Research ArticleClinical Studies

Pooled-analysis of Lipegfilgrastim Effectiveness and Safety Among Patients With Blood Malignancies in the Real-world Setting

RUTH PETTENGELL, THOMAS WOLFF, THOMAS GOEHLER and NICOLA CASCAVILLA
Anticancer Research January 2021, 41 (1) 347-354; DOI: https://doi.org/10.21873/anticanres.14782

Abstract

Background/Aim: The aim of this report was to summarize the real-world experience with lipegfilgrastim as a neutropenia prophylaxis in a large cohort of lymphoma patients receiving immuno-, chemo-therapy. Patients and Methods: Observational clinical data were derived from two phase IV studies (NADIR and LEOS) with similar protocols conducted in eight European countries for 677 patients. Results: Categories for risk of febrile neutropenia were predominantly high (54.5%) or intermediate (38.8%). The most frequent patient-associated risk factors were age >65 years (54.4%), female sex (43.9%), hemoglobin <12 g/dL (25.3%), and prior febrile neutropenia (14.5%). The incidence of febrile neutropenia and Grade 3/4 neutropenia was 5.9% and 14.6%, respectively over all cycles of immuno-, chemo-therapy (n=3018). Adverse drug reactions occurred in 74 patients (10.9%), with bone pain (2.2%), myalgia (1.8%), and pyrexia (1.0%) occurring in ≥1% of patients. Conclusion: Lipegfilgrastim prophylaxis against chemotherapy-induced neutropenia was effective and well tolerated in lymphoma patients in real-world clinical practice.

Key Words:

Neutropenia is a common, serious complication experienced by cancer patients treated with myelosuppressive chemotherapy, increasing the risk of severe and life-threatening infection (1, 2). It is the primary cause of chemotherapy dose delays or dose reductions, which compromises treatment response and survival (1, 3). As neutropenia suppresses host antimicrobial responses, fever is often the only sign of infection: patients with febrile neutropenia require aggressive treatment, typically necessitating hospitalization for intravenous antimicrobial treatment (1).

Recombinant N-methionyl human granulocyte-colony stimulating factors (r-metHuG-CSFs), which stimulate neutrophil proliferation and differentiation, first became available for the management of chemotherapy-induced neutropenia in cancer patients approximately 25 years ago (4, 5). Treatment guidelines recommend the prophylactic use of r-metHuG-CSFs to prevent febrile neutropenia in patients with high (≥20%) or, in particular, intermediate (10%-20%) risk of developing the condition when there are additional patient-related risk factors, notably advanced age, advanced disease, previous febrile neutropenia, and no antibiotic prophylaxis (6-9).

Short-acting r-metHuG-CSFs, e.g., filgrastim, require daily administration during each chemotherapy cycle for a mean of 10-11 days (10, 11) and up to 14 days (4, 5) to adequately effect absolute neutrophil count (ANC) recovery. However, a review of real-world comparative effectiveness studies found that the duration of filgrastim administration was shorter (3.7-7.5 days) (12) and, in combination with an observed delay in starting filgrastim prophylaxis, contributes to lower effectiveness (13-17). Pegylation of filgrastim to form pegfilgrastim decreases renal drug plasma clearance and sufficiently extends the half-life to permit once-per-cycle administration (18). Meta-analyses of randomized controlled trials (RCTs) show that a single dose of pegfilgrastim is equivalent to a 10- to 14-day course of filgrastim with respect to incidence of febrile neutropenia (16-20). Importantly, however, observational studies have suggested that patients treated with pegfilgrastim had a lower risk of developing neutropenia, neutropenia-related complications, and hospitalization compared to filgrastim (14, 21-23). Moreover, this is true for the addition of anti-CD20 monoclonal antibody therapy to chemotherapy, where a small increase in toxicities (in ~5% of patients) is observed (24).

Lipegfilgrastim (Lonquex®, Teva Pharmaceuticals Industries Ltd, Petach Tikva, Israel) is a novel glycopegylated r-metHuG-CSF developed for once-per-cycle administration that is approved in the European Community for reducing the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) (25). The site-specific glycopegylation selectively adds one molecule of methoxyPEG (mPEG) to the natural glycosylation site (threonine134) of the polypeptide backbone of filgrastim. The position of the methoxypegylation may shield the protein from enzymatic degradation by endoproteases like neutrophil elastases (26). A centrally positioned mPEG-chain, as in lipegfilgrastim, might be favorable over an N-terminal-positioned PEG-chain as in pegfilgrastim (27). The site-specific glycopegylation of lipegfilgrastim results in slower clearance/higher bioavailability and longer-lasting increase in ANC compared to the same dose of pegfilgrastim in healthy subjects (26, 28).

