G-CSF Arm Research Articles

A comparison of chemo-free strategy with G-CSF plus plerixafor on demand versus intermediate-dose cyclophosphamide and G-CSF as PBSC mobilization in newly diagnosed multiple myeloma patients: An Italian explorative cost Analysis

BackgroundUpfront single or tandem ASCT still represents an integral part of treatment for patients with multiple myeloma. The combination of intermediate dose (ID) - cyclophosphamide plus G-CSF, has been considered the standard method as mobilization regimen. No prospective randomized clinical trials have compared efficacy and costs using ID - cyclophosphamide against a chemo-free mobilization strategy with G-CSF and plerixafor on demand. MethodsA prospective single arm of 20 patients enrolled in three Italian Centers mobilized with G-CSF plus plerixafor on demand was compared with a retrospective historical control arm of 30 patients mobilized with ID - cyclophosphamide (4 g/sqm) and G-CSF. Costs of the prospective arm was compared with the ones of the retrospective control arm with the aim to collect ≥4 × 106/kg CD34 + . The exploratory cost analysis was performed using microcosting specific inputs of G-CSF plus plerixafor on demand versus ID - cyclophosphamide + G-CSF considering pre-apheresis, peri-apheresis and post-apheresis session. ResultsMobilization with ID - cyclophosphamide and G-CSF resulted in a significantly higher CD34+ peak mean on day 1 yield (119 CD34+ μL vs 67.3; p = 0.06) and in total average CD34+ yield (mean collection 10.6 × 106/kg vs 5.8 × 106/kg; p = 0.004) compared to patients mobilized with G-CSF and plerixafor. There was no significant differences (p = 0.36) in the two groups of patients collecting ≥ 4 million CD34+/Kg with ID - cyclophosphamide and G-CSF (93.3 %) vs G-CSF and plerixafor (90.0 %). None of the patients undergoing G-CSF and plerixafor mobilization had febrile neutropenia compared with 7 patients who received ID - cyclophosphamide and G-CSF (0% vs 23 %, p = 0.03) who had a median of 5 days hospitalization (range 4–6). All patients proceeded to ASCT with a mean of 3.6 CD34+/kg infused for G-CSF and plerixafor arm and 4.4 CD34+/kg for the ID - cyclophosphamide + GCSF group (p = 0.37) with a median time to ANC and PLT engraftment not different in the two groups. Total costs of a mobilizing strategy using a combination of G-CSF and plerixafor on demand was 12.690 euros compared to 16.088 euros with ID - cyclophosphamide and G-CSF (p = 0.07); in particular, mobilization cost components were significantly lower for G-CSF and plerixafor vs G-CSF and ID - cyclophosphamide for hospital stay (3080 euros vs 9653 euros; p < 0.001) whereas for mobilizing agent, there was a significative difference with 5470 euros for G-CSF and plerixafor use due to the cost of plerixafor compared with 1140 euros for ID - cyclophosphamide and G-CSF treatment (P = 0.001). ConclusionsOur data demonstrate that in patients with multiple myeloma eligible for ASCT, a chemo-free mobilization with G-CSF and plerixafor on demand is associated with efficacy in PBSC collection and optimal safety profile with similar average costs when compared to a chemo-mobilization with ID - cyclophosphamide. A prospective randomized multicenter study could address which is the most cost-effective strategy for this setting of patients. Clinical Trial RegistryEudract Number EudraCT 2013−004690-27.

