Single Dose Of Pegfilgrastim Research Articles

Abstract PO2-12-12: REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer

Abstract Background: Granulocyte colony stimulating factor (G-CSF) such as filgrastim (FIL) or pegfilgrastim (PEG) significantly reduces the risk of febrile neutropenia (FN) and treatment-related hospitalization in patients with early breast cancer receiving chemotherapy. However, patients receiving G-CSF can experience clinically significant bone pain. Previous studies examining post-GCSF bone pain were mostly based on physician pain assessment and compared mixed doses (30/60/100 μg/kg) of PEG vs. FIL (5μg/kg/day or 300 μg/day) given for 7 to 14 days. Based on a randomized non-inferiority study, 5 days of FIL is considered non-inferior to 10 days of FIL to prevent FN and hospitalizations and is frequently used in patients receiving chemotherapy for breast cancer. Patient-reported bone pain after 5 days of FIL vs. single dose of PEG has never been compared in a prospective randomized study and has important implications for patient and physician treatment preferences. Methods: In this multicenter, open-label trial, patients receiving neo-/adjuvant chemotherapy for early-stage breast cancer requiring primary FN prophylaxis with G-CSF were randomized 1:1 to either 5 days of FIL (300 μg or 480μg if ≥ 90 kg) or 1 day of PEG (6 mg) with each cycle of chemotherapy. The primary endpoint was bone pain using area under the curve (AUC) of the daily pain score from days 1-5 (AUC score 0 to 40) during cycle 1. We used linear regression adjusting for stratification factors [cancer center (2 centers) and chemotherapy regimen (taxane (TAX) or anthracycline (ANTH)-based during cycle 1] and prespecified baseline covariates: age, pain, and use of pain medications pre-chemotherapy. Supportive analysis of bone pain across cycles 1 to 4 was conducted using repeated linear regression. Key secondary endpoints included incidence of FN, hospitalizations, chemotherapy delay, dose-reduction or discontinuation, and chemotherapy-related deaths. Results: From June 2021 to March 2023, 233 patients were enrolled, with 217 patients (108 FIL/109 PEG) in the intention-to-treat analysis; 16 (7.4%) patients were excluded because of incomplete follow-up. Participants were mean age 55.6 years; almost exclusively female (99.1%), on chemotherapy regimen TAX 57% vs. ANTH 43%, had mean baseline pain score 1.12, and prevalence of pain medication use pre-chemotherapy was acetaminophen 14.7%, non-steroidal anti-inflammatory drugs (NSAIDs) 6.0% and opioids 3.2%. Characteristics were balanced between arms (Table 1). After repeated measures linear regression adjusted for age, chemotherapy regimen, baseline pain, and use of pain medications pre-chemotherapy, mean AUC for bone pain at cycle 1 was 10.94 for FIL and 10.12 for PEG (mean difference 0.82; 95% CI: -1.59, 3.23; p = 0.516). There was no significant difference between arms across treatment cycles (interaction p = 0.785; mean time-averaged difference 0.28; 95% CI: -1.75, 2.32). Across cycles 1 to 4, mean peak pain over 5 days post-GCSF was 3.27 vs. 3.41 (p=0.700); frequency of bone pain during first 8 days (pain score > 0) was 52.5% vs. 51.3%; p=0.358, and mean frequency of severe pain (pain score ≥ 5) was 17.5% vs. 15.2%; p=0.014 for FIL vs. PEG, respectively. The incidence of FN [4.6% vs. 0%, absolute difference 4.6% (95% CI: -0.3%, 9.5%; p=0.069)] and hospitalization [FN and non-FN related: 10.2% vs. 1.8%, absolute difference of 8.4% (95% CI: 1.2%, 15.5%; p=0.021)] was higher in the FIL group. There were no significant differences in chemotherapy delay (13% vs. 11%; p=0.815), dose reduction (14.8% vs. 14.7%; p=0.999), early discontinuation (8.3% vs. 5.5%; p=0.580), or chemotherapy-related death (0.9% vs. 0%; p=0.996) in the FIL vs. PEG groups, respectively. Conclusion: There was no difference in patient-reported bone pain after 5 days of FIL or PEG, even after controlling for important clinical factors. Importantly, the study observed higher rates of FN and hospitalizations in patients receiving FIL for 5 days only. Table 1 Baseline Characteristics Citation Format: Terry Ng, Yuxin Zhang, Carol Stober, Jennifer Shamess, Natalie Mills, Stuart Nicholls, Mohammed Ibrahim, Daniel Davoudpour, Christopher Armiento, Marie-France Savard, Moira Rushton, Arif Awan, Sandeep Sehdev, John Hilton, Xinni Song, Rakesh Goel, Fiona Macdonald, Kelly Daigle, Lisa Vandermeer, Monica Taljaard, Mark Clemons. REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-12.

Efficacy and Safety of Single-dose Pegfilgrastim for CD34 + Cell Mobilization in Healthy Volunteers: A Phase 2 Study.