In a phase III trial in patients with advanced non-small cell lung cancer receiving cisplatin/etoposide (29), 6 mg lipegfilgastim per cycle reduced the incidence and duration of severe neutropenia, time to ANC recovery, and depth of ANC nadir compared to placebo: the incidence of febrile neutropenia during cycle 1 was similar in each group, but post hoc analysis revealed a lower incidence of febrile neutropenia in higher risk elderly patients (>65 years) (30). In another phase III trial in patients with breast cancer receiving doxorubicin/docetaxel comparing lipegfilgrastim and pegfilgrastim (each 6 mg per cycle) (31), lipegfilgrastim was non-inferior to pegfilgrastim with respect to duration of severe neutropenia, and the incidence and duration of dose reductions, hospitalizations, and antibiotic use related to febrile neutropenia were similar. However, statistically significant differences favoring lipegfilgrastim were found for secondary endpoints such as a faster time to ANC recovery, incidence of severe neutropenia, and depth of ANC nadir (32). The safety profile, and notably bone pain-related symptoms, was similar for lipegfilgrastim and pegfilgrastim (31, 33).

Patients receiving immuno-/chemo-therapy to treat lymphoma are often at high risk of febrile neutropenia (7), yet few RCTs of long-acting G-CSFs have been conducted specifically in this clinical setting except for pegfilgrastim (34), although there have been some observational studies in lymphoma patients with pegfilgrastim (35, 36) and lipegfilgrastim (37-40). Here, we report the pooled, full results of the two non-interventional studies with lipegfilgrastim.

Patients and Methods

The two studies (NADIR and LEOS) followed similar protocols: both were prospective, multicenter, observational cohort studies of cancer patients receiving immuno-/chemo-therapy and lipegfilgrastim for primary or secondary prophylaxis. NADIR was conducted from 19 December 2013 to September 2016 in Germany. The final results of NADIR have been published for the entire cohort of patients (40), for the subgroup of patients with non-Hodgkin lymphoma (NHL) (41) and as an interims analysis (37). LEOS was conducted from 20 January 2014 to 30 May 2017 in eight European countries (Austria, Belgium, Germany, Italy, Luxemburg, Poland, Slovakia, and the Netherlands). Both studies did not intervene with the individual course of treatment and followed the International Conference on Harmonization of Good Clinical Practice guidelines. Ethics committee approval was obtained in each country. Patients provided written informed consent to be included in this pseudonymized analysis.

Patients. Adult (≥18 years) male and female cancer patients who received cytotoxic chemotherapy or cytotoxic immunotherapy in combination with chemotherapy for hematological malignancies whose physician has decided to administer lipegfilgrastim as primary or secondary prophylaxis were recruited. Both studies excluded patients with chronic myeloid leukemia and myelodysplastic syndrome, as well as pregnant or lactating women. This analysis only included those patients who had a diagnosis of lymphoma.

Treatment. Cancer therapy was administered according to standard clinical practice and institutional guidelines in the respective countries and the decision of treating physicians. Lipegfilgrastim (6 mg fixed dose subcutaneously at least 24 hours after initiation of chemotherapy cycle) was administered for cycle 1 as per standard clinical practice based on the decision of the treating physician and within approved marketing authorization and was continued up to 6 cycles.

Assessments. Baseline demographic (age, gender, height, weight, ethnicity, and Eastern Cooperative Oncology Group (ECOG) performance status) and clinical characteristics (primary disease/tumor history, previous and current chemotherapy details, history of febrile neutropenia, concomitant diseases and medication, and blood counts) were recorded during screening. The baseline overall risk for developing febrile neutropenia estimated by the physician for each patient, individual patient-related risk factors for febrile neutropenia and intended use of lipegfilgrastim (primary or secondary prophylaxis) were recorded. Patients were followed during the chemotherapy regimen until 6-8 weeks after the last dose of lipegfilgrastim. The efficacy endpoints included incidence of severe neutropenia (Grade 3/4), febrile neutropenia, use of antimicrobial agents, incidence of hospitalizations, and immuno/chemo-therapy dose modifications.

Safety. Adverse events (AEs), serious AEs, adverse drug reactions (ADRs), and serious ADRs were coded according to Medical Dictionary for Regulatory Affairs version 20.0 and are shown by preferred term and graded by NCI CTCAE v4.03. Causality relationship to lipegfilgrastim for AEs (yes or no) was used to differentiate ADRs. One study (LEOS) excluded recording of very common chemotherapy-induced AEs, e.g. nausea, vomiting, alopecia.

