Prevention Of Chemotherapy-induced Neutropenia Research Articles

Abstract 5030: Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages

Abstract The M2 phenotype is dominant in tumor associated macrophages (TAMs) and correlates with poor prognosis. As M1 polarized macrophages possess anti-tumor functions, in vivo reprogramming of macrophages is a promising strategy for cancer treatment. We recently demonstrated that microtubule destabilizing chemotherapeutic agents such as plinabulin induce potent dendritic cell maturation and thereby augment anti-tumor immune responses; yet the effects of plinabulin on macrophage polarization remain unknown. Here we demonstrate that plinabulin, which is currently being investigated for both its anti-tumor effect and prevention of chemotherapy-induced neutropenia in phase II/III clinical trials,induces M1 polarization of ex vivo cultured human monocyte-derived M2 macrophages. This was characterized by a reduction in the cell surface expression of M2 markers CD163 and CD206 and an increase in the expression of co-stimulatory M1 markers CD80 and CD86. Phenotypically, plinabulin-polarized human M1 macrophages secreted increasing levels of iNOS and inflammatory cytokines IL-1β, IL-6 and IL-12 while IL-10 and IL-4 secretion decreased. This suggests a functional skewing from immunosuppressive M2 to pro-inflammatory M1 macrophages upon exposure to plinabulin. Similarly, plinabulin induced the M1 polarization of murine FACS sorted F4/80+ intratumoral M2-TAMs, characterized by increased CD80 and decreased CD206 expression. Moreover, systemic treatment (i.p.) of tumor bearing mice with plinabulin led to a significant reduction in the number of tumor-infiltrating TAMs with a concomitant M1 polarization of the remaining TAMs. Indeed, plinabulin treatment of mice bearing subcutaneous MC38 colon cancer or orthotopic EMT6 breast cancer tumors significantly delayed tumor growth. This efficacy of plinabulin remained unaltered in Rag2-/- mice lacking T cells, suggesting that macrophages are required for its anti-tumor activity. These results identify targeting of TAMs by plinabulin as a promising therapeutic strategy. Testing of plinabulin in combination with other macrophage targeting drugs are currently being explored to investigate the dual effect in reprogramming the tumor immune microenvironment. Citation Format: Elham Pishali Bejestani, G. Kenneth Lloyd, Melanie Buchi, Reto Ritschard, Petra Herzig, Ramon Mohanlal, Lan Huang, James R. Tonra, Alfred Zippelius, Abhishek Kashyap. Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5030.

The Comparison of The Efficacy and Safety of Original and Biosimilar Filgrastim in Prevention of Chemotherapy-Induced Neutropenia in Children with Cancer.

In adults and children, the duration of chemotherapy-induced neutropenia and associated complications has decreased because of the prophylactic use of granulocyte colony-stimulating factors (G-CSFs). Biosimilar G-CSFs can play an important role in reducing treatment costs in daily practice. However, some concerns regarding the efficacy and safety of new biosimilar products exist among clinicians. This study compared the efficacy and safety of original and biosimilar filgrastims for the prophylaxis of chemotherapy-induced neutropenia in children. Thirty children receiving myelosuppressive chemotherapy were enrolled in this study. Filgrastims (5 μg/kg/day) were subcutaneously administered in Group A (biosimilar, Leucostim®; Dem İlaç) and Group B (original drug, Neupogen®; Roche). Hemoglobin, white blood cell (WBC) count, platelet count, transfusion requirements, duration of hospitalization, and frequency and duration of adverse events including fever, neutropenia, and mucositis were evaluated following 25 treatment cycles in both groups. The hemoglobin value, WBC count, and platelet count on days 1, 5, and 10, and the red blood cell and platelet transfusion requirements, frequency, duration, and severity of mucositis, and durations of fever, febrile neutropenia, and hospitalization were similar in both groups. Although the mean WBC counts on days 1 and 5 were lower in Group A, the difference was statistically insignificant. The biosimilar filgrastim, Leucostim, is as effective and safe as the original drug for prophylaxis of chemotherapy-induced neutropenia in children.

