Pegfilgrastim Home Redirection Outcomes: Effectiveness and Timing of Administration in Primary Prophylaxis of Chemotherapy-Induced Neutropenia

J Clin Pathways. 2023;9(3):26-32. doi:10.25270/jcp.2023.05.03

Neutropenia, defined as a decrease in the number of white blood cells called neu­trophils, is a serious consequence of myelosuppressive chemotherapy (CT) and often occurs 7 to 12 days after CT.¹ The most important clinical implication of CT-induced neutropenia (CIN) is febrile neutropenia (FN), which is neutropenia combined with a fever.^1,2 FN may result in delays in treatment or dose reduction of CT, and it can also lead to infection, sepsis, hospitalization, exacerbation of mul­tiple comorbidities, and, in extreme cases, even death.^1,2 Leukocyte (white blood cell) growth factors, also referred to as a granulocyte colony-stimulating factors (G-CSFs), are indicated to prevent complications from neutropenia and decrease the incidence of FN in patients with nonmyeloid malignancies receiving myelosup­pressive CT, which is associated with a clinically significant incidence of FN.¹ Peg­filgrastim is a long-acting, polyethylene glycol (PEG)ylated G-CSF. (PEGylation is a process of attaching repeating units of PEG to polypeptide drugs to protect them and improve their pharmacodynamic and pharmacokinetic profiles.³) Various peg­filgrastim biosimilars are approved by the US Food and Drug Administration (FDA) for primary prophylaxis of CIN.^4-8

The National Comprehensive Cancer Network (NCCN) guidelines for hemato­poietic growth factors recommend G-CSF for prophylactic use in patients receiving myelosuppressive CT associated with a high risk (> 20%) of developing FN.1 NCCN guidelines also recommend consider­ing G-CSF therapy for patients at intermediate risk (10%-20%) who have at least one additional risk factor and for individu­als in certain other scenarios receiving myelosuppressive CT.¹ The American Society of Clinical Oncology (ASCO) also has clinical practice guidelines for the use of G-CSFs to reduce the risk of FN in individuals receiving cancer CT.⁹ FN risk strati­fication (low, intermediate, and high) and standardization of primary prophylaxis with G-CSF for high-risk patients and in­termediate-risk patients with at least one additional risk factor is critical to improving patient outcomes and optimizing care delivery costs.¹⁰ Prophylactic G-CSF use in cancer CT is asso­ciated with significant reductions in expensive hospitalization, antibiotic usage, mortality, morbidity due to the ability to ad­minister high-dose chemotherapy, and savings from reduction in indirect costs, such as loss of productivity and diminished quality of life.¹¹

The FDA and NCCN recommend that a pegfilgrastim in­jection be given to patients at least 24 hours after the last dose of CT in the cycle and 14 days before the first dose of CT in the next cycle; although the NCCN guidelines also state that pegfilgrastim administration up to 3 or 4 days post-CT is acceptable.^4,12,13 ASCO recommends that pegfilgrastim be administered 1 to 3 days after CT, if possible.9 Pegfilgrastim is available in two dosage forms: a single-dose, prefilled sy­ringe administered subcutaneously by a health care provider or self-injected by the patient, and a single-dose, prefilled syringe packaged with an on-body injector affixed to the patient on the day of CT that automatically delivers pegfilgrastim ap­proximately 27 hours after application.⁴

Pegfilgrastim drugs are specialty medications that require special handling, administration, and/or monitoring and are used to treat rare and chronic conditions.14 Injected or infused specialty medications often require administration or super­vision of administration by a qualified licensed health care professional, making these drugs extremely complex and ex­pensive.14 These drugs can be administered in various settings, such as a hospital outpatient setting, doctor’s office, infusion suite, or the patient’s home with a home health nurse, and can be covered under the medical or pharmacy benefit.¹⁴

Site-of-care redirection of injected and infused specialty medications from a hospital outpatient setting and doctor’s of­fice to the patient’s home, when clinically appropriate, results in lower health care spending overall, thus reducing the bur­den of rising costs.¹⁵ In addition, moving the site of care to pa­tients’ homes is convenient for the patients due to the minimal disruption to their lives.¹⁵

Cigna’s site-of-care home-redirection program demon­strates the significance of value-based care in improving patient outcomes by promoting clinically appropriate, safe, cost-effective, and highest value site of care.¹⁴ Even though home administration of injected and infused specialty medica­tions is gaining adherents because of these benefits, providers have expressed reservations about the implications for pa­tient safety of routinely administering these drugs in patients’ homes.¹⁵ Currently, there is no documented research in the US analyzing the impact of home redirection on pegfilgrastim effectiveness and timing of administration in primary prophy­laxis of CIN.

