Secondary Granulocyte Colony-stimulating Factor Research Articles

Risk of chemotherapy-induced febrile neutropenia in intermediate-risk regimens: Clinical and economic outcomes of granulocyte colony-stimulating factor prophylaxis.

BACKGROUND: Chemotherapy-induced neutropenia increases the risk of febrile neutropenia (FN) and infection with resultant hospitalizations, with substantial health care resource utilization (HCRU) and costs. Granulocyte-colony stimulating factor (GCSF) is recommended as primary prophylaxis for chemotherapy regimens having more than a 20% risk of FN. Yet, for intermediate-risk (10%-20%) regimens, it should be considered only for patients with 1 or more clinical risk factors (RFs) for FN. It is unclear whether FN prophylaxis for intermediate-risk patients is being optimally implemented. OBJECTIVE: To examine RFs, prophylaxis use, HCRU, and costs associated with incident FN during chemotherapy. METHODS: This retrospective study used administrative claims data for commercial and Medicare Advantage enrollees with nonmyeloid cancer treated with intermediate-risk chemotherapy regimens during January 1, 2009, to March 31, 2020. Clinical RFs, GCSF prophylaxis, incident FN, HCRU, and costs were analyzed descriptively by receipt of primary GCSF, secondary GCSF, or no GCSF prophylaxis. Multivariable Cox regression analysis was used to examine the association between number of RFs and cumulative FN risk. RESULTS: The sample comprised 13,937 patients (mean age 67 years, 55% female). Patients had a mean of 2.3 RFs, the most common being recent surgery, were aged 65 years or greater, and had baseline liver or renal dysfunction; 98% had 1 or more RFs. However, only 35% of patients received primary prophylaxis; 12% received secondary prophylaxis. The hazard ratio of incident FN was higher with increasing number of RFs during the first line of therapy, yet more than 54% of patients received no prophylaxis, regardless of RFs. Use of GCSF prophylaxis varied more by chemotherapeutic regimen than by number of RFs. Among patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone, 76% received primary prophylaxis, whereas only 22% of patients treated with carboplatin/paclitaxel received primary prophylaxis. Among patients with a first line of therapy FN event, 78% had an inpatient stay and 42% had an emergency visit. During cycle 1, mean FN-related coordination of benefits-adjusted medical costs per patient per month ($13,886 for patients with primary prophylaxis and $18,233 for those with none) were driven by inpatient hospitalizations, at 91% and 97%, respectively. CONCLUSIONS: Incident FN occurred more often with increasing numbers of RFs, but GCSF prophylaxis use did not rise correspondingly. Variation in prophylaxis use was greater based on regimen than RF number. Lower health care costs were observed among patients with primary prophylaxis use. Improved individual risk identification for intermediate-risk regimens and appropriate prophylaxis may decrease FN events toward the goal of better clinical and health care cost outcomes. DISCLOSURES: This work was funded by Sandoz Inc., which participated in the design of the study, interpretation of the data, writing and revision of the manuscript, and the decision to submit the manuscript for publication. The study was performed by Optum under contract with Sandoz Inc. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Dr Li is an employee of Sandoz Inc. Drs Bell and Lal and Mr Peterson-Brandt were employees of Optum at the time of the study. Ms Anderson and Dr Aslam are employees of Optum. Dr Lyman has been primary investigator on a research grant from Amgen to their institution and has consulted for Sandoz, G1 Therapeutics, Partners Healthcare, BeyondSpring, ER Squibb, Merck, Jazz Pharm, Kallyope, Teva; Fresenius Kabi, Seattle Genetics, and Samsung.

Effect of Secondary Prophylactic G-CSF on the Occurrence of Febrile Neutropenia in Breast Cancer.

Docetaxel and cyclophosphamide (TC) combination therapy is widely used as adjuvant chemotherapy for early-stage breast cancer and is associated with a high incidence of febrile neutropenia (FN). Granulocyte colony-stimulating factor (G-CSF) is recommended in the primary prevention of febrile neutropenia (FN). This study aimed to evaluate the FN-suppressing effect of G-CSF in patients with breast cancer receiving TC. We performed 272 treatment cycles after FN onset in 106 patients with breast cancer receiving TC. We retrospectively evaluated the effect of G-CSF as secondary prophylaxis. The frequency of FN was calculated based on the treatment cycles to adjust for differences in the number of cycles per case and FN occurrence. FN occurred in 58 cycles (21.3%). The incidence of FN with and without secondary prophylactic G-CSF was 10.1% and 25.9%, respectively (p=0.003). Multivariate analysis showed secondary prophylactic G-CSF administration to be an independent predictor of FN incidence [odds ratio (OR)=0.33, 95% confidence interval (CI)=0.14-0.74, p=0.007]. Secondary prophylaxis with G-CSF is recommended for patients with breast cancer undergoing TC chemotherapy to reduce the incidence of FN.