Increased Efficacy of Chemomobilization with Intermediate Dose Cytarabine + G-CSF Compared to G-CSF Alone for Patients with Multiple Myeloma: Results of a Prospective, Randomized Trial

INTRODUCTIONHigh-dose therapy with autologous stem cell support (autologous stem cell transplantation, autoSCT) remains the standard of care for eligible patients with multiple myeloma (MM). Planned tandem autoSCT which can also be considered for all transplant candidates requires collection of at least 5 x 10^6 CD34+ cells/kg. Randomized trials comparing chemomobilization with use of cyclophosphamide (CY) + G-CSF to G-CSF alone did not demonstrate clear advantage of addition of CY to growth factor. In recent years, intermediate-dose cytosine arabinoside (ID-AraC) + G-CSF has been proposed, showing high mobilization potential, as demonstrated in retrospective analysis (Giebel et al, Bone Marrow Transplant 2013, 48: 915-21). The goal of this prospective, randomized trial (ClinicalTrials.gov identifier: NCT01908621) was to compare the efficacy of ID-AraC + G-CSF with G-CSF alone in patients with MM referred for double autoSCT. METHODSThe inclusion criteria were set as follows1) the diagnosis of MM, 2) age 18-65 years, 3) at least partial remission achieved after one or more lines of therapy including six or more cycles containing components like thalidomide, lenalidomide , bortezomib, or melphalan, 4) planned tandem autoSCT procedure.The proportion of patients with stem cell yield of at least 5 × 10^6 CD34+ cells/kg was the primary study end-point.Mobilization regimens were as follows1) ID-AraC arm - AraC 2 x 0.4 g/m2 on days 1,2 (total 1.6 g/m2) + filgrastim 10 ug/kg/day starting from day 5; 2) G-CSF arm - filgrastim 10 μg/kg/day for five consecutive days. Leukaphereses were started when the level of circulating CD34+ cells in peripheral blood (PB) reached at least 10/uL and were continued for the maximum period of three days or until reaching the target CD34+ cell yield. Leukaphereses were performed using Spectra Optia Apheresis System, Mononuclear Cell Collection Procedure (Therumo BCT Inc., Lakewood, CO, USA), processing 2 total blood volumes. RESULTSBetween March 2013 and March 2016, 44 and 46 patients were randomly assigned to ID-AraC and G-CSF study arm, respectively. Patients in the ID-AraC arm were younger (median age 56 years, range (33-65) for ID-AraC and 60 years (37-65) for G-CSF, p=0.04). The groups did not differ in terms of MM remission status at mobilization (p=0.3), the number of preceding lines of chemotherapy (p=0.5) and the frequency of preceding radiotherapy (p=0.4).The level of CD34+ cells in PB required to start leukaphereses was achieved in all patients in the ID-AraC arm and in 44 (96%) of them in the G-CSF arm, p=0.2.In the ID-AraC group, 43 patients (98%) collected at least 5 x 10^6 CD34+ cells/kg compared to 32 patients (70%) in the G-CSF group (p=0.0003). In a multivariate model adjusted for age, the use of G-CSF alone was independently associated with increased risk of mobilization failure (Odds ratio = 17.5; 95% CI = 2.1-144.9; p=0.007).The median peak number of circulating CD34+ cells was 346 (11-1044)/µL vs. 40 (1-326)/µL (p<0.000001), while the median number of collected CD34+ cells was 20.2 (2.9-59.4) x10^6/kg vs. 5.9 (0-11) x10^6/kg, respectively (p<0.000001). A single apheresis was sufficient to achieve the threshold number of harvested CD34+ cells in 37 of cases (86%) after ID-AraC+G-CSF compared to 13 (41%) after G-CSF alone (p=0.00008). The median day of the first apheresis was 13 (range, 12-15; SD=0.7) after ID-AraC. CONCLUSIONSMobilization with ID-AraC + G-CSF is associated with significantly higher efficacy than G-CSF alone. In the studied group it allowed for collection of CD34+ cell number adequate for tandem autoSCT in almost all MM patients, usually with a single leukapheresis. This study provides the first evidence coming from prospective, randomized trial for the advantage of chemomobilization over G-CSF monotherapy in terms of proportion of patients achieving CD34+ yield sufficient for autoSCT. DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide with or without Erythropoietin and Granulocyte-Colony Stimulating Factor Shows Efficacy in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndrome with or without Del 5q, Refractory or Unlikely to Respond to Erythropoietin. Results of a HOVON89 Phase II Randomized Multicenter Study. (EudraCT 2008-002195-10)