Pegfilgrastim, a long-acting form of granulocyte-colony stimulating factor, with a convenient single-injection dosage, is being investigated for peripheral blood stem cell (PBSC) mobilization in healthy volunteers. However, data on the adequate dose of pegfilgrastim for PBSC mobilization are limited. This phase 2, single-arm study evaluated the efficacy and safety of pegfilgrastim for PBSC mobilization in healthy volunteers. The study comprised 2 phases: pilot (steps 1-3, dose escalation, a single subcutaneous dose of 3.6, 7.2, and 10.8 mg pegfilgrastim, respectively) and evaluation (step 4, efficacy and safety assessments). The primary endpoint was the proportion of subjects who achieved mobilization of ≥20 × 10 6 /L cluster of differentiation 34 positive (CD34 + ) cells. Thirty-five subjects (6 each in steps 1 and 2 and 23 in step 4) were included. In the pilot phase, step 3 with a 10.8 mg dose was not conducted due to favorable outcomes in step 2 (desired CD34 + cell count), at 7.2 mg pegfilgrastim, which was identified as the optimal dose for the evaluation phase. In the evaluation phase, successful CD34 + mobilization was achieved in all 23 subjects. The mean peripheral blood CD34 + cells count peaked on day 5. Back pain, thrombocytopenia, transient elevations of alkaline phosphatase, and lactate dehydrogenase were the most common adverse events. All adverse events were mild, and none led to study discontinuation. A single-dose pegfilgrastim successfully mobilized an optimal number of CD34 + cells and was well tolerated. Pegfilgrastim could be an alternative option for PBSC mobilization in healthy volunteers. The trial was registered at www.clinicaltrials.gov (NCT03993639).

Cost comparison of filgrastim versus pegfilgrastim and pegfilgrastim biosimilars for inpatient prophylaxis of febrile neutropenia.

The Ohio State University Comprehensive Cancer Center (The James) uses daily subcutaneous filgrastim as the inpatient granulocyte colony-stimulating factor of choice. The coordination of care associated with filgrastim can often be a barrier to patient discharge. The purpose of this study was to compare the inpatient cost of daily filgrastim to single dose pegfilgrastim and biosimilars. Adult patients admitted to The James who received at least one dose of filgrastim between June 1, 2021 and August 31, 2021 were retrospectively identified. This study compared the inpatient cost of filgrastim and biosimilars associated with one chemotherapy cycle to the potential inpatient cost of pegfilgrastim and biosimilars based on average sales price (ASP). Additionally, the number and duration of discharge prescriptions for filgrastim was determined. Of the 44 unique patient encounters that met inclusion criteria, 19 received 300-mcg doses of filgrastim and 25 received 480-mcg doses. The median number of doses administered per admission was eight. If each of these patients were to instead receive the most inexpensive biosimilar, pegfilgrastim reference product, the cost would be 216% higher than with filgrastim-sndz. At discharge, 15 patients (34%) received a prescription for filgrastim to be continued for a median duration of 6 days. Based on ASP, pegfilgrastim was more costly than filgrastim. Potential rebates and negotiation power may alter the financial outlook of adding pegfilgrastim to inpatient formulary. Exploration of delays in discharge due to insurance coordination for filgrastim continuation in the outpatient setting may also impact formulary decisions.

Comparison of Short Acting versus Long Acting Filgrastim for Reduction of Chemotherapy Induced Febrile Neutropenia

Introduction: Febrile neutropenia (FN) is the most frequent complications reported during cytotoxic chemotherapy treatment. Granulocyte colony stimulating factor (GCSF) is used to reduce neutropenia and related complications. This study compares short versus long acting filgrastim for reduction of chemotherapy induced FN. Methods: Histologically confirmed solid cancer patients (n=112) receiving either high risk or intermediate risk chemotherapy regimens for FN were randomized into two groups. Group one received filgrastim 300 mcg subcutaneously for five days and group two received pegfilgrastim 6 mg subcutaneously single dose, starting after 24 hours after completion of chemotherapy during each chemotherapy cycle. The primary end point was the occurrence of FN. The secondary end points were number of hospital visits, duration of hospital stay and total direct costs of filgrastim and pegfilgrastim. Results: Fifty six patients were analyzed in each group. The incidence of FN was significantly lower in pegfilgrastim group (42.90%) than filgrastim group (69.6%), p<0.004. The mean hospital visits were 1.84±1.93 in filgrastim group and 0.84±1.19 in pegfilgrastim group with 58.90% and 33.90% hospital admission respectively in both groups. The mean duration of stay was 4.14±3.69 days in filgrastim group and 2.36±3.35 days in pegfilgrastim group. The mean cost (Nepali rupees) of filgrastim and pegfilgrastim was 20162.50+6645.37 (US$168.17±55.42) and 32210.71±10429.43($268.67±86.99) respectively. Conclusion: Single dose of pegfilgrastim was significantly better than multiple doses of filgrastim for reducing FN incidence in cancer patients receiving chemotherapy.