IVAC +/- R for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era

Introduction Part B of the modified Magrath regimen (ifosfamide, etoposide, and cytarabine; IVAC) with or without rituximab (R) is utilized as a standalone regimen in the management of relapsed/refractory Burkitt lymphoma and other non-Hodgkin lymphomas (NHL). There are no comparative or prospective data and a paucity of retrospective, non-comparative data to support use of this regimen. A small retrospective study described second-line IVAC use without R in a mixed cohort of patients with diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma, suggesting utility as a bridge to hematopoietic cell transplantation (HCT) (Pereira J, et al. Leuk Res. 2006 Jun;30(6):681-5). The activity of this regimen in B-cell NHL, particularly in conjunction with R, and its toxicity remain incompletely described. In this study, we describe our institutional experience with IVAC +/- R in relapsed/refractory B-cell NHL. Methods We reviewed all patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 1 January 2004 and 30 September 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. Patients who received IVAC as part of sequential or alternating chemotherapy were excluded. Standard dosing consisted of ifosfamide 1500mg/m2 IV over 60min days 1-5, etoposide 60mg/m2 IV over 60min days 1-5, cytarabine 2000mg/m2 IV over 3 hours every 12 hours days 1-2, with or without rituximab 375mg/m2 IV day 0 or 1 in 21- to 28-day cycles (Lacasce A, et al. Leuk Lymphoma. 2004 Apr;45(4):761-7). Results Cohort and treatment characteristics are described in Table 1. Among 54 eligible patients (median age 51 years), 76% had DLBCL; 30% had lymphomatous central nervous system involvement at the time of initiating IVAC. Patients had received median 2 prior lines of therapy, with the last dose of the most recent line of therapy administered a median of 3 weeks prior to initiating IVAC. Patients received median 2 cycles of IVAC +/- R; 48% received IVAC-R. Prophylactic antimicrobials with cycle 1 were utilized in 94%. Most patients received herpesvirus- (81%) and Pneumocystis- (80%) directed prophylaxis; broad-spectrum prophylaxis with a fluoroquinolone was less common (24%). Primary granulocyte colony stimulating factor (GCSF) was utilized in 93% of patients with cycle 1; primary or secondary GCSF was utilized in 94% of cycles. Efficacy outcomes are described in Table 1. Objective response rate (ORR) among 46 evaluated patients was 48%; 17% achieved CR. ORR did not vary significantly between patients who did or did not receive R (58% vs 42%; p = 0.5) but was associated with number of IVAC cycles administered (among responders, 69% received 3-4 cycles while 31% received 1-2 cycles; p < 0.001). At median follow-up of 22 months, median progression-free survival (PFS) and overall survival (OS) were 3.1 months and 4.9 months, respectively (Figure). In Cox proportional hazard regression analysis of survival, patients who received R with every cycle (p = 0.025) and received 3 or more cycles (p < 0.001) experienced significantly longer PFS. Patients who achieved CR (p < 0.001) or PR (p = 0.003), received R with every cycle (p < 0.001), received 3 or more cycles (p < 0.001), or underwent subsequent HCT or CAR-T cell therapy (p = 0.001) experienced significantly longer OS. Toxicity outcomes are described in Table 2. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common, regardless of number of cycles received. Febrile neutropenia (FN) occurred in 65% of patients and complicated 47% of cycles; documented infection occurred in 44%. Risk of FN and infection did not appear to be influenced by use of antimicrobial or GCSF prophylaxis. Grade ≥ 3 elevations in AST/ALT or total bilirubin were uncommon (5.6% and 9.3%, respectively). Neurotoxicity attributed to cytarabine or ifosfamide occurred in 17% of patients and was usually low-grade; hemorrhagic cystitis occurred in one patient. In patients for whom cause of death was documented (n = 37), mortality was attributed to a treatment-related complication in 19%. Conclusion IVAC-R may be a useful bridging therapy for patients with relapsed/refractory B-cell NHL who are planned for HCT. However, its potential for profound hematologic toxicity and life-threatening complications despite prophylactic measures requires careful consideration of less toxic alternatives. Disclosures Straus: Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A retrospective analysis of nadir‐neutropenia directed pegylated granulocyte‐colony stimulating factor on febrile neutropenia rates in (neo)adjuvant breast cancer chemotherapy regimens