Efficacy and safety of PEG-rhG-CSF in primary and secondary prevention of chemotherapy-induced neutropenia.

e19051 Background: This study was to evaluate the efficacy and safety of PEG-rhG-CSF (brand name:jinyouli) in primary and secondary prevention of CIN(chemotherapy-induced neutropenia). Methods: This is a single-center,one-arm clinical study.Patients with non-myeloid malignant tumors were enrolled. PEG-rhG-CSF was given subcutaneously at 24-48h after chemotherapy. The indicator was febrile neutropenia(FN) and IV grade absolute neutrophil count. Results: From January 2016 until June 2018,217 patients were enrolled including 119 lymphoma patients, 50 breast cancer patients, 30 bone tumor patients,18 gynecologic oncology patients, and While146 with primary prevention and 71 with secondary prevention. The incidence of FN was 5.0% (35/692), which was 4.3% (21/478) in the primary prevention patients and 6.5% (14/214) in the secondary prevention patients ( p= 0.233).Logistic regression analysis showed that the longer the treatment cycle, the lower the incidence of FN. Comparison of the indicators of different chemotherapy cycles showed that the IV grade absolute neutrophil count (ANC) reduction was significantly lower in the primary prevention patients than in the secondary prevention patients in the first cycle of chemotherapy[17.1%(25/146) vs.46.5%(33/70),p = 0.000],the incidence of FN and IV grade ANC reduction were significantly lower in the second cycle of treatment than in the first cycle(p < 0.05).The adverse event were mainly bone pain, the incidence of 1/2 grade bone pain was 3.7% (8/217) and the incidence of grade 3/4 bone pain was 1.8% (4/217). Conclusions: The prevention of CIN with PEG-rhG-CSF after chemotherapy can effectively reduce the incidence of FN.For the first chemotherapy cycle, primary prevention is more effective than secondary prevention in preventing the incidence of IV grade ANC reduction. Clinical trial information: NCT02905916.

Plinabulin (Plin) combined with half-dose pegfilgrastim (Peg) compared with full-dose peg alone for chemotherapy- induced-neutropenia (CIN): Neutrophil, bone pain, and immunosuppressive effects.

e12017 Background: Peg is used for CIN prevention. Plin, a novel, non-G-CSF agent is in Phase (Ph) 3 trials for CIN prevention and as an anticancer (NSCLC) agent. In contrast to Peg, Plin does not cause bone pain and maintains absolute neutrophil counts (ANC) within the normal range. Furthermore, Peg, but not Plin, increases Neutrophil-to-Lymphocyte Ratio (NLR) and Lymphocyte-to-Monocyte Ratio (LMR) to immune suppressive values; i.e. NLR>5 and LMR<3.2 (Blayney, ASCO 2018, ESMO 2018, ASCO-SITC 2018). We tested the effects on CIN, bone pain and immune-suppressive profile (i.e. NLR> 5 and LMR<3.2), comparing Plin+half Peg dose to full dose Peg alone (the current CIN standard of care). Methods: Early stage Breast Cancer patients (pts) received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either full dose Peg 6 mg (Peg6; n=22) or Peg 3 mg (half dose) + Plin 20 mg/m2 (Peg3/Plin; n = 21) in a Ph 2 trial (NCT03294577). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood was drawn for ANC, NLR, MLR daily on Day (D) 0 to D15 in cycle 1. Validated bone pain assessments were done at predose D1, 2,3,4,6,7 and 8 in cycle 1. NLR and LMR were calculated from D6 on (ANC effects with Peg or Plin occur after D6). Results: Grade 4 and Grade 3/4 Neutropenia occurred in 59.1% and 81.2% of pts in the Peg6 arm vs 52.4% and 57.1% in the Peg3/Plin arm. Peg3/Plin was well-tolerated and non-inferior to Peg6 for duration of severe neutropenia (P<0.05). FN occurred in 1 pt each in Peg6 and Peg3/Plin. Bone pain with Peg3/Plin was less vs Peg6: frequency of pts with at least 1,3 or 5 days of bone pain was 90.9%, 36.7% and 18.2 % with Peg6, whereas 33.3%, 14.3% and 4.76% with Peg3/Plin (p<0.0001 for at least 1 day). Frequency of NLR≥5 and LMR≤3.2 was higher with Peg6 vs Peg3/Plin (p<0.045 to P<0.0004 between D8 to D15). Clinical trial information: NCT03294577. Conclusions: Half dose Peg combined with Plin is equally effective against CIN as full dose Peg, but with much less bone pain and immune-suppressive potential.[Table: see text]

Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving chemotherapy

BackgroundTreatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen.MethodsTwo hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 109/L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2–4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes.ResultsThe mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI -0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified.ConclusionsTreatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated.Trial registrationThe trial was registered prospectively, prior to study initiation. EudraCT number (2013–003166-14). The date of registration was 12 July, 2013.

Plinabulin, a Novel Small Molecule in Development for Chemotherapy-Induced-Neutropenia (CIN) Prevention, Mobilizes CD34+ Cells through a Mechanism of Action (MoA) Different from G-CSF and from CXCR4 Inhibition

Introduction: Hematopoietic cell transplantation (HCT) involves the transplantation of hematopoietic stem and progenitor cells (HSCs/HPCs) from autologous or histocompatible allogeneic donors. HCT restores bone marrow function after conditioning, high dose chemotherapy (Bendall, Cytokine & Growth Factor Reviews 2014). G-CSF, which prevents CIN, is also used to mobilize HSCs/HPCs (CD34+ cells) prior to HCT. Plinabulin (Plin), a small molecule with immune-enhancing anticancer activity, is under clinical development for cancer treatment and CIN prevention. Plin has anticancer activity in lung cancer (NSCLC) patients (pts) (Mohanlal, ASCO-SITC 2017), and patient-derived multiple myeloma (MM) cell lines (Singh, Blood 2011). Single-dose-per-cycle Plin and pegfilgrastim (Peg) are equally effective for the prevention of Docetaxel (Doc)-induced grade 4 Neutropenia in NSCLC pts (Blayney; ASCO 2018; ASH 2016). Plin has a different MoA vs Peg; Plin acts through reversal of Doc-induced hematopoietic stem cell (LSK) maturation arrest in mouse bone marrow (Lloyd, AACR 2016) and increases neutrophil (N) demargination in pts (Blayney, SLB/IEIIS 2018). In contrast to Peg, Plin causes minimal bone pain, Plin ameliorates Doc-induced thrombocytopenia, and Plin does not increase N-to-Lymphocyte ratio (NLR) to immunosuppressive values of >5 in NSCLC pts (Blayney, IASCL 2018, ESMO 2018). Plerixafor (Pler), a chemokine receptor 4 (CXCR4) antagonist, inhibits CXCR4/SDF-1 binding facilitating CD34+ cell mobilization. Plinabulin does not inhibit CXCR4 (19% inhibition at 10μM Plin) in-vitro, thus Plin and Pler also have different MoAs. Although both G-CSF and Pler are effective in mobilizing CD34+ cells, up to 40% of pts fail to adequately mobilize HSCs/HPCs with G-CSF, or Pler combined with G-CSF (Jantunen, Eur J Hematol 2010). Predominantly due to high cost, Pler is not widely used. Since Plin has a different MoA vs G-CSF or Pler, Plin could be a valuable option for the mobilization of CD34+ cells prior to HCT, in particular if CD34+ response to G-CSF or G-CSF/Pler is inadequate. Peak CD34+ blood cell counts with G-CSF was ~6 cells/μL (Zarxio FDA Briefing Book, 2015). In a CIN phase 2 trial in NSCLC pts, designed to study Plin's efficacy to prevent Doc CIN, we also prospectively measured CD34+ peripheral blood cell count to assess whether Plin mobilized HSCs/HPCs.Method: In study BPI-2358-105 (NCT03102606), NSCLC pts received 75 mg/m2 Doc with Plin at 5 mg/m2 (n=14), 10 mg/m2 (n=13) or 20 mg/m2 (n=14) on D1. Blood CD34+ cell counts were measured before (D0) and after (D 2,6,8 of Cycle 1 and D1 of Cycle2) Doc+Plin administration. CD34+ measurements were obtained in at least 9 pts on both D0 and D8 for each Plin dose. No blood draws for CD34+ cells were taken after D8.Results. Predose D0 CD34+ cell counts were comparable among Plin groups (p<0.8; figure 1, left). D8 was the earliest time point that showed increase in CD34+ cell counts. No blood draws for CD34+ after D8 in Cycle 1 was taken. Blood CD34+ cell count (Figure 1, right) on D8 had increased dose-dependently with Plin (p<0.0004; Jonckheere Terpstra test for dose-response). Change in CD34+ cell count from D0 was also increased dose-dependently on D8 (P<0.0004). In the 5 mg/m2 Plin group, median CD34+ cell counts on D8 had slightly declined, presumably due to myelosuppression with concomitant Doc. The frequency of pts with an increase in blood CD34+ cell count on D8 vs D0 was 89%, 60% and 50% in the 20, 10 and 5 mg/m2 Plin groups, respectively (P<0.0001 for dose response). Doc dose intensity was similar in all Plin dose arms.Conclusion: Plin (20 mg/m2), an agent with anticancer activity for MM and NSCLC, mobilized CD34+ cells to clinically relevant blood counts in the vast majority of pts, through a MoA different from G-CSF or Pler. The CD34+ cell counts with Plin in the HCT setting is likely to be higher than observed in this CIN study, since concomitant myelosuppressive Doc was used with Plin. Furthermore CD34+ cell counts after D8 are likely to increase further with Plin, but this was not measured in this study. Based on current data evidence, Plin has the potential to become a viable option for the mobilization of CD34+ cells from the bone marrow prior to HCT, in particular in pts failing to respond to G-CSF or G-CSF/Pler. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 4805: Plinabulin ameliorates chemotherapy-induced neutropenia: Mechanistic insights