Statistics. The data were analyzed using descriptive statistics with continuous variables as mean±standard deviation (SD) and median (range), and different categories of discrete variables as frequencies (%). IBM SPSS Statistics (Version 21.0 or higher; IBM, Armonk, New York, USA) and StatXact (Version 6.0; Cytel, Waltham, Massachusetts, USA) were used for the statistical analyses. Missing values were not replaced or extrapolated.

Results

Demographics and clinical characteristics. The study included a total of 677 patients who had received at least one dose of lipegfilgrastim, which constituted the safety population. A total of 609 patients had received ≥2 cycles of immuno-/chemo-therapy, which constituted the efficacy population. The demographics and clinical characteristics of the entire study population (N=677) and the major subpopulations with Hodgkin lymphoma (HL, n=349) and Non Hodgkin Lymphoma (NHL) (n=328) are summarized in Table I. Compared with HL patients, those with NHL were older and more likely to have received previous chemotherapy, and had a lower ECOG performance status score and a longer time from diagnosis to inclusion.

View this table:
Table I.

Demographics and clinical characteristics of patients.

Comorbidities are summarized by number and System Organ Class in Table II. About 70% of the entire cohort had ≥1 comorbidity. The mean (SD) number of comorbidities was 1.43±1.29, being higher among those with NHL compared with HL. Cardiovascular comorbidities were the most frequent.

View this table:
Table II.

Comorbidities of patients.

Patient-associated risk factors for neutropenia, chemotherapies, chemotherapy setting, chemotherapy febrile neutropenia risk, and type of prophylaxis are summarized in Table III. The mean (SD) number of patient-associated risk factors for febrile neutropenia in the entire cohort was 1.38±1.00, with the most frequent risk factors being age >65 years (54.4%), female sex (43.9%), hemoglobin <12 g/dl (25.3%), and prior febrile neutropenia (14.5%). About two-thirds of patients (65%) received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based chemotherapy with (53%) or without (12%) rituximab. The risk categories for febrile neutropenia, estimated by the treating physicians, resulting from chemotherapy or chemotherapy plus immunotherapy were generally high (54.4%) or intermediate (38.8%). Lipegfilgrastim was generally administered as primary prophylaxis (n=546, 80.6%).

View this table:
Table III.

Neutropenic risk, chemotherapies, and prophylaxis type.

Effectiveness. The incidence of febrile neutropenia and Grade 3/4 neutropenia is summarized in Table IV. The overall incidence of febrile neutropenia was 1.6% and 5.9% over the first and all chemotherapy cycles, respectively: corresponding results were 1.8% and 5.1% for primary prophylaxis, and 1.0% and 11.1% for secondary prophylaxis. The overall incidence of Grade 3/4 neutropenia was 2.1% and 14.6% over the first and all chemotherapy cycles, respectively: corresponding results were 2.0% and 13.8% for primary prophylaxis, and 3.0% and 21.2% for secondary prophylaxis.

View this table:
Table IV.

Incidence of febrile neutropenia and neutropenia over all cycles and in the first cycle according to intention of lipegfilgrastim treatment.

Anti-infective (antibacterial and antiviral) drug use was reported during 883 of a total of 3,018 chemotherapy cycles (29.3%). Anti-infective drugs were used in 279 of 609 patients (45.8%) overall, including 238 of 492 patients (48.4%) during primary prophylaxis and 21 of 99 patients (21.2%) during secondary prophylaxis. When known, the reason for anti-infective drug use was prophylaxis (n=779), treatment of confirmed or suspected infection (n=51), febrile neutropenia (n=9), and chemotherapy-induced neutropenia (n=16). When known, the route of anti-infective drug administration was oral (n=846) or intravenous (n=26). Antimycotic drug use was evaluable during 254 of a total of 3,018 chemotherapy cycles (8.4%). Antimycotic drugs were used in 79 of 609 patients (13.0%), including 69 of 492 patients (14.0%) during primary prophylaxis and 10 of 99 (10.1%) during secondary prophylaxis. When known, the reason for antimycotic drug use was prophylaxis (n=225), treatment of confirmed or suspected infection (n=9), febrile neutropenia (n=4), and chemotherapy-induced neutropenia (n=3). When known, the route of antimycotic drug use was oral (n=246) or intravenous (n=7).