Pegfilgrastim, a pegylated granulocyte colony-stimulating-factor (GCSF), reduces chemotherapy morbidity and mortality in early stage breast cancer. The optimal approach to individual patient selection for GCSF is unknown, in particular whether secondary GCSF should be given after asymptomatic neutropenia, or only after febrile neutropenia (FN). To determine if preplanned nadir blood counts and subsequent nadir-neutropenia directed GCSF was effective to reduce rates of FN associated with (neo)adjuvant breast cancer chemotherapy. We also aimed to describe (neo)adjuvant chemotherapy and GCSF prescribing practices at our institution. This was a retrospective electronic medical record review. The rate of FN with secondary GCSF after cycle 1 nadir-neutropenia <1.0 × 109 cells/L was compared with the rate of FN in patients who did not have cycle 1 nadir blood counts or secondary GCSF, and analyzed according to patient and treatment data. Between 11/4/2011 and 22/4/2018, 584 patients received (neo)adjuvant chemotherapy. Over all rates of FN were 17%, compared with 9% in patients who received primary GCSF. Rates of FN were highest in docetaxel/carboplatin/trastuzumab (TCH, 27%) and docetaxel/cyclophosphamide (TC, 27%). There were 268 patients (46%) who received primary GCSF and 238 patients (41%) who received secondary GCSF. Rates of FN did not differ between patients who received nadir-neutropenia directed secondary GCSF (6/125, 5%, 95% CI 1.1-8.6), and those who did not have nadir blood counts or secondary GCSF (0/49, 0%, 95% CI not calculable) (P = .1186). GCSF use was associated with lower rates of non-FN hospital admissions. Patients ≥65 years were more likely to have FN and non-FN admissions. Two of three treatment related deaths occurred due to FN. In this population, nadir-neutropenia directed secondary GCSF was not associated with reduced rates of FN. Observed rates of FN >20% in TC and TCH in routine clinical practice should guide primary GCSF use in accordance with international guidelines.

Maintaining Dose Intensity of Adjuvant Chemotherapy in Older Patients With Breast Cancer

IntroductionMaintaining the relative dose intensity (RDI) of adjuvant chemotherapy at ≥ 85% has been associated with improved treatment outcomes in early-stage breast cancer (ESBC). Increasing evidence has suggested that patients aged ≥ 65 years can maintain the optimal RDI for standard chemotherapy regimens. The present study investigated the RDI of newer adjuvant chemotherapy regimens in this demographic. Patients and MethodsWe retrospectively analyzed the data from 281 patients aged ≥ 65 years with a diagnosis of ESBC who had received adjuvant chemotherapy across 3 sites in Queensland, Australia from 2010 to 2015. The primary endpoint was the proportion of patients who had received an RDI of ≥ 85%. ResultsThe median age at diagnosis was 68 years (range, 65-85 years), with 36.3% aged > 70 years. The patient characteristics included tumor stage T3 or T4 in 17% and node-positive disease in 60%. The common chemotherapy regimens included docetaxel/cyclophosphamide (23%), 5-fluorouracil/epirubicin/cyclophosphamide plus docetaxel or paclitaxel (17%); Adriamycin/cyclophosphamide/weekly paclitaxel (38%); and docetaxel/carboplatin/trastuzumab (11%). Primary (15%) and secondary (54%) granulocyte colony-stimulating factor (G-CSF) was used. An RDI of ≥ 85% was achieved in 63% of the patients. Significant associations were noted between a reduced RDI and age ≥ 70 years (P < .001), Charlson comorbidity index ≥ 1 (P = .043), initial dose reductions (P = .01), secondary G-CSF use (P = .45), hospital admission (P < .001), and febrile neutropenia (P = .007). Treatment-related toxicities were the most common reason for noncompletion, with high rates of hospital admissions (46%) and febrile neutropenia (22%). ConclusionOur findings suggest that patients aged ≥ 65 years with ESBC can maintain an optimal RDI with modern chemotherapy regimens. Appropriate geriatric assessment and the use of supportive measures such as G-CSF could better assist select groups to maintain an optimal dose intensity.