Abstract OT2-21-01: A randomized, multicenter pragmatic trial comparing bone pain from a single dose of pegfilgrastim to 5 doses of daily filgrastim in breast cancer patients receiving neoadjuvant/adjuvant chemotherapy (REaCT-5G)

Abstract Background: Current guidelines recommend the use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis to prevent febrile neutropenia (FN) associated with commonly used breast cancer chemotherapy regimens. Filgrastim (FIL) is a short-acting G-CSF injection that requires daily subcutaneous injection starting 24-72 hours after chemotherapy for 5 to 10 days. Pegfilgrastim (PEG) is a long-acting, pegylated formulation that requires a single injection 24-72 hours after chemotherapy. G-CSF causes bone pain in approximately 70% of patients, which can be severe in over 25% of cases. While registration trials for PEG showed bone pain from PEG was comparable to FIL when given for a median duration of 11 days, many oncologists are now only prescribing FIL for 5 days based on a multicenter RCT showing that 5 days of FIL is non-inferior to 7 or 10 days of FIL in terms of FN and treatment-related hospitalizations. Furthermore, the cost of 5 days of FIL ($CA 721.55 for 300 mcg dose) is half of the price of a single dose of PEG ($CA 1424.63). Therefore, if 5 days of FIL leads to significantly less bone pain, this may improve health-related quality of life (HR-QoL) for patients, improve adherence to G-CSF, and improve cost-effectiveness. Methods: Patients receiving neo-/adjuvant chemotherapy for early stage breast cancer requiring primary FN prophylaxis with G-CSF will be approached for this pragmatic, multicenter, open-label superiority RCT. Using the Rethinking Clinical Trials (REaCT) methodology that incorporates an integrated oral consent model, eligible and consented patients will be randomized to either 5 days of FIL or one day of PEG with each cycle of chemotherapy. The primary endpoint is bone pain during the first 5 days after G-CSF injection using area under the curve (AUC) of the daily pain score from days 1-5 (AUC score 0 to 40) of the Bone Pain Diary. Secondary endpoints include incidence of FN and treatment-related hospitalizations, incidence of chemotherapy delay, dose-reduction, or discontinuation, incidence of chemotherapy-related mortality, rate of G-CSF compliance, healthcare resource utilization, HR-QoL, and cost-effectiveness. Participants will also complete a Treatment Preference Questionnaire (TPQ) exploring the relative importance of different factors in deciding between PEG vs. 5 days of FIL both before randomization and at the end of the study. To achieve 80% power in an ANCOVA analysis and assuming 5% are loss to follow-up, the planned sample size is 232 patients (116 per arm). The randomization (1:1 ratio) will be stratified by treatment center (4 centers) and chemotherapy regimen (taxane-based vs. anthracycline-based in the first 4 cycles). Results: The study opened for enrollment on June 9, 2021. As of July 6, 2021, the study has opened at one site, and 13 patients have been randomized.Conclusion: This will be the first RCT using a patient-reported Bone Pain Diary that was co-developed by patient partners to measure bone pain between 5 days of FIL vs. PEG. In collaboration with patient partners, the study incorporates a tool (TPQ) that explores factors that may be important in deciding between PEG and FIL, with the aim of translating the findings of this study into real world clinical practice. Citation Format: Terry L. Ng, Monica Taljaard, Marie-France Savard, Carol Stober, Stuart Nicholls, Lisa Vandermeer, Kednapa Thavorn, Claudia Hampel, Jennifer Shamess, Natalie Mills, John F. Hilton, Mark Clemons. A randomized, multicenter pragmatic trial comparing bone pain from a single dose of pegfilgrastim to 5 doses of daily filgrastim in breast cancer patients receiving neoadjuvant/adjuvant chemotherapy (REaCT-5G) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-21-01.

Stem‐cell mobilization of healthy sibling donors with pegfilgrastim—A prospective open‐label phase II trial (EudraCT no: 2005‐004971‐39)

Pegfilgrastim is a covalently bound conjugate of filgrastim and mono-methoxypolyethylene glycol with a longer half-life. We report on phase II prospective monocentric trial examining the feasibility of stem cell mobilization with 12 mg single dose pegfilgrastim in related donors. The objectives were to determine the optimal collection day, defined as CD34+ concentration in peripheral blood (PB) >50 cells/μl, the number of donors collected with single leukapheresis, and the peak level of pegfilgrastim in donor-serum. Furthermore, the cell composition of grafts was assessed and compared to published data. The results included about 28 matched related donors. The median pegfilgrastim serum level remained >200 ng/mL for 48 hours before declining, with the maximal measured concentration of 259.49 ng/ml 24 h after application. The median white blood cell count and CD34 count in PB peaked on day four with 52.6 (range 22.8-85.0) Gpt/l and 66.25 (range 22.9-136.6) cells/μl, respectively. A CD34+ count >50 cells/μl on day four was detected in 75% of donors. 79% of the donors underwent a single collection. Conventional filgrastim was administered additionally in two donors, due to insufficient CD 34+ concentration in PB. 89% of donors showed CD34+ yields ≥4 (median 6.5, range 4.6-14.5) × 10/kg body weight of the recipient. All grafts were administered without rejections. The results of this trial showed that stem cell mobilization with pegfilgrastim is a feasible, and attractive option. This is the first trial presenting the kinetics of pegfilgrastim serum levels in healthy donors.