Abstract Chemotherapy-induced Neutropenia (CIN) increases the risk of serious infections, sepsis, hospitalizations and mortality, in patients receiving chemotherapy. CIN is currently being treated with G-CSF, which has significant limitations; G-CSF cannot be administered in the first 24 hours after chemotherapy, and its use is associated with bone pain in the majority of patients. There is a need for new therapies with an improved profile. Plinabulin is an inhibitor of tubulin polymerization, which is currently in Phase 3 clinical trials for the treatment of non-small cell lung canacer (NSCLC) in combination with docetaxel. In a previous Phase 2 trial plinabulin significantly ameliorated CIN in patients undergoing docetaxel chemotherapy and this is currently prospectively being evaluated in a series of Phase 2/3 trials. However, the mechanisms by which plinabulin ameliorates neutropenia are unknown. We investigated the role of plinabulin in the regulation of neutrophil homeostasis under chemotherapy-induced neutropenia in mice. We tested the effect of the novel small molecule plinabulin on blood and bone marrow neutrophils and their precursors using complete differential blood counts (CBC) by electrozoning analyzer and flow cytometry of blood and bone marrow. Neutropenia was induced by single injection of the chemotherapeutic agent docetaxel (25 mg/kg, iv.), with and without plinabulin (10 or 20 mg/kg, ip, 12 mice each group) one hour later. Blood was collected on days 3, 4 and 5 post-injection from the retro-orbital plexus and analyzed for CBC. After 5 days of treatment, bone marrow was harvested and analyzed by flow cytometry for the percentage of neutrophils and their progenitors. Blood Neutrophil counts were significantly decreased in mice as a result of docetaxel treatment. Plinabulin ameliorated the docetaxel-induced neutropenia at day 5 (p&amp;lt;0.05) versus the docetaxel-treated mice. Bone marrow neutrophil counts were decreased by docetaxel monotherapy, but this was significantly prevented when plinabulin was given with docetaxel, (p&amp;lt;0.001 for plinabulin 10 mg/kg; p&amp;lt;0.01 for plinabulin 20 mg/kg). The docetaxel-induced accumulation of LSK cells (uncommitted hematopoietic stem cells) was significantly decreased by adding plinabulin to docetaxel-treated mice. The plinabulin effect was neutrophil-specific, because plinabulin had no effect on monocytes and monocyte precursors in the bone marrow. Collectively, these data suggest that plinabulin ameliorates chemotherapy-induced neutropenia by promoting the transition of LSK to common myeloid precursors in mice. This represents a novel mechanism for the prevention of chemotherapy-induced neutropenia. Citation Format: Amlan K. Ghosh, Yanfang P. Zhu, Jacqueline F. Miller, Catherine C. Hedrick, Ramon Mohanlal, Huang Lan, George K. Lloyd, Klaus Ley. Plinabulin ameliorates chemotherapy-induced neutropenia: Mechanistic insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4805.

Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF).

111Background: Sandoz biosimilar filgrastim has been approved in the US since 2015 for several indications including prevention of chemotherapy-induced neutropenia. US approval was based on results...

Defining the impact of the use of granulocyte colony stimulating factors on the incidence of chemotherapy-induced neutropenia in patients with gynecologic malignancies.

Purpose The objectives of this study were to characterize the incidence of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) with specific chemotherapy agents commonly used in the treatment of gynecologic malignancies, as well as defining the impact of granulocyte colony stimulating factors (G-CSF) on the prevention of CIN and FN in this patient population. Methods This retrospective analysis was conducted from a database of 635 gynecologic cancer patients who received chemotherapy between 1 September 2007 and 31 August 2008. A logistic regression analysis was conducted to determine the impact of potential covariates on the overall incidence of CIN. Results Overall, 28.3% of patients experienced CIN with one or more cycles chemotherapy, and 13.1% had treatment delays or dose reduction associated with CIN. The use of G-CSF prior to administration of chemotherapy resulted in a decrease in the incidence of CIN from 29.8% to 19.6% compared to no G-CSF use. No difference was observed in number of treatment delays or dose reductions in the 46 (7.2%) of gynecologic cancer patients that received G-CSF prophylaxis. Multivariate analysis found that both age and the number of current cycles jointly may predict risk of CIN. Conclusions Patients with gynecologic malignancies appear to be at a higher risk of development of neutropenia when treated with chemotherapy. The proactive use of G-CSF did decrease the risk of CIN by over 30%. Prospective study is warranted to determine the impact of G-CSF to reduce CIN in patients with gynecologic malignancies receiving chemotherapy.

1613 Biosimilar filgrastim in the treatment and prevention of chemotherapy-induced neutropenia in patients with breast cancer: A sub-analysis of the NEXT study

1613 Biosimilar filgrastim in the treatment and prevention of chemotherapy-induced neutropenia in patients with breast cancer: A sub-analysis of the NEXT study

1-Pamitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol May Reduce Incidence of Gemcitabine-Induced Neutropenia: A Pilot Case-Controlled Study