▪Purpose: This randomized phase II study (HOVON89) in patients with low/int-1 risk MDS refractory or unlikely to respond to erythropoietin and granulocyte-colony stimulating factor (EPO/G-CSF) assessed efficacy and safety of lenalidomide without (Arm A) or with EPO+/-G-CSF (Arm B) in case of no erythroid response after 4 cycles.Patients and methods: In total 200 patients were randomly 1:1 assigned to either Arm A or Arm B. All patients were treated with lenalidomide (10 mg/day/day 1-21) for a minimum of 6 months in arm A and 12 months in arm B or until loss of response or disease progression. Patients in arm B without hematological improvement-erythroid (HI-E) after 4 cycles received EPO (30,000 IU/wk). In those patients who did not show HI-E after 6 months, EPO was increased to 60,000 IE/wk. G-CSF (3x 300-480 µg/wk) was added if no HI-E was reached at 8 month. The current pre-final evaluation was based on the first180 patients and included 85% non-del5q MDS and15% patients with isolated del5q. The median age was 71years (range 38-89). No differences were observed between both arms regarding sex (55% male), WHO PS, WHO diagnostic subgroup and IPSS, baseline Hb, WBC, platelets, endogenous erythropoietin level, pretreatment with EPO+/-G-CSF (67% of the patients were pretreated) and pre-study transfusions. Patients had received a median of 13 (range 0-72) units of RBC and 4 (range 0-13) within 8 weeks for prior study entry.Results: Adverse events were consistent with the known safety profile of lenalidomide/EPO/G-CSF. HI-E according to IWG criteria was achieved in 38% and 41% of the patients for arm A and B, respectively (p = 0.46). HI-E was significantly lower in non-del5q versus del5q patients (33% vs 78%, respectively). Time-to-HI-E was 3.1 months (median; range 1.6-12.3) for both arms with a median duration of 10 months (range 1 - 76). The median PFS was 14.4 vs 15.4 months in arms A and B (p=0.43). OS was 51.1 and 37.7 months for arm A and B (p=0.09). At 2 years 17% of patients had progressed to AML (no differences between arms). The median FU of patients still alive is 31 months. PFS and OS was significantly longer in those who achieved HI-E, (median 13 vs 19 months, p=0.02 for PFS and median 31 vs 63 months for OS, p<0.001); non-responders vs responders). A Landmark analysis at 12 month confirms a significant prolonged OS in patients who achieved HI-E (28 and 51 months, p<0.002, non-responders vs responders). Endogenous erythropoietin level, pretreatment with EPO/G-CSF, and WHO subgroup did not predict for HI-E, PFS and OS. However, an IPSS of 0 was favorable in comparison to a score of 0.5-1.0 (p=0.02). To better predict response we are currently analyzing baseline flowcytometry and NGS data.Conclusion: Lenalidomide yields sustained HI-E in 33% of patients with non-del5q low/int-1 risk MDS refractory or unlikely to respond on EPO/G-CSF. The addition of EPO/G-CSF did not improve HI-E. Achievement of HI-E significantly improves PFS and OS. DisclosuresOssenkoppele:J&J: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding.

High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk‐oriented consolidation: A critical review of a 10‐year, single‐center experience in younger, non M3 AML patients

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc.

A randomised trial of secondary prophylaxis using granulocyte colony-stimulating factor (‘SPROG’ trial) for maintaining dose intensity of standard adjuvant chemotherapy for breast cancer by the Anglo-Celtic Cooperative Group and NCRN

Guidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI. Adult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups. Most regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF. Secondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

The prophylactic use of granulocyte-colony stimulating factor during remission induction is associated with increased leukaemia-free survival of adults with acute lymphoblastic leukaemia: A joint analysis of five randomised trials on behalf of the EWALL

