Two decades of pegfilgrastim: what have we learned? Where do we go from here?

Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires early therapeutic intervention since it is associated with increased hospitalizations and high mortality risk of 5%-20%. FN-related hospitalizations are higher in patients with myeloid malignancies than in those with solid tumors due to the myelotoxicity of chemotherapy regimens and the compromised bone marrow function. FN increases the burden of cancer by causing chemotherapy dose reductions and delays. The administration of the first granulocyte colony-stimulating factor (G-CSF) filgrastim reduced the incidence and duration of FN in patients undergoing chemotherapy. Filgrastim later evolved into pegfilgrastim, which has a longer half-life than filgrastim and is associated with a lower rate of severe neutropenia, chemotherapy dose reduction, and treatment delay. Nine million patients have received pegfilgrastim since its approval in early 2002. The pegfilgrastim on-body injector (OBI) is an innovative device facilitating the time-released auto-injection of pegfilgrastim approximately 27 h after chemotherapy, as clinically recommended for the prevention of FN, thus eliminating the need for a next-day hospital visit. Since its introduction in 2015, one million patients with cancer have received pegfilgrastim using the OBI. Subsequently, the device was approved in the United States (US), European Union, Latin America, and Japan, with studies and a postmarketing commitment demonstrating device reliability. A recent prospective observational study conducted in the US demonstrated that the OBI substantially improved the adherence to and compliance with clinically recommended pegfilgrastim therapy; patients receiving pegfilgrastim via the OBI experienced a lower incidence of FN than those receiving alternatives for FN prophylaxis. This review discusses the evolution of G-CSFs leading to the development of the OBI, current recommendations for G-CSF prophylaxis in the clinic, continued evidence supporting next-day pegfilgrastim administration, and improvements in patient care made possible with the OBI.

For over 20 years, treatment with pegfilgrastim (a therapy that supports the growth of immune cells) has been used in patients with cancer to prevent febrile neutropenia (FN) ­ an unwanted effect of cancer treatment or chemotherapy. FN is defined as the loss of healthy immune cells and development of fever possibly due to an infection. Patients with FN may be very ill or may die, depending on the seriousness of the condition. However, treatment with pegfilgrastim reduces the occurrence of FN and improves survival.Treatment guidelines recommend that pegfilgrastim should be given 24 h after chemotherapy, requiring patients to travel to the hospital on the next day of chemotherapy. Some patients may choose the less helpful option of receiving pegfilgrastim on the same day of chemotherapy to avoid travel. This need led to the development of an on-body injector (OBI) device that is applied on the skin on the last day of chemotherapy and administers pegfilgrastim approximately 27 h after chemotherapy. The highly reliable OBI ensures timely delivery of therapy with a success rate of 99.9%, reduces the travel burden, and helps in following the recommended guidelines for pegfilgrastim administration. For two decades, pegfilgrastim has played a significant role in the treatment and prevention of FN, and the new OBI device provides the required treatment support for improving patient care.

A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.

INTRODUCTION: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 µg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. RESULTS: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. CONCLUSIONS: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.

Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.

Transfusion practice patterns in patients with anemia receiving myelosuppressive chemotherapy for nonmyeloid cancer: results from a prospective observational study.

PURPOSE: The decision to prescribe packed red blood cell (PRBC) transfusions in patients with chemotherapy-induced anemia (CIA) includes assessment of clinical features such as the patient's cancer type and treatment regimen, severity of anemia symptoms, and presence of comorbidities. We examined contemporary transfusion practices in patients with nonmyeloid cancer and CIA. METHODS: Key inclusion criteria were age ≥ 18 years with nonmyeloid cancer, receiving first/second-line myelosuppressive chemotherapy, baseline hemoglobin (Hb) ≤ 10.0 g/dL, and planned to receive ≥ 1 PRBC transfusions. Exclusion criteria were receipt of erythropoiesis-stimulating agents within 8 weeks of screening and/or chronic renal insufficiency. Data were collected from patients' medical records, laboratory values, and physician/provider questionnaires. Proportion of patients for each clinical consideration leading to a decision to prescribe a PRBC transfusion and 95% exact binomial confidence intervals were determined. RESULTS: The study enrolled 154 patients at 18 sites in USA; 147 (95.5%) received a PRBC transfusion. Fatigue was the most common symptom affecting the decision to prescribe a PRBC transfusion (101 [69.2%] patients). Of the three reasons selected as primary considerations for prescribing a PRBC transfusion, anemia symptoms (106 [72.1%] patients) was the most frequently reported, followed by Hb value (37 [25.2%] patients) and medical history (4 [2.7%] patients). CONCLUSIONS: In this study, the primary consideration for prescribing a PRBC transfusion was anemia symptoms in 72.1% of patients, with only 25.2% of patients prescribed a transfusion based exclusively on Hb value. Results indicate that clinical judgment and patient symptoms, not just Hb value, were used in decisions to prescribe PRBC transfusions.