Safety. There were 120 ADRs in 74 of 677 patients (10.9%). ADRs occurring in >1 patient are summarized in Table V. The most common events occurring in ≥1% of patients were bone pain (2.2%), myalgia (1.8%), and pyrexia (1.0%). Nineteen serious ADRs occurred in 13 patients (1.9%), which were Grade 1, 2, and 3 in 3, 3, and 13 patients, respectively. Serious ADRs occurring in >1 patient were: asthenia (0.4%), pyrexia (0.4%) and pneumonia (0.3%). Twenty-three serious AEs were categorized as deaths in 20 patients (3.0%), none of which was considered as related to lipegfilgrastim.

View this table:
Table V.

Adverse drug reactions occurring in >1 patient in the safety population (N=677).

Discussion

The overall incidence of febrile neutropenia and Grade 3/4 neutropenia was 5.9% and 14.6%, respectively, over all chemotherapy cycles (n=3018) during which lipegfilgrastim was administered as neutropenia prophylaxis in 609 evaluable patients with blood malignancies (predominantly HL or NHL). The incidence of febrile neutropenia and Grade 3/4 neutropenia was considerably lower at 1.6% and 2.1%, respectively, when the analysis was restricted to the first chemotherapy cycles. As the majority of patients received lipegfilgrastim as primary prophylaxis (~80%), the incidence of febrile neutropenia (5.9% vs. 5.1%) and Grade 3/4 neutropenia (14.6% vs. 13.8%) was similar comparing all chemotherapy cycles for the entire cohort and those who received primary prophylaxis, respectively, while the respective incidences were higher (11.1% and 21.2%, respectively) in the minor subgroup who received secondary prophylaxis. The final results of the observational NADIR study of lipegfilgrastim in 2489 patients (main tumor types: breast cancer (n=1198), lung cancer (n=303), and NHL (n=337) showed an overall incidence of febrile neutropenia and Grade 3/4 neutropenia of 2.7% and 26.8%, respectively (38), and corresponding results were 4.5% and 34.1%, respectively, for the 337 NHL patients specifically (41).

Close to half of the study population (54.4%) had a high risk (≥20%) of febrile neutropenia from the chemotherapy regimen that was used and most of the remaining patients (38.8%) had an intermediate risk (10%-20%). This combined with the relatively high proportion of patients with patient-associated risk factors for febrile neutropenia (age >65 years (54.4%), female sex (43.9%), hemoglobin <12 g/dl (25.3%), and prior febrile neutropenia (14.5%) would appear to account for the use of lipegfilgrastim prophylaxis. About 80% of patients received lipegfilgrastim as primary prophylaxis. This generally reflects current treatment guidelines that recommend G-CSF prophylaxis for patients at high risk, and those at intermediate risk in combination with patient-related risk factors (4, 7-9).

With respect to safety, any grade ADRs were reported in 10.9% of patients, with bone pain (2.2%) and myalgia (1.8%) occurring in >1% of patients. Serious ADRs occurring in >1 patient were asthenia (0.4%), pyrexia (0.4%) and pneumonia (0.3%). None of the observed death cases was considered related to lipegfilgrastim. This safety profile is similar to that previously reported for lipegfilgrastim in other cancers (29-31), which was generally similar to that reported for other long- and short-acting G-CSFs.

Limitations in this study included the relatively low number of patients evaluated and the high number of patients with missing data. The observational nature of the study may allow the introduction of bias into the reporting of the results but allows the real-world use of lipegfilgrastim to be evaluated in clinical practice.

Lipegfilgrastim was effective and well tolerated for the prophylaxis of chemotherapy-induced neutropenia in patients with lymphoma in the real-world setting. The use of lipegfilgrastim in these patients generally appeared to comply with approved indications of the product, as well as current treatment recommendations and guidelines.

Acknowledgements

The Authors thank Robert Scheuerlein (Scheuerlein Consulting, Leipzig, Germany) for editorial review and assistance. Medical editorial assistance was provided by Peter Todd Ph.D. (Tajut Ltd, Kaiapoi, New Zealand), and Zhizhi Fiske (Ketchum Ltd, England) which were funded by Teva.

Footnotes

  • Authors’ Contributions

    All Authors participated meaningfully in the analysis, critically reviewed the manuscript for important intellectual content, and approved the final submitted version of the manuscript.

  • Conflicts of Interest

    All Authors have no conflicts of interest to disclose regarding this study.

  • Received September 5, 2020.
  • Revision received November 18, 2020.
  • Accepted November 19, 2020.

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Pooled-analysis of Lipegfilgrastim Effectiveness and Safety Among Patients With Blood Malignancies in the Real-world Setting
RUTH PETTENGELL, THOMAS WOLFF, THOMAS GOEHLER, NICOLA CASCAVILLA
Anticancer Research Jan 2021, 41 (1) 347-354; DOI: 10.21873/anticanres.14782
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