BackgroundGranulocyte-colony stimulating factor (G-CSF) is used to prevent febrile neutropenia and support intense chemotherapy. However, its impact on long-term outcome in oncological patients including adults with acute lymphoblastic leukaemia (ALL) has not been determined so far. MethodsIn the current study follow-up data from individual patients recruited in five multicentre, prospective, randomised trials were pooled to perform a joint analysis. Among 347 adults and adolescents with ALL, 185 were assigned to receive prophylactically G-CSF along with induction chemotherapy while 162 patients were treated without G-CSF support. ResultsWith the median follow-up of 5.3years, there was a tendency towards increased 5year probability of the overall survival for the G-CSF arm compared to the controls (32%±4% versus 23%±4%, p=.07), which reached statistical significance in a subgroup of T-ALL (51%±8% versus 29%±9%, p=.01) and among patients aged 21–40years (44%±6% versus 27%±6%, p=.03). The probability of leukaemia-free survival was 38%±4% and 24%±4% (p=.01) while the median remission duration equalled 33 and 17months (p=.007), respectively. In a multivariate analysis the prophylactic use of G-CSF was independently associated with reduced risk of relapse (hazard ratio (HR)=.64, p=.007) and treatment failure (HR=.67, p=.02). ConclusionsThe prophylactic use of G-CSF during induction of ALL is associated with improved long-term outcome and should be recommended especially in a setting of T-ALL and in ‘young adults’. Our analysis provides the first direct evidence coming from prospective trials for the impact of primary G-CSF prophylaxis on disease-free survival of oncological patients.

Phase III Randomized Trial of Dose Intensive Neoadjuvant Chemotherapy with or Without G-CSF in Locally Advanced Breast Cancer: Long-Term Results

To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer. Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m(2); doxorubicin, 50 mg/m(2); cyclophosphamide, 500 mg/m(2)) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m(2); doxorubicin, 60 mg/m(2); cyclophosphamide, 1,000 mg/m(2)) plus G-CSF every 18 days for four cycles. Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm. A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.

Rescue from Failed Growth Factor and/or Chemotherapy HSC Mobilization with G-CSF and AMD3100: An Institutional Experience.

The inability to mobilize sufficient number of hematopoietic stem cells (HSC) using standard cytokine-assisted mobilization strategies excludes eligible patients from potentially curative autologous stem cell transplantation (ASCT). AMD3100, a novel antagonist of the SDF-1α / CXCR4 complex, has been reported to augment peripheral stem cell (PBSC) mobilization in patients undergoing their first planned stem cell collection attempt. AMD3100 can rapidly increase circulating CD34+ progenitor cells in preclinical murine models and healthy volunteers, alone or in combination with G-CSF. In phase II trials, when combined with G-CSF, AMD3100 appeared effective at mobilizing heavily pretreated patients during their first apheresis (Stiff, ASBMT, 2005). The ability of AMD3100 plus G-CSF to mobilize patients who were unable to collect significant CD34+ cells with G-CSF also has been observed. Patients undergoing their first attempt at PBSC mobilization were enrolled in a cross-over design trial comparing G-CSF with G-CSF and AMD3100 (Flomenberg, BLOOD, 2005). Nine patients did not mobilize PBSC when initially treated with G-CSF, but were subsequently collected when treated with AMD3100 plus G-CSF. In contrast, no patients on the AMD3100 + G-CSF arm failed to mobilize adequate PBSC.AMD3100 has been available on compassionate use for patients, otherwise eligible for ASCT but who have failed to mobilize adequate PBSC. Effective rescue of patients was been achieved in >50% of the population (McGuirk, ASH, 2005). Our center has participated in this compassionate use program and seven patients (4 NHL, 1 Hodgkin's Disease, 1 AILD, 1 myeloma) were enrolled in a local IRB- approved compassionate use protocol using AMD3100 in combination with G-CSF. A detailed analysis of these seven patients has been performed.Pretreatment characteristics include: patient median age was 58, median # of previous chemotherapy regimens was 3, and that five patients had failed chemotherapy + growth factor based PBSC mobilization strategies. Two patients had undergone previous autologous transplantation and that of the 5 patients for whom PBSC collection was attempted, the median # of CD34 progenitors collected was 0.53 × 106/kg.Results: 6 of seven patients had successful mobilization of CD34+ PBSC when treated with the combination treatment strategy with the median number of CD34+ progenitors/kg = 3.6 × 106 with a mean of 2.3 days for collection (median = 2 days). All six of the patients have since gone on to ASCT and all have had documented engraftment with median time to ANC of 500 by Day 12 and median time to platelet counts of 20,000 and 50,000 by Days 24 and 37, respectively. Only the myeloma patient who had previously undergone two independent ASCT, among other treatments, failed to mobilize PBSC and was unable to pursue ASCT. Thus, we confirm the ability to rescue G-CSF failures (1 patient) as well as demonstrate that patients who fail G-CSF plus chemotherapy mobilization attempts (5 of 6 patients) can effectively be rescued with a combination of AMD3100 and G-CSF. We have found this strategy safe and we recommend this combination mobilization strategy for patients with failed PBSC mobilization attempts to allow patients to pursue ASCT options.