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis in chemotherapy-induced febrile neutropenia among breast cancer and Non-Hodgkin's lymphoma patients under Taiwan's national health insurance system.

The beneficial effects of granulocyte colony-stimulating factor (G-CSF) prophylaxis on reducing the risk of chemotherapy-induced febrile neutropenia (CIFN) were well documented throughout the literature. However, existing data regarding its cost-effectiveness were conflicting. We estimated the cost-effectiveness of G-CSF prophylaxis in CIFN under Taiwan's National Health Insurance (NHI) system. Data on clinical outcomes and direct medical costs were derived for 5179 newly diagnosed breast cancer and 629 non-Hodgkin's lymphoma (NHL) patients from the NHI claims database. Patients were further categorized into three subgroups as "primary-", "secondary-" and "no -" prophylaxis based on their patterns of G-CSF use. Generalized estimating equations were applied to estimate the impact of G-CSF use on the incidence of CIFN. The incremental cost-effectiveness ratios of primary and secondary prophylactic G-CSF use were calculated and sensitivity analyses were performed. Primary prophylaxis of G-CSF decreased the incidence of CIFN by 27% and 83%, while secondary prophylaxis by 34% and 22% in breast cancer and NHL patients, respectively. Compared with those with no prophylaxis, the incremental cost per CIFN reduced in primary prophylaxis is $931 and $52 among patients with breast cancer and NHL, respectively. In contrast, secondary prophylaxis is dominated by no prophylaxis and primary prophylaxis in both cancer patients. Primary but not secondary prophylactic use of G-CSF was cost-effective in CIFN in breast cancer and NHL patients under Taiwan's NHI system.

Chemotherapy treatment patterns and neutropenia management in gastric cancer.

Potentially myelosuppressive doublet and triplet chemotherapy combination regimens are considered the most active treatments in gastric cancer. This multicenter prospective observational study was designed to gain insight into the chemotherapy regimens being used in Europe and to evaluate neutropenia management in patients identified as at high risk for febrile neutropenia (FN). Eligible patients had gastric cancer, were scheduled for ≥ 3 cycles of myelosuppressive chemotherapy, and had an investigator-assessed overall FN risk ≥ 20%. Data were collected for up to ten cycles. The primary endpoint was the proportion of patients who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis (defined as G-CSF initiated on days 1-7 of cycle 1). Secondary endpoints included FN incidence, chemotherapy administration, and G-CSF use. Of 199 patients who met the eligibility criteria and started at least one cycle of chemotherapy, mean age was 63 years, 76% were men, 83% had an ECOG score of 0 or 1, 54% had metastatic disease, and 24% had received prior chemotherapy. A total of 27 different backbone regimens were given; the most common regimen was modified docetaxel, cisplatin, and 5-fluorouracil (DCF). Despite all patients having been identified as having a ≥ 20% FN risk, only 70 (35%) received G-CSF primary prophylaxis. FN occurred in 14 patients overall (7%). Most FN events occurred in patients who received DCF/modified DCF (9/14 events, 64%). The results of this study reveal a high use of myelotoxic treatment regimens in gastric cancer in Europe and low adherence to clinical practice guidelines for the use of primary and secondary G-CSF prophylaxis for FN.

Abstract P6-07-06: Primary prophylaxis of febrile neutropenia during adjuvant docetaxel and cyclophosphamide (TC) chemotherapy for breast cancer

