunity for the instigation of preventative measures to mitigate the infection risk for patients.

Disclosures
Pleimes: Bayer: Consultancy, Equity Ownership; Myelo Therapeutics: Employment, Equity Ownership. Möbus:Teva: Consultancy; Roche: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Myelo Therapeutics: Other: Chair of the Steering Committee of the MyeloConcept Study. Mayer:MSD: Speakers Bureau; Lily: Other: Medical Advisory Board; Myelo Therapeutics: Other: Member of the Steering Committee and Principle Investigator of MyeloConcept Study; BMS: Speakers Bureau; Incyte: Speakers Bureau. Schmidt:Janssen: Honoraria; Sividon: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pierre-Fabre: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Myriad Genetics: Consultancy, Honoraria; Myelo Therapeutics: Other: Member of the Steering Committee of MyeloConcept Study; Eisai: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Asang:Myelo Therapeutics GmbH: Employment. Flunkert:Myelo Therapeutics GmbH: Consultancy, Other: Kathrin Flunkert is a salaried employee of M.A.R.C.O. GmbH & Co. KG. M.A.R.C.O. GmbH & Co. KG. had a master service agreement and received payments by Myelo Therapeutics GmbH to conduct the statistical analysis for Myelo Therapeutics. . Mikus:Myelo Therapeutics: Consultancy, Other: Member of the Data Safety Monitoring Board.