A Randomized Trial To Evaluate the Impact of Cytokines (G-CSF or GM + G-CSF) on Dendritic Cell and T-Cell Content and Function When Mobilizing Normal Donors for Allogeneic Progenitor Cell Transplant.

Introduction: Optimal cellular immunity following allogeneic HPC transplant is a balance between effective anti-tumor immunity and the avoidance of life threatening GvHD. Our group previously demonstrated that DC content following allogeneic BMT can impact EFS (Waller et al, Blood 2001), and that mobilization cytokines can impact DC content of the autologous PBSC graft (Lonial et al, BBMT 2004). The current trial was designed with the hypothesis that the use of G + GM-CSF will result in fewer tolerogenic DC2 cells within the graft, and increased Th1 phenotype among the mobilized T-cell when compared with normal donors mobilized with G-CSF alone.Methods: 43 normal donors were randomized to receive G-CSF alone (7.5 mcg/kg BID) or G-CSF (7.5mcg/kg qd) and GM-CSF (7.5 mcg/kg qd) which was administered for 5 days or longer if additional days of apheresis were necessary. Side effects between the 2 cytokine regimens were documented using a questionnaire that was administered within 2 weeks of successful collection. Graft content was evaluated using multi-color flow cytometry, and pre-mobilization blood was collected to test for T-cell and DC content as well as T-cell function. DC1 (myeloid DC) were defined as Lin−/HLA-DR+/CD11C+/CD123−, while DC2 (lymphoid DC) were defined as Lin−/HLA-DR+/CD11C−/CD123+. T-cell proliferation was assessed using thymidine incorporation assays following mitogen exposure, and T-cell activation profile was assessed using ELISA assays of secreted cytokines and intracellular cytokine measurements following mitogen stimulation.Results: 19 patients received G+GM-CSF and 24 patients received G-CSF alone. All 43 donors were successfully mobilized, though more patients in the G-CSF arm required multiple days of collection (mean number of collections 1.4 G-CSF vs 1.1 G+GM-CSF, p=0.06). There was no difference in %CD34+ or CD34+ content of the grafts between groups. There was a marked reduction in DC2 content as measured by percent (0.33% vs 0.45%, p=.03) absolute DC2 content (1.98e6 vs 3.66e6, p=0.0003), and delivered DC2 dose e6/kg (2.8 vs 5.2, p=.0002) for the donors randomized to received the combination of GM/G-CSF vs G-CSF alone. There was no statistical difference in DC1 content measured in an analogous fashion. Additionally, grafts collected with G-CSF alone had significantly greater numbers of total T-cells than compared with G+GM-CSF (379e6/kg vs 230e6/kg, p=0.0007). This percent reduction in total T-cell content was identical to the reduction in the CD4 and CD8 subsets between the 2 randomized groups. Interestingly, cells collected from the recipients of G+GM-CSF on the day of mobilization secreted higher amounts of IL-2 at rest, though when stimulated with PMA, G-CSF mobilized cells secreted significantly higher amounts of IL-2. Other secreted cytokines were measured, and to date do not show a clear trend towards a difference. Side effects between the 2 randomized arms were similar with 1 patient in the G-GM-CSF arm having to stop growth factors secondary to bone pain and fever.Conclusion: The combination of G+GM-CSF mobilizes significantly fewer DC2 cells as well as 40–50% fewer T-cells, and is more likely to result in a successful single PBSC collection than the use of G-CSF alone. Further laboratory evaluation of the graft, survival, and GvHD data following transplant will also be presented.

Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients

The use of a combination of G-CSF and GM-CSF versus G-CSF alone, after cyclophosphamide (4 g/m2) was compared in two randomized phase III studies, including 120 patients. In study A, 60 patients received 5 x 2 microg/kg/day of G-CSF and GM-CSF compared to 5 mug/kg/day of G-CSF. In study B, 60 patients received 2.5 x 2 microg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 microg/kg/day). With the aim to collect at least 5 x 10(6)/kg CD34 cells in a maximum of three large volume leukapherises (LK), 123 LK were performed in study A, showing a significantly higher number of patients reaching 10 x 10(6)/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P=0.00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P=0.003). In both the study, the total harvest of CD34 cells/kg was twofold higher in G-CSF plus GM-CSF group (18.3 x 10(6) in study A and 15.85 x 10(6) in study B) than in G-CSF group (9 x 10(6) in study A and 8.1 x 10(6) in study B), a significant difference only seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups.

A Randomized Trial To Evaluate the Impact of Cytokines (G-CSF or GM + G-CSF) on Dendritic Cell and T-Cell Content and Function When Mobilizing Normal Donors for Allogeneic Progenitor Cell Transplant.

Introduction: Optimal cellular immunity following allogeneic HPC transplant is a tenuous balance between effective anti-tumor immunity and the avoidance of life threatening GvHD. The events necessary for potentially curative GvL are related to tumor burden, T-cell content, NK cell content, and dendritic cell content. Our group previously demonstrated that DC content following allogeneic BMT can impact EFS (Waller et al, Blood 2001), and that cytokines used during mobilization impact DC content of the autologous graft (Lonial et al, BBMT 2004). The current trial was designed with the hypothesis that the use of G + GM-CSF will result in fewer tolerogenic DC2 cells within the graft, and increased Th1 phenotype among the mobilized T-cells.Methods: 40 normal donors were randomized to receive G-CSF alone (7.5 mcg/kg BID) or G-CSF (7.5mcg/kg qd) and GM-CSF (7.5 mcg/kg qd) for 5 days or longer if additional apheresis were necessary. Side effects between the 2 cytokine regimens were documented using a questionnaire that was administered within 2 weeks of successful collection. Graft content was evaluated using multi-color flow cytometry, and pre-mobilization blood was collected to test for T-cell and DC content as well as T-cell function. T-cell proliferation was assessed using thymidine incorporation assays following mitogen exposure, and T-cell activation profile was assessed using ELISA assays of secreted cytokines following mitogen stimulation. DC1 (myeloid DC) were defined as Lin-/HLA-DR+/CD11C+/CD123−, while DC2 (lymphoid DC) were defined as Lin-/HLA-DR+/CD11C−/CD123+.Results: 18 patients received G+GM-CSF and 22 patients received G-CSF alone. All 40 donors were successfully mobilized, though more patients in the G-CSF arm required multiple days of collection (mean number of collections 1.5 G-CSF vs 1.0 G+GM-CSF, p=0.01). Donors mobilized with G-CSF alone had a higher overall cell count (765e8/ml compared with 615e8/ml for G+GM-CSF, p=0.04), though the CD34 content of the grafts were comparable. Again, there was a significant reduction in delivered DC2 content of graft mobilized with G+GM-CSF when compared with G-CSF alone (5.1e6/kg compared with 2.85e6/kg, p=0.001), with a trend towards fewer DC1 cells as well (2.6e6/kg vs 1.7e6/kg, p=0.05). Overall, the DC1:DC2 ratio favors DC1 among donors mobilized with G+GM-CSF. Additionally, grafts collected with G-CSF alone had nearly twice the total T-cell content of grafts mobilized with G+GM-CSF (420e6/kg vs 220e6/kg, p=0.0001). The reduction in total T-cells was evenly distributed between CD4 and CD8 cells with similar magnitude of reduction in both subsets amongst those receiving G+GM-CSF. Interestingly, grafts collected from the recipients of G+GM-CSF produced more IL-2 at rest, and secreted significantly more IL-12 in response to mitogen. Toxicity between the 2 arms were similar with 1 patient in the G+GM-CSF arm having to stop growth factors due to bone pain and fever.Conclusion: The combination of G+GM-CSF mobilizes fewer DC2 cells as well as 40–50% fewer T-cells, and is more likely to result in a successful single PBSC collection than the use of G-CSF alone. Preliminary data suggests that the combination of G+GM-CSF shifts T-cells towards a Th1 phenotype, despite fewer overall T-cells. Further laboratory evaluation of the graft, survival, and GvHD data following transplant will also be presented.