Feasibility and Kinetics of CD34+ Hematopoietic Cells Mobilization By Low-Dose Pegfilgrastim in Lymphoma Patients

▪Introduction: Hematopoietic stem cell rescue with autologous peripheral blood stem cells (PBSC) following high-dose chemotherapy has been used for the treatment of lymphoma and myeloma. Granulocyte colony-stimulating factor (G-CSF) is used for PBSC mobilization but data on PBSC mobilization by pegfilgrastim is limited. Recent studies showed successful PBSC harvest by single dose of pegfilgrastim given at 6mg or 12mg within 4 days after chemotherapy in patients with malignant lymphoma. However, administration of pegfilgrastim early after chemotherapy administration induces overshoot of neutrophils, which may result in rapid plasma clearance of G-CSF due to internalization of the G-CSF/G-CSF receptor complexes via endocytosis in neutrophils. Previous studies demonstrated that day 7 injection of pegfilgrastim in the course of chemotherapy mitigated the neutrophil overshoot compared to day 4 injection of pegfilgrastim. We hypothesized that day 7 administration of lower dose 3.6mg pegfilgrastim could avoid neutrophil overshoot and efficiently mobilize PBSCs. Here we show the kinetics of CD34+ PBSC mobilization after 3.6mg pegfilgrastim given on day 7 in the course of chemotherapy.Patients and Methods: Between February 2016 and May 2017, twenty patients with malignant lymphoma enrolled in this study (14 DLBCL, 2 AITL, 2 ALCL, 1 ATLL, 1 FL). Median age was 54 (range 30-65). Eight patients had clinical stage III-IV. Median number of prior chemotherapy was 0 (range 0-2). All patients received cytotoxic chemotherapy (13 CHOP, 2 DeVIC, 2 ESHAP, 1 DHAP, 1 EPOCH, 1 HD-AraC) on day 1 and 3.6mg of pegfilgrastim was administered subcutaneously on day 7. Peripheral blood CD34+ cell counts were analyzed from day 11 to 14 after chemotherapy by flowcytometric analysis using single platform method based on ISHAGE guideline. The primary objective is to clarify the kinetics of peripheral blood CD34+ cells without harvesting intervention. CD34+ values on each time point is statistically tested using one-sample t-test. To visualize the primary result, bar graph with mean and its confidence interval on each day is represented with the reference line (Figure). The secondary objectives are to search peak point of CD34+ cell counts after each chemotherapy regimen and the feasibility of pegfilgrastim administration on day 7. Successful mobilization was defined as to achieve more than 10×106/L peripheral blood CD34+ cells on any time points between day 11 and 14. All patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria, version 4.0. This study was approved by the institutional review board and conducted in accordance with the Declaration of Helsinki.Results: Successful mobilization was achieved in 19 of the 20 patients (95%). Mean number (SD) of WBC (×109/L) on each day between day 11 and day 14 was 5.4 (3.7), 11.4 (9.1), 14.2 (9.1) and 13.9 (7.4), respectively. Mean number (SD) of CD34+ cells (×106/L) on each day between day 11 and day 14 was 20.3 (22.5), 38.0 (35.7), 40.3 (39.8), and 40.1 (53.5), respectively. The 98.75% confidence interval [CI] of CD34+ cells (×106/L) on each day between day 11 and day 14 was [6.39-34.22], [16.16-60.25], [15.77-64.97] and [7.09-73.16], respectively (Figure). The number of CD34+ cells on day 12 or 13 showed significantly higher than 10×106/L CD34+ cell (P = 0.0022 and 0.0030, respectively) (Figure). We then compared the peak of CD34+ cells in a peripheral blood in each chemotherapy regimens. The peak day of CD34+ cell in patients who received CHOP regimen was day 13 (mean 54.3 ×106/L, range 15.8-151.0×106/L) . However, in 4 of 5 patients who received platinum containing regimen, CD34+ cells failed to reach the peak before day 14 because of prolonged myelosuppression. The number of prior chemotherapy regimen (0 vs 1-2) was not associated with the kinetics of CD34+ cells (p = 0.35). No infectious events including febrile neutropenia were observed. Pain and LDH elevation (Grade 1-2) were the main adverse events related to pegfilgrastim administration. We had not detected any severe adverse events.Conclusion: Our data indicated that 3.6mg pegfilgrastim on day 7 can efficiently mobilize CD34+ cells to peripheral blood without any severe adverse events. [Display omitted] DisclosuresTeshima:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Kyowa-Hakko Kirin: Research Funding; Pfeizer: Research Funding; Chugai: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Pegfilgrastim improves the outcomes of mobilization and engraftment in autologous hematopoietic stem cell transplantation for the treatment of multiple myeloma.

Autologous stem cell transplantation (ASCT) is the only curable therapy for multiple myeloma (MM), while its success primarily relies on mobilization to obtain sufficient hematopoietic stem/progenitor cells (HPC). Although the role of Pegfilgrastim (PEG), a novel PEGylated form of the recombinant G-CSF filgrastim (FIL), in mobilization has been demonstrated, it remains unclear whether this approach is cost-effective in MM treatment. Here, we performed a real-world analysis to evaluate the efficacy and cost of PEG for mobilization in a cohort of MM patients, of which 53% carried high-risk cytogenetic abnormalities. A total of 91 patients who received either a single dose of PEG (6 or 12 mg, n = 42) or multiple dosing of 10 μg/kg/day FIL (n = 49) after chemotherapy for HPC mobilization were included. The yield of MNCs and CD34+ cells per milliliter of blood collected via apheresis was significantly greater in the PEG group than that in the FIL group (P = 0.014 and P = 0.038). Mobilization with PEG yielded significantly higher median number of collected CD34+ cells than FIL (5.56 vs. 4.82 × 106/kg; P = 0.038). Moreover, the average time-to-recovery of leukocytes and platelets after transplantation was markedly shorter in the PEG group than that in the FIL group (leukocyte, 11.59 ± 1.98 vs 12.93 ± 2.83 days, P = 0.019; platelet, 12.86 ± 2.62 vs 14.80 ± 5.47, P = 0.085). However, the total cost of mobilization and apheresis using PEG or FIL was comparable (P = 0.486). Of note, mobilization with 12 mg PEG further shortened time-to-recovery of leukocytes (10.64 ± 0.51 vs. 12.04 ± 2.26 days, P = 0.05) and platelets (10.60 ± 2.89 vs. 13.33 ± 2.35 days, P = 0.031) compared with 6 mg PEG. Our results support a notion that PEG (especially 12 mg) combined with chemotherapy is a cost-effective and convenient regimen of mobilization, which might improve the outcome of ASCT in MM.