Abstract Background: The combination of docetaxel and cyclophosphamide (TC) for adjuvant treatment of early stage breast cancer improves overall survival compared with doxorubicin and cyclophosphamide (AC) (Jones et al., 2006). Although cardiotoxicity is avoided with TC, the risk of febrile neutropenia (FN) is higher. For TC, reported rates of FN without prophylactic granulocyte colony-stimulating factor (G-CSF) range from 5% in the phase III trial to as high as 46% in retrospective chart reviews. G-CSF is not covered by our provincial cancer funding agency for primary prophylaxis of FN with TC chemotherapy, however it is often prescribed for patients with private insurance. Our aims were twofold: i) to determine the incidence of FN with TC chemotherapy with and without prophylactic G-CSF or antibiotics in two Ontario comprehensive cancer centres, and ii) to evaluate the cost-effectiveness of primary prophylaxis with G-CSF vs. antibiotics. Methods: Patients who received adjuvant TC chemotherapy between January 1, 2008 and December 31, 2012 were identified through pharmacy databases. Electronic charts were retrospectively reviewed to extract patient characteristics, treatment details including G-CSF and antibiotic use, as well as incidence of FN and duration of hospitalization. A Markov model comparing primary G-CSF prophylaxis, primary antibiotic prophylaxis and secondary G-CSF prophylaxis was constructed to compare the cost-effectiveness of these strategies over a four cycle time horizon. Costs were based on resource utilization from this retrospective cohort and supplemented by the published literature, adjusted to 2012 Canadian dollars. The model took the perspective of the third party payer. Both one-way and probabilistic sensitivity analyses were performed. Results: 340 patients were treated with TC over the study period. Of the 73 (21%) who did not receive any primary prophylaxis with G-CSF or antibiotics, 23 (32%) developed FN requiring hospitalization and treatment with intravenous antibiotics. However, only 2 of the 192 patients (1%; P &amp;lt;0.0001) who received primary G-CSF prophylaxis (funded by the patient or a third party payer), and 6 of the 53 patients (11%; P &amp;lt;0.01) who received primary antibiotic prophylaxis (97% receiving ciprofloxacin) developed FN. Age ≥65 was a significant risk factor for FN in the absence of G-CSF (56% vs. 25%, P = 0.02). The results of the cost-effectiveness analysis will be presented at the meeting. Conclusions: The FN rate associated with TC chemotherapy without primary prophylaxis exceeds 30% but may be reduced with prophylactic antibiotics or G-CSF. Unless prophylactic antibiotics are substantially more cost-effective than prophylactic G-CSF for TC chemotherapy in a particular region or country, primary prophylactic G-CSF should be funded, given its greater effectiveness than antibiotics and the global need to minimize the emergence of antibiotic resistance. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-06.

Reply to N. Lathia et al

Lathia et al comment on our meta-analysis of granulocyte colony-stimulating factor (G-CSF) primary prophylaxis reported in Journal of Clinical Oncology in 2007, demonstrating significant reductions in infection-related mortality, all-cause early mortality, and febrile neutropenia in patients randomly assigned to receive primary G-CSF prophylaxis compared with those receiving secondary G-CSF prophylaxis or untreated controls. Among the 17 eligible randomized controlled trials, relative risk for febrile neutropenia was 0.54 (95% CI, 0.43 to 0.67) overall and 0.61 (95% CI, 0.53 to 0.72) for filgrastim. Despite the use of different statistical programs and exclusion of certain trials, Lathia et al arrived at estimates of treatment effect nearly identical to ours. To consider all relevant studies, we included the study by Zinzani et al, because it reported clinically relevant infections during the period of neutropenia, a better approximation for febrile neutropenia than the alternative of including all neutropenic events. As Lathia et al confirm, removal of the Zinzani et al study from the meta-analysis would not only reduce heterogeneity but also have no clinically meaningful impact on estimated treatment effect, nor would it alter any study conclusions. No significant heterogeneity was observed in filgrastim studies, regardless of the inclusion of the study by Zinzani et al. In addition, because Zinzani et al reported no meaningful beneficial effect of G-CSF on early mortality or infection-related mortality, inclusion of this study in the meta-analysis is the more conservative approach. For each trial using a 2 2 factorial design, rather than assessing the visual effect of point estimates as Lathia et al suggest, we formally assessed interaction between randomization strata. Statistically significant interaction between subgroups was determined by comparing the ratio of the difference in the natural logarithm of relative risks and the SE of the difference in log relative risks with the standard normal distribution. Significant interaction was observed for survival between chemotherapy and G-CSF assignments in the Osby et al study but not in the Fossa et al study. Therefore, separate comparisons of the results for the Osby et al study were included. Although we recognize that investigators may differ in their approaches to the analysis in this circumstance, no meaningful differences in effect estimates were observed with either approach. The minimal differences in estimated rates for the two studies noted by Lathia et al are most likely attributable to rounding differences, use of differing statistical programs, and varying presence of updated study information. Overall, it is gratifying that Lathia et al have essentially replicated and confirmed the results of our meta-analysis.