BackgroundChemotherapy-induced neutropenia (CIN) may compromise planned chemotherapy, resulting in severe infection, dose reduction or delayed treatment. Orally administered 1-pamitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a synthetic monoacetyldiglyceride, a product found in the antlers of sika deer. The aim of this study was to evaluate the effectiveness of PLAG for the prevention of CIN.MethodsA total of 48 patients with unresectable pancreatic cancer received gemcitabine-based palliative chemotherapy. Among those patients, 16 patients received PLAG (500 mg) twice daily from the start of chemotherapy to the completion.ResultsThe PLAG group showed a significantly lower incidence of neutropenia (absolute neutrophil count < 1,500 cells/mm3, grade 2-4), as compared to the control group (37.5% vs. 81.3%, P < 0.05). The absolute neutrophil counts (ANCs) of the PLAG group significantly less decreased from the baseline level compared to those of the control group (P < 0.05) and this significant difference in the reduction percentage of ANCs between the two groups was sustained throughout the courses of chemotherapy. No adverse events related to PLAG were observed.ConclusionsPLAG was shown to be clinically effective and safe in reducing the incidence of CIN in pancreatic cancer patients receiving gemcitabine-based chemotherapy.

Interventions to optimize the use of colony-stimulating factors.

92 Background: The Food and Drug Administration approved granulocyte colony-stimulating factors filgrastim (fil) and pegfilgrastim (peg) for use in the prevention of chemotherapy-induced neutropenia. The objective of this study was to characterize and optimize the current utilization of these costly colony-stimulating factors within a tertiary care health system. Methods: Data parameters and improvement measures were defined based on the current literature, national guidelines and institutional standards. Data was collected retrospectively by chart review and analyzed to develop interventions that would optimize fil/peg utilization. Existing policies and procedures were updated, and feedback and approval was obtained through collaborative groups. Improvement measurements will be reassessed post implementation of the proposed interventions. Results: Chart review yielded 156 fil/peg orders. The following observations and interventions were applied. All indications were determined appropriate per established oncology guidelines; however, 3 patients received an unwarranted fil/peg dose within a week of peg administration. An electronic alert was created to prevent administration of an additional fil dose if a recent peg dose had been administered. Of inpatient fil orders (n=38), 24% of weight-based dose rounding and 32% of predetermined discontinuation parameters were not compliant with the institutional standards. Fill electronic order entries were modified to automatically round doses based on patient weight. If an additional one-time absolute neutrophil count (ANC) discontinuation parameter was applied, it is anticipated that fil treatment duration could decrease in 30% of patients. The one-time ANC discontinuation parameter for fil was added. Conclusions: Although our system’s utilization of colony-stimulating factors was in compliance with national guidelines and institutional standards, opportunities for optimization were identified and targeted for improvement.

Biosimilar filgrastim in the treatment and prevention of chemotherapy-induced neutropenia in elderly patients: A subanalysis of the next study

Biosimilar filgrastim in the treatment and prevention of chemotherapy-induced neutropenia in elderly patients: A subanalysis of the next study

Biosimilar filgrastim in the treatment and the prevention of chemotherapy-induced neutropenia: The next study

Biosimilar filgrastim in the treatment and the prevention of chemotherapy-induced neutropenia: The next study

Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia

BackgroundNivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen®. Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of Nivestim™ for the prevention and treatment of febrile neutropenia (FN) in patients treated with cytotoxic chemotherapy in general clinical practice.Methods/DesignThe NEXT (Tolérance de Nivestim chez les patiEnts traités par une chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE (VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der Behandlung malinger Erkrankungen) trials are multicentre, prospective, longitudinal, observational studies evaluating the safety profile of Nivestim™ in 'real-world’ clinical practice. Inclusion criteria include patients undergoing cytotoxic chemotherapy for malignancy and receiving Nivestim as primary or secondary prophylaxis (NEXT and VENICE), or as treatment for ongoing FN (NEXT only). In accordance with European Union pharmacovigilance guidelines, the primary objective is to evaluate the safety of Nivestim™ by gathering data on adverse events in all system organ classes. Secondary objectives include obtaining information on patient characteristics, efficacy of Nivestim™ therapy (including chemotherapy dose intensity), patterns of use of Nivestim™, and physician knowledge regarding filgrastim prescription and the reasons for choosing Nivestim™. Data will be gathered at three visits: 1. At the initial inclusion visit, 2. At a 1-month follow-up visit, and 3. At the end of chemotherapy.Recruitment for VENICE commenced in July 2011 and in November 2011 for NEXT. VENICE completed recruitment in July 2013 with 407 patients, and NEXT in September 2013 with 2123 patients. Last patient, last visit for each study will be December 2013 and March 2014 respectively.DiscussionThe NEXT and VENICE studies will provide long-term safety, efficacy and practice pattern data in patients receiving Nivestim™ to support myelosuppressive chemotherapy in real world clinical practice. These data will improve our understanding of the performance of Nivestim™ in patients encountered in the general patient population.Trial registrationNEXT NCT01574235, VENICE NCT01627990