Risk of neutropenia-related hospitalization (NRH) related to duration of short-acting granulocyte colony stimulating factor (sG-CSF) for primary prophylaxis.

e18181 Background: In clinical trials, efficacy of 10–11 days of primary prophylactic (PP) sG-CSF is similar to a single dose of pegfilgrastim for preventing febrile neutropenia (FN). However, most patients receive < 10 days of PP sG-CSF in clinical practice. This study assessed the effect of PP sG-CSF duration on the risk of NRH. Methods: Using Medicare 20% sample data, we conducted a nested case-control study within a cohort of patients aged ≥66 y with breast, colorectal, lung, ovarian, or prostate cancer or NHL who initiated first cycle of chemotherapy 1/1/2008–9/30/2016, had ≥1 y continuous coverage in Medicare parts A and B before cycle day 1 (baseline), and received PP sG-CSF. We identified NRH cases (ICD-9, 288.0X; ICD-10, D70.X) from cycle day 5 to end of cycle 1. We matched each case to up to 4 controls based on age (± 1 y), tumor type, regimen risk for FN (intermediate/high [ > 10%], other), and year using incidence density sampling. Duration of sG-CSF (days of use from cycle day 1 to the day before case date) was categorized as < 5 and ≥5 days. We used conditional logistic regression adjusted for race, sex, and Charlson comorbidity index (CCI) at baseline to estimate relative risk of NRH related to duration of sG-CSF. Results: Of 1431 patients receiving PP sG-CSF, 68 cases matched 231 controls. Cases were similar to controls in age (76 vs 75 y), tumor type (NHL, 62% vs 62%; lung cancer, 25% vs 25%), intermediate-/high-risk regimen (65% vs 67%), and male sex (50% vs 48%) but had slightly higher CCI (3.9 vs 3.3). The percentage of patients with ≥5 days of PP sG-CSF use was 26% in cases and 41% in controls. The adjusted OR (95% CI) for NRH was 0.48 (0.25–0.93) for ≥5 vs < 5 days of PP sG-CSF; results were consistent across sensitivity analyses (Table). Conclusions: Among elderly cancer patients receiving PP sG-CSF, ≥5 days of sG-CSF use was associated with substantial reduction in the risk of NRH.[Table: see text]

Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction

BackgroundThe current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. Patients and MethodsWe analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, −4.36 to 0.70 × 106/kg). ResultsNo significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). ConclusionThe present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.

Practical Strategies for Management of Lenalidomide-Associated Cytopenias in Myelodysplastic Syndromes With del(5q)

CASE STUDY A male patient aged 67 years with a 2-year history of refractory anemia and myelodysplastic syndromes (MDS) with del(5q) started lenalidomide (Revlimid) treatment as a participant in the MDS-001 trial (List et al., 2005). At the time of the study, this patient had been transfusion-dependent since 2001, and at study entry he had received a total of 12 units of red blood cells (RBCs). The patient started lenalidomide at 25 mg daily for 21 days of each 28-day cycle on April 2, 2002. (Please note that as a result of subsequent trials, the approved starting dose for lenalidomide in patients with del[5q] MDS is 10 mg.) The patient developed treatment-related pancytopenia in the first 3 weeks of treatment (see Figure on next page). On day 24, lenalidomide was withheld. Platelet and white blood cell (WBC) counts were recovered during a 21-day period, and treatment was resumed with lenalidomide at 10 mg daily. During this initial dose interruption, the patient's hemoglobin level improved. He achieved RBC-transfusion independence (TI) during week 5 of treatment-his last RBC transfusion was on April 22, 2002. Bone marrow (BM) analysis, including fluorescence in situ hybridization, after 3 months of therapy, did not show the del(5q) abnormality. A repeat BM analysis after 57 months of treatment revealed minimal residual dyspoiesis, normal metaphase cytogenetics, and normal cell morphology. Subsequent BM biopsies showed transient trisomy 8 abnormalities but no del(5q) abnormality. The patient required one additional dose reduction during the first year of treatment. The patient did not require hospitalization during lenalidomide treatment but did have a history of seasonal allergies and a propensity for acute sinusitis. He received a single dose of pegfilgrastim (Neulasta) and a short course of antibiotics for active infections, generally one course of antibiotics per year. This patient continued on lenalidomide at 5 mg daily for 21 days of every 28-day cycle without further dose reduction. The patient achieved durable RBC-TI and continued to receive treatment for more than 11 years. The levels of hemoglobin, platelets, and WBCs for an 11-year period in this patient are shown in the Figure. This patient had one normal platelet count in 11 years of lenalidomide treatment but no bleeding episodes. The average platelet count in the 11-year period was 67 × 1,000/∝L (normal range, 150-425 × 1,000/∝L). Similarly, the WBC count remained below normal, with an average of 3.1 × 1,000/∝L (normal range, 3.4-10.4 × 1,000/∝L). He remained active and continued working as an aerospace engineer until age 75. This case demonstrates how effective management of cytopenias, through dose interruptions and modifications in the early weeks of treatment, helps to enable long-term lenalidomide treatment and a high quality of life. Despite the persistence of moderate, asymptomatic cytopenias, the patient was able to remain on lenalidomide therapy and maintained RBC-TI for more than 11 years. The patient died on October 4, 2014, at age 79.5, due to coronary artery disease and heart failure.