G-CSF as Secondary Prophylaxis of Febrile Neutropenia In the Management of Advanced-Stage Hodgkin Lymphoma Treated with ABVD Chemotherapy: A Decision Analysis.

AbstractAbstract 3831 Background:ABVD is the standard treatment for advanced stage Hodgkin Lymphoma (HL) with rates of complete remission achieved in the majority of patients treated. Current practice guidelines (American Society of Clinical Oncology, Smith TJ et al. JCO 2008) recommend the use of granulocyte colony stimulating factor (G-CSF) in secondary prophylaxis despite lack of a survival benefit and potential toxicities, including bleomycin pulmonary toxicity (BPT). Recently, small retrospective series and expert opinion (Horning S, ASH Education Program Book 2007) advocate for the omission of G-CSF, although this approach has not been prospectively studied. The purpose of this study was to perform a decision analysis that compared the life expectancy and quality-adjusted life expectancy of advanced-stage HL managed with and without secondary prophylactic G-CSF. Methods:We constructed a decision-analytic model to compare the strategy of secondary prophylaxis with G-CSF to a strategy of no G-CSF with severe neutropenia for a hypothetical cohort of 40 year-old patients with clinical stage IIB to IV Hodgkin Lymphoma treated with 8 cycles of ABVD chemotherapy. Markov models were used to simulate a 2-year clinical course of patients. Baseline probability estimates were derived from a systematic review of relevant published studies. Utilities for various health states were derived from expert opinion. One-way sensitivity analysis was performed on key variables such as severe neutropenia, febrile neutropenia and bleomycin pulmonary toxicity, as well as the utilites associated with these health states. Results:The life expectancy was 1.858 years for the G-CSF strategy and 1.875 years for no G-CSF, yielding a net expected benefit of 0.017 years for no G-CSF use in severe neutropenia. The quality-adjusted life expectancy was 1.371 years for the G-CSF strategy and 1.408 years for no G-CSF with a net expected benefit for no G-CSF of 0.037 QALYs. On microsimulation (10,000 trials), 96% of the simulations showed that the no G-CSF strategy is preferred to the use of G-CSF. This analysis was not sensitive to the odds ratio of lung toxicity with G-CSF, the hazard ratios of febrile neutropenia and severe neutropenia, the probability of death from febrile neutropenia, or the utilities associated with bleomycin pulmonary toxicity, hospitalization for febrile neutropenia and musculoskeletal pain from G-CSF. Conclusions:While the difference between the two strategies is small, our model predicted that for a 40 year-old patient with advanced-stage Hodgkin Lymphoma treated with ABVD chemotherapy, the strategy of avoiding use of G-CSF with severe neutropenia is preferred. This finding is robust across a wide range of sensitivity analyses. Disclosures:No relevant conflicts of interest to declare.

Evaluation of treatment-related acute myeloid leukemia or myelodysplastic syndrome risk following standard chemotherapy versus dose-intensified chemotherapy plus granulocyte colony-stimulating factor.