Safety and efficacy of dicarbamin in patients with early breast cancer receving DAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy in adjuvant setting.

e12012 Background: One of the most serious potential side effects of chemotherapy is neutropenia. Grade 3 and 4 neutropenia is especially problematic because of increased incidence of infections, hospitalization, antibiotic treatment, necessity to reduce therapy intensity. The intensity of adjuvant chemotherapy is the key to successful treatment. Dicarbamin is agent for the prevention of chemotherapy-induced neutropenia. Dicarbamin therapy decreases dystrophic changes in myeloid progenitor cells and decreases the relative number of cells with signs of apoptosis. We conducted an analysis of efficacy of dicarbamin in patients during docetaxel-based chemotherapy. Methods: Between May 2011 and July 2012, 87 patients with early breast cancer were treated with adjuvant DAC regimens (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 every 3 weeks). All patients were female. All patients were treated with these regimens without prophylactic growth factor support. 42 patients of control (group A) were not given any prophylaxis of neutropenia. 45 patients (group B) were given dicarbamin 100 mg/day on day 5 before chemotherapy administration. Treatment with dicarbamin continued for all treatment period. Neutropenia was evaluated with Common Toxicity Criteria, Version 3.0. Results: Median age was 47 (29 – 55). Grade 4 neutropenia was reported in 13 (30.9%) patients treated without dicarbamin (A) and in 8 (17.7%) patients treated with dicarbamin (B). Grade 4 neutropenia was observed in 39 cycles in group A and in 22 cycles in group B (p=0.016). The beneficial effect of dicarbamin was also demonstrated by a quick recovery of granulocytes levels than in controls. In 17 (37.7%) patients treated with dicarbamin granulocytes levels were normal all period of chemotherapy. The dose intensity of chemotherapy was more in group with dicarbamin prophilaxis. The toxicity of dicarbamin was not observed. Conclusions: Dicarbamin is an active agent for prophylaxis of neutropenia without specific toxicity. The intensity of the DAC-chemotherapy was more in group with dicarbamin prophilaxis.

Chemotherapy-induced neutropenia in lung cancer patients: The role of antibiotic prophylaxis

Chemotherapy-induced neutropenia can cause fatal bacterial infections. Colony-stimulating factors (CSFs) are usually recommended as prophylaxis, while routine use of prophylactic antibiotics remains controversial. Based on our literature search in PubMed, quinolones and trimethoprim/sulfamethoxazole were the most frequently used prophylaxis, while CSFs were administered in 22.1% of patients. Lung cancer patients who received prophylactic antibiotics exhibited significantly fewer episodes of febrile neutropenia, fewer documented infections as well as shorter duration of related hospitalisations. Prophylactic use of wide spectrum antibiotics seems effective and should be considered as an alternative strategy in the prevention of chemotherapy-induced neutropenia in lung cancer patients.

XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy

Recombinant granulocyte colony-stimulating factors (G-CSFs) such as filgrastim or lenograstim are being used to treat chemotherapy-induced neutropenia. The aim of the present study was to investigate a new G-CSF, XM02, in comparison to filgrastim in terms of safety and efficacy in the prevention of chemotherapy-induced neutropenia in non-Hodgkin-lymphoma (NHL). A total of 92 patients receiving chemotherapy were randomised in cycle 1 to treatment with daily injections (subcutaneous 5 µg/kg/day) of XM02 (n = 63) or filgrastim (n = 29) for at least 5 days and a maximum of 14 days. In subsequent cycles, all patients received XM02. The mean duration of severe neutropenia (DSN) was 0.5 and 0.9 days in cycle 1 for XM02 and filgrastim, respectively (p = 0.1055). In cycle 1, the incidence of febrile neutropenia (FN) was 11.1% for XM02 and 20.7% for filgrastim (p = 0.1232). The adverse event profile was similar between XM02 and filgrastim. XM02 demonstrated equivalent efficacy and similar safety profile as the reference medication filgrastim. Treatment with XM02 is as beneficial as filgrastim in ameliorating severe neutropenia and FN in patients with NHL receiving chemotherapy. XM02 is safe and well tolerated in the doses applied in this study.

Management of Chemotherapy-Induced Neutropenia: Opportunities for Pharmacist Involvement

Purpose This article highlights the clinical impact of chemotherapy-induced neutropenia (CIN) and reviews the clinical evidence supporting the updated guideline recommendations from leading scientific organizations that focus on cancer care regarding the use of myeloid growth factors to reduce the incidence of febrile neutropenia (FN) from chemotherapy. The aim is to provide insight for practicing pharmacists regarding how they can be more proactive in developing best-practice strategies for the management of CIN as well as the prevention of FN. Summary CIN, the primary dose-limiting toxicity of chemotherapy, is common in many tumor types that are treated with myelosuppressive chemotherapy and occurs with the greatest frequency in the first cycle of treatment. Treatment with myeloid growth factors, or colony-stimulating factors (CSFs), has shown to be effective in reducing the risk, severity, and duration of FN from chemotherapy. Despite recent revisions to various clinical guidelines that have resulted in alignment on the recommendation for prophylactic CSF use in patients with a greater than or equal to 20% risk of developing FN, a gap remains between actual clinical usage and best practice. Pharmacists are key members of multidisciplinary health care teams and are uniquely positioned to evaluate current practice and develop strategies that ensure appropriate CSF use. This paper summarizes the recent changes to CSF guidelines, reviews clinical data that support those changes, and discusses strategies for pharmacist involvement in the management of CIN and FN prevention using real-world examples of improvement initiatives. Conclusion Neutropenia is a dose-limiting toxicity of chemotherapy that has significant implications for effective cancer treatment and patient health outcomes. Pharmacists are uniquely positioned to perform various interventions, which help ensure appropriate CSF use and improve the management of CIN.

Prevention of Chemotherapy-Induced Neutropenia by Special Honey Intake

Febrile neutropenia is a serious side effect of chemotherapy. Colony-stimulating factors (CSFs) are used for primary and secondary treatment in patients with grade 4 neutropenia. The use of CSFs is expensive and accompanied by side effects. In the current study, Life-Mel Honey (LMH) was administered to prevent neutropenia and to reduce the need for CSFs in patients treated with chemotherapy. Thirty cancer patients receiving chemotherapy for primary or metastatic disease were included. All patients had grade 4 neutropenia and were treated with CSFs. The patients repeated the same chemotherapy schedule, with the addition of LMH for 5 d. Blood count was performed weekly. There was no recurrence of neutropenia after LMH intake and no need for treatment with CSFs in 12 (40%) of patients. Eighteen (60%) patients with LMH developed neutropenia grade 4 and were treated with CSFs (p=0.007). Hemoglobin levels remained >11 g/dL during LMH intake in 19 (64%) patients. Only three (10%) patients had thrombocytopenia. Eight (32%) patients reported improvement in quality of life. The use of LMH in patients who are at high risk of developing neutropenia as a result of chemotherapy decreases the risk of pancytopenia and the need for CSFs. LMH is inexpensive, has no side effects, and is easy to administer.