Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis)

This was a subanalysis of a retrospective observational study conducted between January 2015 and June 2017 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Full details of the STOP FN in NHL 2 study (UMIN000029534) have been published [10]. In brief, we used the database of our institute to extract data from the medical records of patients who were treated at our institute and met the eligibility criteria. During cycle 1, all patients were hospitalized. During cycle 2 and subsequent cycles, patients were managed in an outpatient basis and only hospitalized if deemed necessary. The type of prophylactic treatment, daily G-CSF or pegfilgrastim, and the corresponding dosing that the patients received were decided by each patient’s treating physician. Further, in cycle 1, daily G-CSF was started at a mean (standard deviation [SD]) of 10.18 (2.67) days, and pegfilgrastim was started at a mean (SD) of 2.59 (1.39) days. Daily G-CSF was administered for a mean (SD) of 2.98 (1.58) days. In cycle 1, 2.4 and 90.7% of patients receiving daily G-CSF and pegfilgrastim, respectively, started treatment on days 0–3 [10].

The study was approved by the institutional Ethical Review Board. The analysis was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical Research on Individuals, the Law Concerning the Protection of Personal Information, and all other applicable laws and regulations concerning the handling of personal information. As this was a retrospective observational study on data from medical records, the need for informed consent from patients was waived.

Patients diagnosed with B-NHL who had received and completed R-CHOP regimens, or patients who had discontinued the R-CHOP treatment after receiving three or more scheduled cycles were eligible for inclusion in this study. The main exclusion criterion was a diagnosis of human immunodeficiency virus-related B-NHL.

For this subanalysis, patients were divided into three groups according to the type of FN prophylaxis received in cycle 1: those who did not receive any prophylactic G-CSF preparation (no G-CSF administration); those who received daily G-CSF; and those who received FN prophylaxis with 3.6 mg pegfilgrastim by subcutaneous administration.

Characteristics of patients prior to the initial R-CHOP regimen were collected for evaluation, including age, sex, performance status (PS), body mass index (BMI), disease characteristics (diagnosis, stage, and presence or absence of myeloid infiltration), presence or absence of complications (including diabetes, liver/kidney/heart disease, and incomplete wounds), presence or absence of previous history (last [< 1 month prior to initiation of (R) CHOP regimens] infection or FN), and hematologic parameters (albumin, total bilirubin, hemoglobin, absolute neutrophil count [ANC], and absolute lymphocyte count).

Data related to each chemotherapy cycle, including details related to the prescribed R-CHOP regimen (i.e., drug doses and days to the next cycle), were collated for analysis. Dose reduction was defined as more than a 20% reduction in the dose of cyclophosphamide or doxorubicin in each cycle after cycle 2 compared with that in the first cycle. Dose delay was defined as more than 7 days behind schedule in each cycle after cycle 2.

Information related to the development of FN after completion of the R-CHOP regimen was also analyzed, including body temperature, neutrophil counts, preventive and therapeutic measures (oral antibiotics, G-CSF, and treatment days calculated from the initiation of chemotherapy), and hospitalizations for the development of FN. For hospitalized patients, temperature measurements were taken daily and prior to initiation of the R-CHOP regimen and blood samples were collected every 2 days, wherever possible. For outpatients, temperature measurement was self-reported by the patient.

The specific outcomes assessed during the study were: identification of patient background factors that may aid in the selection of G-CSF preparation (pegfilgrastim or daily G-CSF); changes in neutrophil count in cycle 1 by G-CSF preparation; duration (number of days) of neutropenia (< 500 cells/μL), the incidence of grade 4 neutropenia (< 500 cells/μL), lowest neutrophil count (neutrophil nadir), and day of onset of the neutrophil nadir, all by type of G-CSF preparation; identification of risk factors that may cause dose reduction or delay of R-CHOP therapy after cycle 2; and actual status of treatment with pegfilgrastim, daily G-CSF, or no G-CSF after cycle 2.