Chemo-Mobilization of Autologous Hematopoietic Progenitor Cells (HPCs) with a Single Dose of Pegfilgrastim and Supplemental Filgrastim in Patients with Multiple Myeloma and Lymphoma: A Practical Schema

Hematopoietic Progenitor Cell (HPC) mobilization should take into consideration efficacy, predictability, convenience and cost. Despite many different schemas available, the optimal growth factor regimen for chemo-mobilization is still debatable. The standard growth factor used in HPC mobilization is filgrastim (G-CSF) 10mcg/kg/day, administered subcutaneously. Patients usually receive daily G-CSF injections after chemotherapy in average of 10 days before starting apheresis. Medicare patients have to go to hospital or clinic every day to have their G-CSF injections given. We retrospectively evaluated our experience with pegylated-filgrastim given in conjunction with a subsequent short course G-CSF in 15 patients (8F/7M) with multiple myeloma (n=6) and lymphoma (n=9) who underwent chemo-growth factor HPC mobilization for high-dose chemotherapy and autologous stem cell transplantation. Median age was 68 (52-78). Chemotherapy regimen used for mobilization was at the discretion of the transplant physician and included cyclophosphamide (n=2), DV-PACE (n=5), DHAP (n=2), ESHAP (n=2), EPOCH (n=2), ICE (n=1), mostly combined with Rituximab. We planned ahead of time that chemotherapy is completed by the end of the week so that the patient could spend the weekend at home and receive pegfilgrastim at a single fixed dose (6 mg) subcutaneously in the following week with a median 3 (2-4) days after the last day of chemotherapy. At the time of recovery when median WBC was 0.6/mcL (0.1-3.8), daily G-CSF, at a median dose of 6 mcg/kg/day (5-12) was initiated in 5 (4-7) days after the dose of pegfilgrastim. Five patients (33%) received additional Plerixafor. HPC collection was started based on peripheral CD34 count in a median 3 days (1-6) after the initiation of G-CSF and in 16 days (11-18) after the initial chemotherapy administration. After 2 days (1-3) of apheresis, all patients but one had adequate (>2 x 106) CD34+ cells/kg in HPC product. Median CD34+ cell count on peripheral blood on day+1 apheresis was 32 (4.6-407) x 106/kg. All patients had full myeloid recovery and median time to ANC>500 x 3 consecutive days was 11 days (10-18) days. No graft failure was observed. All patients tolerated the mobilization regimen well with no serious side effects. Our preliminary data suggest that single dose pegfilgrastim in conjunction with low dose short course G-CSF can provide satisfactory HPC mobilization and be considered an alternative convenient growth factor regimen for select patients. A prospective study is currently underway in our institution.

R-ESHAP plus pegfilgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory diffuse large B-cell lymphoma

Stem cell (SC) mobilization is significantly influenced by the mobilization schedule in patients with lymphoma. We evaluated data from 30 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) undergoing SC mobilization. All received R-ESHAP plus a single dose of pegfilgrastim. All patients collected ⩾ 2 × 10(6) CD34+cells/kg, 80% of them at least 5 × 10(6) CD34+cells/kg. Adverse effects of the regimen included myelosuppression and neutropenic fever. Herein, our results suggest that R-ESHAP plus pegfilgrastim is a highly effective mobilization strategy in patients affected by DLBCL associated with a low incidence of adverse events.

Daily G-CSF (filgrastim) and a Single Dose Of Pegylated G-CSF (pegfilgrastim) After Chemotherapy Result In Different Kinetics Of Circulating Hematopoetic Progenitors: Implication For Potential Stem Cell Harvesting