The two research questions of this study were the follow­ing: (1) Does home redirection impact the effectiveness of pegfilgrastim in preventing complications from CIN among patients receiving myelosuppressive CT? (2) Does home redi­rection impact the timing of pegfilgrastim administration fol­lowing CT among patients receiving myelosuppressive CT?

Program Background

Cigna’s site-of-care redirection programs use prior authoriza­tion to identify patients on specialty medications administered in high-cost settings (eg, outpatient hospital) and, when clini­cally appropriate, redirect them to affordable, less-intensive sites of care (eg, home).¹⁴ Pegfilgrastim and its biosimilars are eligible for redirection under this program.¹⁴

Data

Cigna’s proprietary administrative and commercial medical claims data were used as the source of retrospective data for the study. The company routinely collects this standard data to fulfill its operational purposes; claims and administrative data were only utilized for the purposes of the study analyses post facto. These data were completely deidentified, in accordance with security measures, by a separate internal team to protect member confidentiality prior to any secondary data analysis. The information contained in these data is sensitive and propri­etary in nature and thus cannot be shared externally. The study methods are in compliance with the ethical guidelines of the 1975 Declaration of Helsinki.

The study’s sample consisted of 13,493 patients receiving CT between September 1, 2020, and August 31, 2022. All of these patients had received pegfilgrastim for FN prophylaxis, and we included pegfilgrastim and its biosimilars in this study. These drugs were eligible for redirection under the Cigna pro­gram and were redirected from a high-cost setting to a qual­ity, cost-effective site of care, such as a contracted provider’s office, customer’s home with infusion nurses, or nonhospital-based ambulatory infusion center. Breast, colorectal, lung/ bronchus, non-Hodgkin lymphoma, pancreatic, ovarian, and uterine cancers comprised approximately 80% of patient can­cer types (Table 1).

Data regarding risk of developing FN was missing for 19.1% of patients. This reduced the study sample to 10,916 patients. Because 96% of the patients in the study had received more than one cycle of CT, 45,925 records were used in the study model, each representing a single cycle of CT. Overall, 10,916 patients who received a combined total of 45,925 cycles of CT were included in the analysis.

Measures

CT claims were identified based on Healthcare Common Pro­cedure Coding System codes and drug names. Patients on CT who received pegfilgrastim drugs for FN prophylaxis were identified for the data period. All CT cycles that any given pa­tient was on for the data period were included in the study. Pa­tients’ risk for developing FN was ascertained based on disease, CT regimens, and patient-specific risk factors. Patient-specific risk factors were assessed based on the NCCN guidelines for hematopoietic growth factors.^12,* Based on this risk assessment for FN, patients were placed into one of the following three risk groups: low, intermediate, or high.

A dichotomous variable was created by grouping patients into home redirection “yes” vs home redirection “no” catego­ries. Patients who received pegfilgrastim either exclusively at the home setting or at the nonhome setting (hospital outpatient/ physician’s office) followed by the home setting were categorized as “yes” for home redirection. Patients who received pegfilgras­tim exclusively at the nonhome setting (hospital outpatient or physician’s office) were considered “no” for home redirection.

Patient characteristics studied include age, gender, and co­morbidity. Patient comorbidity was measured using Agency for Healthcare Research and Quality Elixhauser Comorbidity Index scores.¹⁶ The comorbidity index score for each patient was calculated as a weighted sum of each of the 31 Elixhauser binary comorbidity variables. Additional variables used in the analyses include number of CT cycles and medical cost. Medi­cal cost included costs for all medical services for the duration that any given patient was managed by Cigna during the study data period.

The outcome measures studied were pegfilgrastim effective­ness and timing of administration following CT. Effectiveness was evaluated by incidence of neutropenia, fever, pneumonia, and sepsis. Timing of pegfilgrastim administration following CT was classified as <24 hours or >24 hours.

Statistical Analysis

Descriptive and chi-square (χ2) statistics were performed to assess any overall associations between pegfilgrastim home re­direction and clinical outcome measures, such as pegfilgrastim effectiveness and timing of administration following CT. Logistic regression models were used to compute odds ratios (ORs) and their 95% confidence intervals (CIs) to determine the magnitude and direction of potential associations between home redirection of pegfilgrastim and outcomes, such as peg­filgrastim effectiveness and timing of administration. Analy­ses were conducted using SAS Enterprise Guide, version 8.2 (SAS Institute Inc).