A target sample size for this analysis was not statistically calculated, and all patients identified in the database who met the study eligibility criteria during the study period were included. A classification tree was used to analyze 15 background factors for drug selection by G-CSF preparation in the first R-CHOP cycle [19]. Supplementary Table 1 (see Additional file 1) shows the analysis setting and variables used to create the classification tree. Two-tailed Dunnett’s multiple comparisons tests were performed with pegfilgrastim as a control group to compare outcomes associated with neutrophil count in cycle 1 by G-CSF type. Univariate and multivariate logistic regression with stepwise selection was used to identify factors associated with dose reduction or delay of anticancer drugs after the second cycle of R-CHOP. All statistical analyses were conducted by the Institute of Japanese Union of Scientists & Engineers, using SAS Version 9.3 (SAS Institute Inc., Cary, NC, USA).

The STOP FN in NHL 2 study [10] enrolled a total of 239 patients. For the current analysis, five patients were excluded because the necessary data were not available. Thus, 234 patients were included: 60 (25.6%) patients did not receive any G-CSF, 122 (52.1%) received daily G-CSF, and 52 (22.2%) received pegfilgrastim in cycle 1.

Table 1 summarizes the patient and disease characteristics before the first cycle of R-CHOP. Overall, 53.0% of patients were women and 47.0% were men. Patients had a mean (SD) age of 63.7 (12.7) years. Slightly more women than men received daily G-CSF and pegfilgrastim. The majority (75.6%) of patients had a PS of 0, and this was similar across the three groups. Most patients (67.5%) were diagnosed with diffuse large B-cell lymphoma, followed by follicular lymphoma (17.1%), and other (9.8%); a similar pattern was observed across all three groups. The mean (SD) ANC at baseline was 4147.7 (1425.1), 4246.5 (2286.0), and 4043.8 (1767.7) cells/μL in the no G-CSF administration, daily G-CSF, and pegfilgrastim groups, respectively.

As one of the specific objectives of this subanalysis was to identify the patient background factors that may aid in the selection of G-CSF preparations (pegfilgrastim or daily G-CSF), we developed a classification tree using the background factors of patients undergoing the first R-CHOP cycle as explanatory variables to predict the FN incidence rates at that time (Fig. 1). The classification path of the tree analysis was as follows: age (< 65, 65–79, and ≥ 80 years), lymphocyte count (< 1000, 1000–2000, and ≥ 2000 cells/μL), age (< 65 and 65–79 years), and neutrophil count (< 4235 and ≥ 4235 cells/μL), with those who had neutrophil count < 4235 cells/μL being further categorized based on BMI (< 23 and ≥ 23 kg/m²). The most frequent use of pegfilgrastim was in patients aged ≥ 80 years. Conversely, the frequency of daily G-CSF use was greatest in patients aged ≤ 79 years and with lymphocyte counts of < 1000 cells/μL, and these patients were also found to have the highest FN rate. This classification tree analysis showed that the most relevant factors for selecting a G-CSF preparation in the first R-CHOP cycle were age ≥ 80 years and lymphocyte count < 1000 cells/μL, followed by neutrophil count < 4235 cells/μL and BMI < 23 kg/m².

We evaluated whether receiving no G-CSF preparation or receiving daily G-CSF or pegfilgrastim during cycle 1 would have any effect on neutrophil count (Fig. 2). Over time, there was no notable difference in the change in neutrophil count between the no G-CSF administration and daily G-CSF groups; however, the neutrophil count began to increase relatively more rapidly after pegfilgrastim administration.

We also compared the duration of neutropenia (< 500 cells/μL), the incidence of grade 4 neutropenia (< 500 cells/μL), lowest neutrophil count (i.e., neutrophil nadir), and day of onset of the neutrophil nadir by type of G-CSF preparation (Fig. 3). Of note, the duration of neutropenia and incidence of grade 4 neutropenia were significantly higher in the no G-CSF administration group (p = 0.0026 and p = 0.0032, respectively) and the daily G-CSF group (p < 0.0001 for both) compared with the pegfilgrastim group. The neutrophil nadir was significantly lower in the no G-CSF group and the daily G-CSF group (p < 0.0001 for both) compared with the pegfilgrastim group. The day of onset of the minimum neutrophil count was significantly later for patients in the no G-CSF and daily G-CSF groups (p < 0.0001 for both) compared with the pegfilgrastim group. Although patients receiving pegfilgrastim had a significantly earlier onset of neutrophil nadir, they had a significantly shorter neutropenia duration, a lower incidence of grade 4 neutropenia, and a significantly higher neutrophil count nadir compared with patients treated with daily G-CSF and those who did not receive any G-CSF preparation.