Several studies have shown that a single dose of pegylated G-CSF (pegfilgrastim, Neulasta®) administered after chemotherapy allows sufficient collection of hematopoietic progenitor cells (HPC) for autologous transplantation. Pegfilgrastim has not been approved for HPC mobilization, but the decision for stem cell harvesting may be made after pegG-CSF has already been given. In this case, particular kinetics of circulating HPC after pegG-CSF must be taken into account to guide stem cell harvesting. In an intra-individual analysis, we compared mobilization of HPC in 12 lymphoma patients undergoing two identical cycles of salvage chemotherapy (etoposide, ifosfamide, cisplatin, ± epirubicin, ± rituximab) within a clinical trial (ClinicalTrials.gov: NCT00306111). G-CSF (filgrastim, Neupogen® 5 ug/kg/d) was given daily after the 1st cycle starting at day 3, while a single dose of pegfilgrastim (Neulasta®, 6 mg) was administered after the 2nd cycle. Circulating HPC were analyzed by flow cytometry and colony assays. We found that neutrophil recovery was remarkably pronounced after pegG-CSF resulting in a significant higher white blood count at day 12 compared with filgrastim (WBC: 6.8 ± 1.9 G/l vs. 3.2 ± 0.8 G/l, mean ± SEM), but a similar WBC at day 14 and day 16. However, kinetics of circulating HPC were markedly different: A trend to higher numbers of CD34+ progenitors was observed after pegfilgrastim at day 12 compared to filgrastim, followed by a sharp drop at day 14: 25 ± 12 /μl (pegfilgrastim) vs. 69 ± 22 /μl (filgrastim). Particularly the number of more primitive CD34+CD38- progenitors was significantly reduced at day 14: 3.7 ± 3.0 /μl (pegfilgrastim) vs. 11.7 ± 6.3 /μl (filgrastim). Similar results were found for the more primitive CD34+CD133+ und CD34+CD90+ populations. The colony formation (cloning efficiency) of the HPC was not different. Also, coexpression of homing-related receptors (CXCR4, CD62L/L-selectin) was similar in both groups. We conclude that after chemotherapy and pegG-CSF, sufficient numbers of HPC are circulating which allows for HPC collection during the early recovery phase. However, the HPC count is rapidly dropping once the WBC has recovered, in line with the known elimination of pegGCSF by binding to neutrophils. Thus, when a stem cell harvest is scheduled after neutrophil recovery in these patients, daily addition of non-pegylated G-CSF should be considered. Disclosures: Kanz: Amgen GmbH: Research Funding. Möhle:Amgen GmbH: Research Funding. Off Label Use: Pegfilgrastim is not approved for stem cell mobilization.

Similar Incidence Of Febrile Neutropenia With Same-Day Versus Subsequent Day G-CSF Administration In Non-Hodgkin Lymphoma Patients Receiving R-CHOP Chemotherapy

▪ BackgroundThe chemotherapy regimen of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) every 21 days remains a standard first line treatment for many subtypes of B-cell non-Hodgkin lymphoma (NHL). R-CHOP chemotherapy carries a significant risk of febrile neutropenia (FN). FN is a potentially life threatening complication which typically requires hospital admission and empiric administration of broad spectrum antibiotics. FN can also cause delays and dose reductions with treatment, which are associated with poorer outcomes. Granulocyte colony stimulating factors (G-CSF) are indicated for primary prophylaxis with high risk patients to ameliorate this serious complication of treatment. Prescribing guidelines recommend that G-CSF's not be given until 24 hours after receiving chemotherapy. However, due to logistical issues of outpatient insurance coverage, travel, and patient convenience, it is not always practical to delay G-CSF administration until the day after chemotherapy. Therefore, some patients at our institution received G-CSF on the same day as chemotherapy. Patients and MethodsWe identified 113 lymphoma patients treated with R-CHOP who also received G-CSF primary prophylaxis at our institution from 6/21/04-1/12/12. G-CSF primary prophylaxis with daily filgrastim or a single dose of pegfilgrastim was administered within the first six days of starting R-CHOP, categorized as either same day (D1) or later (D2+). We retrospectively analyzed FN incidence and associated outcomes in patients receiving growth factor as primary prophylaxis administered the same day compared with >24 hours after chemotherapy. FN was estimated using the cumulative incidence method and compared between groups with the Pepe-Mori test. Cox analysis was used to identify prognostic factors for survival and relapse-free survival. ResultsIn our study, 113 patients received R-CHOP and G-CSF as primary prophylaxis (31 D1, 82 D2+). FN occurred in 8 out of 31 D1 patients (25.8%), and in 21 out of 82 patients in the D2+ group (25.6%). FN incidence did not differ between the two groups (P=0.91). No significant differences in relapse-free or overall survival were observed. Risk factors associated with mortality in multivariable analysis included development of FN (hazard ratio 4.33, 95% CI 1.88-10.0, P<0.001) and receiving R-CHOP while hospitalized as an inpatient (hazard ratio 7.16, 95% CI 3.08-16.6, P<0.001). ConclusionsAmong patients receiving G-CSF as primary prophylaxis with R-CHOP, we observed no difference in FN between G-CSF administered the same day and D2+. Not surprisingly, the development of FN and receiving R-CHOP while hospitalized, were both found to be significant risk factors associated with mortality. Previous prospective studies showed more severe and prolonged level of neutropenia, with higher rates of FN with same day versus next day administration in a small cohort of R-CHOP treated NHL patients (Burris et al, 2010). In our retrospective study, we were not able to evaluate neutrophil levels at multiple time points throughout each cycle, and longer follow-up is necessary to evaluate other long-term endpoints of potential interest, such as the incidence of secondary myeloid malignancies after same-day versus next-day G-CSF treatment. For patients who require G-CSF support, next day administration remains the recommended schedule. However, same day administration may be a reasonable alternative if access to care and patient compliance are concerns. Disclosures:Hill:Celgene: Honoraria, Research Funding.