Patients who underwent home redirection had received 15.3% of the sample CT cycles, and patients who did not undergo home redirection had received 84.7% of sample CT cycles (Table 2). A large majority of CT cycles (73.8%) were admin­istered to patients aged 40 to 64 years compared to a small mi­nority of CT cycles (10.6%) administered to patients aged 18 to 39 years. More than two-thirds (70.4%) of CT cycles were administered to female patients. Among 45,925 cycles of study sample pegfilgrastim prophylaxis, incidence of neutropenia, fe­ver, pneumonia, and sepsis occurred in 543 (1.2%) CT cycles. Pegfilgrastim was administered on the same day as CT in 29.8% of CT cycles. The risk for developing FN was high in 51.4% of CT cycles and intermediate in 35.1%. A majority of patients had medical costs between $100,000 and $500,000 (71.2%).

The results of χ2 analyses showed that home redirection de­creased the likelihood of same-day pegfilgrastim administration (21.9%; P < .05) (Table 3). Among patients who received high-risk CT cycles, a significant percentage had been administered pegfilgrastim on the same day (32.0%; P < .05) compared to patients who received low-risk cycles. Age and gender were significantly associated with pegfilgrastim effectiveness and timing of administration (P < .05). Male patients had a higher likelihood of FN incidence compared to female patients, but the likelihood of same-day pegfilgrastim administration was higher in female patients compared to male patients. Patients aged ≤ 17 years had the highest incidence of FN compared to other age groups (17.7%; P < .05). Among the various age groups, patients aged 18 to 39 years had a significantly higher number of same-day pegfilgrastim administrations (34.5%; P < .05). Patients with medical costs of more than $1 million had the highest likelihood of developing neutropenia, fever, pneu­monia, and sepsis following pegfilgrastim prophylaxis, and of experiencing same-day pegfilgrastim administration.

Logistic regression analyses revealed that the incidence of neutropenia, fever, pneumonia, and sepsis was 32% less likely in patients who underwent home redirection vs those who did not (OR: 0.68; 95% CI: 0.53-0.87) (Table 4). Similarly, the odds of same-day pegfilgrastim administration were 43% lower in the home-redirection group (OR: 0.57; 95% CI: 0.54-0.61). There were 6% higher odds of neutropenia, fever, pneumonia, and sepsis in patients who experienced same-day pegfilgrastim administration compared to those who received pegfilgrastim administration after > 24 hours, but the results were not statisti­cally significant.

The incidence of neutropenia, fever, pneumonia, and sepsis in patients was 24% less likely in CT cycles with intermediate risk compared to CT cycles with high risk (OR: 0.76; 95% CI: 0.63-0.92) (Table 4). Additionally, the odds of patients receiv­ing same-day pegfilgrastim were 10% lower in CT cycles with intermediate risk than in CT cycles with high risk (OR: 0.90; 95% CI: 0.86-0.94.)

Patients aged ≤ 17 years were 9.91 times more likely to de­velop neutropenia, fever, pneumonia, and sepsis than those aged 40 to 64 years (95% CI: 6.49-15.14) (Table 4). In addi­tion, patients aged 18 to 39 years were 1.14 times more likely to have same-day pegfilgrastim administration than those aged 40 to 64 years (95% CI: 1.07-1.22). The odds of same-day peg­filgrastim administration were 35% lower in male patients than in female patients (OR: 0.65; 95% CI: 0.62-0.68).

The odds of developing neutropenia, fever, pneumonia, and sepsis increased by 4% for a one-unit increase in comorbidity score (OR: 1.04; 95% CI: 1.03-1.04) (Table 4). Also, the odds of developing FN decreased 24% (OR: 0.76; 95% CI: 0.73- 0.79), and the odds of same-day pegfilgrastim administration decreased by 5% (OR: 0.95; 95% CI: 0.95-0.96) for every one-unit increase in CT cycle.

To our knowledge and based on a literature review, this is the first study in the US analyzing the clinical outcomes of pegfil­grastim site-of-care redirection from a high-cost hospital set­ting to a cost-effective home setting. This study showed sta­tistically significant clinical outcomes regarding pegfilgrastim effectiveness and timing of pegfilgrastim administration in pa­tients who underwent home redirection. The incidence of FN following prophylactic pegfilgrastim administration and the odds of same-day pegfilgrastim administration were lower in patients who underwent home redirection compared to those who did not.

The recommended timing for prophylactic pegfilgrastim administration is at least 24 hours after CT.^9,12 Evidence-based US guidelines for prophylactic pegfilgrastim administration from ASCO and NCCN are 1 to 3 days and 1 to 4 days after CT, respectively.9,12 These guidelines were established out of concern that pegfilgrastim administration too soon after CT may potentially exacerbate neutropenia by stimulating pro­genitor cells that can then be targeted by the CT agents.^13,17,18 Systematic literature review studies showed increased incidence and longer duration of neutropenia and FN among patients re­ceiving same-day pegfilgrastim vs those treated 1 to 4 days after CT.19,20 These studies also showed that data appearing to sup­port same-day pegfilgrastim administration were from uncon­trolled studies that were limited in size.^19,20 Our study’s findings showed a 43% reduction in the odds of same-day pegfilgrastim administration for patients who underwent home redirection compared to those who did not. Aligning with evidence-based US guidelines from ASCO and NCCN, these findings showed highly favorable outcomes in the home-redirection group re­garding the ideal timing of prophylactic pegfilgrastim adminis­tration compared to that of the nonhome-redirection group.