We compared the dose reductions and dose delays after cycle 2 by no administration of G-CSF preparation, daily G-CSF, and pegfilgrastim groups (Table 2). There were a total of 36 (15.4%) dose reductions after cycle 2, consisting of eight cases (13.3%) in the no G-CSF administration group, 18 cases (14.8%) in the daily G-CSF group, and 10 cases (19.2%) in the pegfilgrastim group. Overall, there were 97 (41.5%) dose delays in cycle 2: 24 (40.0%) in the no G-CSF administration group, 54 (44.3%) in the daily G-CSF group and 19 (36.5%) in the pegfilgrastim group. Of note, the use of G-CSF preparations did not seem to markedly contribute to a lesser number of dose reductions or delays compared with no use of G-CSF preparations.

Another important objective was to identify potential risk factors that may lead to dose reductions and dose delays of R-CHOP therapy after cycle 2. Thus, we conducted univariate logistic regression analyses (Supplementary Table 2 (see Additional file 1)) and multivariate logistic regression analyses (Table 2) of relevant patient background factors. In univariate logistic regression for dose reduction, FN onset in cycle 1, age (≥ 65 years), female sex, hemoglobin (< 12 g/dL), and ANC (< 2690 cells/μL [1st quintile]) were identified as significant factors. As a result of the stepwise method, FN onset in cycle 1 and female sex were identified as significant risk factors for dose reduction after cycle 2. As a result of univariate logistic regression for delay after cycle 2, FN onset at cycle 1, albumin (< 3.5 g/dL), and hemoglobin (< 12 g/dL) were identified as significant factors. As a result of the stepwise method, hemoglobin (< 12 g/dL) was extracted as a risk factor for delay after cycle 2. Based on our analysis, female patients and those who present FN in cycle 1 are at significant risk of dose reductions after cycle 2. In contrast, patients with hemoglobin < 12 g/dL are at a significant risk for dose delays after cycle 2.

Finally, we aimed to clarify the actual status of G-CSF preparation use (or no G-CSF use) after cycle 2 and onward (Fig. 4). Overall, the percentages of patients using pegfilgrastim increased markedly after cycle 2 and subsequent cycles (72.6%) from cycle 1 (22.2%). As a result, patients receiving daily G-CSF decreased by 40%. Patients who were not receiving treatment decreased by almost 10% (Fig. 4a). Among patients with FN in cycle 1, patients who received no G-CSF decreased from 56.0 to 4.0%, and those who received daily G-CSF decreased from 36.0 to 4.0% in cycle 2 and onward. Patients who received pegfilgrastim increased from 8.0 to 92.0% in cycle 2 and onward (Fig. 4b). Twenty-five of the 234 patients developed FN in cycle 1: 14 patients (23.3%) received no G-CSF; nine patients (7.4%), daily G-CSF; and two patients (3.8%), pegfilgrastim. Of patients receiving pegfilgrastim during cycle 1, 75% continued to receive pegfilgrastim during cycle 2 and onward (p < 0.0001). Among patients receiving daily G-CSF during cycle 1, 81.9% switched to pegfilgrastim (p < 0.0001), while 14.8% remained on daily G-CSF. Those who received no treatment had the highest incidence of FN (23.3%) during cycle 1, and slightly more than half switched to pegfilgrastim (51.7%; p = 0.7963) (Fig. 4c). Among patients with FN, 12 of 14 (85.7%) and all patients who received no G-CSF and daily G-CSF in cycle 1, respectively, switched to pegfilgrastim from cycle 2 (see Supplementary Figure 1 in Additional file 1). Of note, in cycle 2 and onward, the proportion of patients who were not receiving any G-CSF preparation decreased markedly, and even more so among patients with FN onset in cycle 1. The use of pegfilgrastim increased markedly in cycle 2 and onward, which was largely attributed to the switching of over 80% of patients (regardless of FN) receiving daily G-CSF in cycle 1 and switching of over 85% of patients who developed FN in cycle 1 but were receiving no G-CSF preparation.