Abstract Abstract #6135 Background Retrospective studies of the risk of acute myeloid leukemia or myelodysplastic syndrome (t-ML) in cancer patients receiving granulocyte colony-stimulating factor (G-CSF) have reported conflicting findings. To evaluate the impact of chemotherapy with G-CSF support on both overall survival (OS) and the risk of t-ML in patients with breast cancer, an exhaustive literature review and meta-analyses were conducted of prospective, randomized, controlled clinical trials.&amp;#x2028; Methods Electronic databases including Medline, EMBASE, BIOSIS were searched through January 2008 identifying 5410 articles for initial screening. Eligibility criteria included: patients with non-myeloid malignancies receiving chemotherapy (CT) with or without G-CSF (filgrastim or pegfilgrastim) with adequate follow-up (≥2 years). Of the 65 publications identified, 6 were from unique, prospective, randomized, controlled trials in patients with breast cancer. Excluded reports consisted of retrospective studies, duplicate reports and studies with either no control group or with stem cell transplantation. Meta-analyses were performed based on the method of Mantel and Haenszel with summary estimates [±95% CLs] provided for both relative risk (RR) and risk difference (RD). Any asymmetry in the associated funnel plots was assessed utilizing the Egger regression intercept.&amp;#x2028; Results A total of 2848 and 2839 patients were randomized to receive CT with G-CSF support versus standard CT, respectively. In the only trial to randomize breast cancer patients receiving the same CT to prophylactic G-CSF versus no primary or secondary prophylactic G-CSF, t-ML was reported in 1/254 (0.4%) receiving CT plus G-CSF compared to 0/243 in those not receiving G-CSF. The remaining 5 studies compared treatment with different CT intensities permitting dose intensification with G-CSF support. Meta-analyses for both OS and t-ML were performed comparing dose intensified CT with G-CSF support to standard CT without G-CSF. No significant heterogeneity was observed across trials for both outcomes. A significant increase in OS was found among patients receiving CT with G-CSF support (RR=0.88; 0.80-0.98; P=.020). A non-significant increase in the incidence of t-ML was observed among patients receiving dose intensified CT with G-CSF support (RR=1.94; 0.89-4.22; P=.097 and RD=.003; P=.090). Funnel plot analysis revealed evidence for a publication bias for t-ML reporting studies (t=3.69; 2 sided P=.034).&amp;#x2028; Conclusions Of over 5000 studies reviewed, 1 prospective study with the same CT in both study arms found no significant increase in the risk of t-ML with G-CSF support. Meta-analyses demonstrated that chemotherapy with G-CSF support results in a significant improvement in OS with a non-significant increase in t-ML. There is insufficient data to definitively examine the role of G-CSF on t-ML risk independent of the concomitant use of dose intensified chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6135.

Routine prophylactic granulocyte colony stimulating factor (GCSF) is not necessary with accelerated (dose dense) paclitaxel for early breast cancer

Prophylactic granulocyte colony stimulating factor (GCSF) is recommended with accelerated adjuvant chemotherapy but is expensive and causes bone pain. We have reviewed a series of patients with early breast cancer treated with accelerated 2-weekly paclitaxel without routine GCSF to assess its need. Patients receiving accelerated (dose dense) paclitaxel 175 mg/m2 2 weekly for 4 courses as adjuvant/neoadjuvant treatment for early breast cancer were treated electively without prophylactic GCSF, and monitored for absolute neutrophil count (ANC) before each cycle, grade and duration of neutropenia, incidence of neutropenic sepsis, treatment delays and requirements for secondary GCSF. Results were compared with prior patients given prophylactic GCSF. Of the 61 patients, 42 (69%) did not require prophylactic GCSF. Mild/moderate neutropenia was more common than in the prior group given GCSF, but secondary GCSF was required in only 6 (10%) patients due to grade 3 neutropenia and in 12 (20%) with grade 2 neutropenia. There were no episodes of neutropenic sepsis and no dose reduction or treatment delay was required. Accelerated paclitaxel in breast cancer patients without prophylactic GCSF is safe, avoids side effects, reduces costs and is not associated with an increase risk of neutropenic sepsis or treatment delays.

Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m(2) and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohn's disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34(+) cells/microl differed significantly by disease. Collected CD34(+) cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34(+) cell yields, respectively. Ex vivo CD34(+) cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34(+) cells/microl correlated positively with initial CD34(+) cells/kg/apheresis and enriched product CD34(+) cells/kg. Mean WBC and platelet engraftment (ANC>0.5 x 10(9)/l and platelet count >20 x 10(9)/l) occurred on days 9 and 11, respectively. Infused CD34(+) cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34(+) cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.

The Safety of Full-Dose Chemotherapy with Secondary Prophylactic Granulocyte Colony Stimulating Factor (G-CSF) Following a Prior Cycle with Febrile Neutropenia