This study analyzed the efficacy of pegfilgrastim adminis­tered in a home setting vs a nonhome setting. The results showed that the odds of incidence of neutropenia, fever, pneumonia, and sepsis with pegfilgrastim prophylaxis were 32% lower in home-redirection CT cycles compared to nonhome-redirection CT cycles. These favorable clinical outcomes regarding pegfil­grastim effectiveness observed in this real-world clinical practice among a large sample of patients show that pegfilgrastim could be administered effectively in the home setting.

Historically, starting in the 1980s, specialty injection and infusion medication administration has shifted from hospitals to physician-owned or hospital-affiliated outpatient centers.¹² Home administration offers innovative opportunities in im­proving access and affordability of specialty injection and in­fusion medications.²¹ Cigna’s site-of-care redirection program provides access to pegfilgrastim administration in a home set­ting, where patients could have a home health nurse instruct on self-administration before the patient begins the process. This program offers additional benefits to the patients, such as minimizing outpatient visits for patients with cancer who are at an increased risk of infection, convenience of in-home administration and avoidance of costs and logistics associated with traveling to a physician’s office or nonhospital-based am­bulatory infusion center 24 hours after CT administration. Further, this program emphasizes value-based care by promot­ing high value care, optimizing patient outcomes, and enhanc­ing the patient experience.²²

We acknowledge certain limitations of our study. The main limitation of this study is that the claims sample is not repre­sentative of the Medicare and uninsured US population. The study did not control for race, education, and socioeconomic status. Our sample patients had heterogeneity in cancer type, which may have added additional variability in the data. We conducted rigorous review of cancer types, CT treatment reg­imens, and patient risk factors in risk assessment for FN and stratification of risk cohorts. We utilized this risk profile along with medical cost and number of CT cycles to minimize het­erogeneity of the patient sample. An additional limitation of this study is that the results are from a single home-redirection program. Despite these limitations, reflection of real-world clinical practice and inclusion of large numbers of patients add significant clinical value to our study.

Our findings show that Cigna’s site-of-care pegfilgrastim redirection from high-cost hospital outpatient settings to cost-effective home settings has favorable clinical outcomes regard­ing pegfilgrastim effectiveness and timing of administration in primary prophylaxis of CIN. The post-CT timing of pegfil­grastim administration in the home setting aids compliance and adherence to published US guidelines, thus reducing the risk of FN and hospitalization and improving outcomes for patients. These findings show that home redirection of complex and ex­pensive specialty medications might present new opportunities in health care delivery by maximizing access, improving effec­tiveness, increasing affordability, and enhancing convenience for patients. Further research with prospective randomized clinical trials might provide additional insights into causal ef­fects of home administration on pegfilgrastim effectiveness.

Overall, this retrospective, real-world claims study presents significant evidence supporting favorable clinical outcomes associated with Cigna’s program for home redirection of peg­filgrastim. The results showed that compared to nonhome settings, home settings were associated with better outcomes regarding pegfilgrastim effectiveness and timing of admin­istration in preventing complications from CIN. These find­ings signify the impact of Cigna’s home-redirection program in increasing affordability and access while addressing concerns regarding effectiveness of pegfilgrastim in the home setting. Widespread adoption of similar programs that can effectively redirect medications from high-cost settings to quality, cost-effective settings when clinically appropriate might reduce the burden of rising health care costs while increasing access and affordability for patients.

Authors:  Lavanya Raj, MBBS, MS; Pam McManus

Affiliations: The Cigna Group, Bloomfield, CT

Address correspondence to: 

Lavanya Raj, MBBS, MS
900 Cottage Grove Road
Bloomfield, CT, 06002
Email: lavanya.raj@evernorth.com
Phone: (224) 216-6288

Acknowledgements: We thank the following individuals for their expertise and assistance with this study: Tim Dollear and Lauren Murray for study methodology assistance; Dr Stephen Hamilton, Dr Robinson Ortiz, and Dr Jeffrey Langsam for measures refine­ment and manuscript review; Brenna Brown for data col­lection and manuscript review; Dr Ajani Nimmagadda for manuscript review/approval process; and Dr Bhuvana Sagar for conception of the study objective.

Disclosures: The authors disclose no financial or other conflicts of interest.