Cost-Effectiveness of Filgrastim and Pegfilgrastim as Primary Prophylaxis Against Febrile Neutropenia in Lymphoma Patients

Febrile neutropenia is a serious toxicity of cancer chemotherapy that is usually treated in hospital. We assessed the cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in diffuse large B-cell lymphoma (DLBCL) patients undergoing chemotherapy. We used a Markov model that followed patients through induction chemotherapy to compare the three prophylaxis strategies: 1) no primary prophylaxis against febrile neutropenia; 2) primary prophylaxis with 10 days of filgrastim therapy; and 3) primary prophylaxis with a single dose of pegfilgrastim. The target population was a hypothetical cohort of 64-year-old men and women with DLBCL. Data sources included published literature and current clinical practice. The analysis was conducted from a publicly funded health-care system perspective. The main outcome measures included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). In the base-case analysis, costs associated with no primary prophylaxis, primary prophylaxis with 10 days of filgrastim, and primary prophylaxis with pegfilgrastim were CaD $7314, CaD $13947, and CaD $16290, respectively. The QALYs associated with the three strategies were 0.2004, 0.2015, and 0.2024, respectively. The ICER for the filgrastim vs no primary prophylaxis strategy was CaD $5796000 per QALY. The ICER for the pegfilgrastim vs filgrastim primary prophylaxis strategy was CaD $2611000 per QALY. All one-way sensitivity analyses yielded ICERs greater than CaD $400000 per QALY. Cost-effectiveness acceptability curves show that 20.0% of iterations are cost-effective at a willingness-to-pay threshold of CaD $1595000 for the filgrastim strategy and CaD $561000 for the pegfilgrastim strategy. Primary prophylaxis against febrile neutropenia with either filgrastim or pegfilgrastim is not cost-effective in DLBCL patients.

Primary Prophylaxis With Hematopoietic Colony Stimulating Factor: Insights From a Canadian Cost-Effectiveness Analysis

Primary Prophylaxis With Hematopoietic Colony Stimulating Factor: Insights From a Canadian Cost-Effectiveness Analysis

Sweet's syndrome with subcutaneous involvement associated with pegfilgrastim treatment: first reported case

Neutrophilic panniculitis is an infrequent entity, considered by most authors as part of the 'neutrophilic dermatosis' spectrum. Few cases have been reported to be related with granulocyte colony-stimulating factor (G-CSF); we report a case of neutrophilic panniculitis and Sweet's syndrome lesions related with pegfilgrastim, a long-acting G-CSF. A 77-year-old woman with M2 acute myeloid leukemia was treated with chemotherapy as well as broad-spectrum antibiotics and antifungal drugs because of febrile neutropenia. Ten days after a single dose of pegfilgrastim, she developed a limited number of purple plaques on the neck, left leg, both arms and several indurated and slightly mobile nodules on her forearms. Skin biopsy of a plaque showed a diffused dermal neutrophilic infiltrate with dermal edema. Biopsy of a nodule showed a lobular neutrophilic panniculitis without vasculitis. No foreign material was found in those biopsies. No organisms were detected in blood, urine or tissue cultures. She was started with prednisolone 40 mg once a day, with dramatic improvement within the next 2 days. This case is noteworthy for the simultaneous appearance of Sweet's syndrome and neutrophilic panniculitis and it is the first case of neutrophilic panniculitis associated with this drug, pegfilgrastim.

Pegfilgrastim compared with filgrastim for cytokine-alone mobilization of autologous haematopoietic stem and progenitor cells

Haematopoietic stem and progenitor cells (HSPC) mobilization, using cytokine-alone, is a well-tolerated regimen with predictable mobilization kinetics. Single-dose pegfilgrastim mobilizes HSPC efficiently; however, there is surprisingly little comparative data on its use without chemotherapy for HSPC mobilization. Pegfilgrastim-alone and filgrastim-alone mobilization regimens were compared in 52 patients with haematological malignancy. Pegfilgrastim 12 mg (n=20) or 6 mg (n=2) was administered Day 1 (D1) in 22 patients (lymphoma n=17; myeloma n=5). Thirty historical controls (lymphoma n=18; myeloma n=12) received filgrastim 10 mcg/kg daily from D1. Peripheral blood (PB) CD34(+) counts reached threshold (5 × 10(6)/L) and apheresis commenced on D4(4-5) and D4(4-6). Median PB CD34(+) cell count on D1 of apheresis was similar (26.0 × 10(6)/L (2.5-125.0 × 10(6)/L) and 16.2 × 10(6)/L (2.6-50.7 × 10(6)/L); P=0.06), for pegfilgrastim and filgrastim groups, respectively. Target yield (2 × 10(6) per kg CD34(+) cells) was collected in 20/22 (91%) pegfilgrastim patients and 24/30 (80%) in the filgrastim group (P=0.44), in a similar median number of aphereses (3(1-4) versus 3(2-6), respectively; P=0.85). A higher proportion of pegfilgrastim patients tended to yield 4 × 10(6) per kg CD34(+) cells; 16/22 (73%) versus 14/30 (47%) filgrastim patients (P=0.09). One pegfilgrastim patient developed hyperleukocytosis that resolved without incident. Pegfilgrastim-alone is a simple, well-tolerated, and attractive option for outpatient-based HSPC mobilization with similar mobilization kinetics and efficacy to regular filgrastim.

Pegfilgrastim overdose: case report and review of the literature

Single-dose pegfilgrastim is commonly used for the prophylaxis of neutropenia in patients receiving myelotoxic chemotherapy. We report a case of a 69-year-old man who was treated with chemotherapy for small-cell lung cancer and mistakenly self-administered a 36 mg overdose of pegfilgrastim, a sixfold increase over the scheduled dose.