Secondary prophylactic administration of recombinant human granulocyte colony stimulating factor (G-CSF) following an episode of febrile neutropenia is recommended if maintenance of dose-intensity is desired. This policy was adopted in our center in patients treated with an intent for cure or durable complete response. The purpose of this study was to evaluate the safety and feasibility of this policy. Patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. Fifty-one patients who developed febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with the support of filgrastim (300 or 480 mg/d sc for at least 10 consecutive days). Diagnoses included lymphoma (n = 19), breast cancer (n = 15), germ cell tumor (n = 7), small-cell lung cancer (n = 5), and other solid tumors (n = 5). The incidence of febrile neutropenia during the first cycle given with filgrastim support (N1) was 8/51 (16%). Intravenous antibiotics were required for 3-7 d (median, 4.5 d). During the following cycle (N2), febrile neutropenia developed in 4/41 (10%) patients. Intravenous antibiotics were given for 2, 4, 5, and 7 d. Other dose-limiting toxicities developed in 1/51 patients who received N1 and in 1/41 patients who received N2. There was no drug-related death associated with either cycle. In conclusion, a policy of full-dose chemotherapy with secondary G-CSF support in patients who develop febrile neutropenia following moderately myelotoxic chemotherapy is relatively safe and feasible.

Synergistic Factors for Stem Cell Proliferation: Further Studies of the Target Stem Cells and the Mechanism of Stimulation by Interleukin-1, Interleukin-6, and Granulocyte Colony-Stimulating Factor

Serial observations of blast cell colony development from spleen cells of mice treated with 5-fluorouracil (5-FU) four days earlier revealed that either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This activity was essentially indistinguishable from the effect of interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system, an effect that we have ascribed previously to a shortening of the G0 period of the dormant stem cells. We also analyzed the time courses of colony formation from cultures of day-2 post-5-FU marrow cells supported by IL-1 alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of colonies and increased the numbers of multilineage colonies relative to cultures of IL-3 alone. This observation, together with our previous data from the human system, suggests that the synergistic effect of IL-1 is likely due to induction of secondary growth factors, including IL-6 and G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was confirmed by analysis of the cycling status of progenitor cells in short-term culture. While neither IL-3 nor IL-6 alone had any effect on the cycling status, the combination of factors resulted in a rapid recruitment of quiescent cells into cell cycle (within 48 hours) as represented by a twofold increase in the numbers of multipotential progenitors and a significant increase in the sensitivity of these cells to 3H-thymidine with high specific activity. Combinational testing of all of these synergistic factors revealed that the target cell populations for the IL-1, IL-6, and G-CSF overlap considerably, suggesting that they all may act through a common mechanism. This is further supported by our finding that cells from blast cell colonies grown in the presence of a combination of any one of the synergistic factors with IL-3 replate with higher efficiency and yield more multilineage secondary colonies than those from colonies grown in IL-3 alone. These findings provide further evidence that IL-1, IL-6, and G-CSF serve to integrate the immediate host responses to infection through augmentation of effector cells and antibody production as well as the longer term host responses by recruitment of dormant hemopoietic stem cells into active cell cycling.

Synergistic factors for stem cell proliferation: further studies of the target stem cells and the mechanism of stimulation by interleukin-1, interleukin-6, and granulocyte colony-stimulating factor

Serial observations of blast cell colony development from spleen cells of mice treated with 5-fluorouracil (5-FU) four days earlier revealed that either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This activity was essentially indistinguishable from the effect of interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system, an effect that we have ascribed previously to a shortening of the G0 period of the dormant stem cells. We also analyzed the time courses of colony formation from cultures of day-2 post-5-FU marrow cells supported by IL-1 alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of colonies and increased the numbers of multilineage colonies relative to cultures of IL-3 alone. This observation, together with our previous data from the human system, suggests that the synergistic effect of IL-1 is likely due to induction of secondary growth factors, including IL-6 and G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was confirmed by analysis of the cycling status of progenitor cells in short-term culture. While neither IL-3 nor IL-6 alone had any effect on the cycling status, the combination of factors resulted in a rapid recruitment of quiescent cells into cell cycle (within 48 hours) as represented by a twofold increase in the numbers of multipotential progenitors and a significant increase in the sensitivity of these cells to 3H-thymidine with high specific activity. Combinational testing of all of these synergistic factors revealed that the target cell populations for the IL-1, IL-6, and G-CSF overlap considerably, suggesting that they all may act through a common mechanism. This is further supported by our finding that cells from blast cell colonies grown in the presence of a combination of any one of the synergistic factors with IL-3 replate with higher efficiency and yield more multilineage secondary colonies than those from colonies grown in IL-3 alone. These findings provide further evidence that IL-1, IL-6, and G- CSF serve to integrate the immediate host responses to infection through augmentation of effector cells and antibody production as well as the longer term host responses by recruitment of dormant hemopoietic stem cells into active cell cycling.