Phase III Trial Comparing Granulocyte Colony-Stimulating Factor to Leridistim in the Prevention of Neutropenic Complications in Breast Cancer Patients Treated with Docetaxel/Doxorubicin/Cyclophosphamide: Results of the BCIRG 004 Trial

This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin- 3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 νg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 νg/kg s.c. daily (n = 139), or leridistim 10 νg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m 2, doxorubicin 50 mg/m 2, cyclophosphamide 500 mg/m 2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ νL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm ( P = 0.003 for comparison with GCSF) and 22% in the alternate-day leridistim arm ( P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%–88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group ( P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group ( P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline—based combination chemotherapy.

Economic analysis of a phase III study of G-CSF vs placebo following allogeneic blood stem cell transplantation

Hematopoietic colony-stimulating factors (CSF) decrease the duration of neutropenia following stem cell transplantation (SCT). With CSF-mobilized allogeneic blood SCT (alloBSCT), the yields of CD34+ cells are several-fold higher than in other SCT settings, raising concern that post-transplant CSF use may be unnecessary. In this study, we estimate the resource and cost implications associated with CSF use following alloBSCT. A cost identification analysis was conducted for 44 patients on a randomized, double-blind placebo-controlled trial of G-CSF following alloBSCT. Study drug was given daily until an absolute neutrophil count (ANC) > or = 1000 cells/microl. Billing information from the time of transplant to day +100 was analyzed. The median number of days to an ANC > or = 500 cells/microl was shorter in the G-CSF arm, 10.5 days vs 15 days (P < 0.001), while platelet recovery and rates of acute graft-versus-host disease (GVHD) and survival were similar. Resource use was similar, including days hospitalized, days on antibiotics, blood products transfused and outpatient visits. Total median post-transplant costs were $76577 for G-CSF patients and $78799 for placebo patients (P = 0.93). G-CSF following allogeneic blood SCT decreased the median duration of absolute neutropenia and did not incur additional costs, but did not result in shorter hospitalizations, or less frequent antibiotic use.

248 Growth factors in combination: Phase I study of dose intensified carboplatin (CB), cyclophosphamide (CT) and etoposide (VP) in patients (PTS) with advanced, refractory cancer

This phase I study was designed in order to verify the toxicity of CB. CTX, VP given at high doses, in combination with GCSF alone or GCS and GMCSF given sequentially. The two lymphokines, with different properties, might have their ideal integration in the sequential administration. A group of 10 heavily pretread patients (PTS) with stage IV disease (2 breast cancer, 2 small cell and 1 non small cell lung cancer, 1 sarcoma, 1 colorectal cancer, 1 ependymoblastorna, 1 signet-ring cell bladder cancer, 1 neuroendocrine prostate cancer) were enrolled into the study between August and September 1994. Median (M) PS (ECOG) was 1, M age 41 years (22–65). Previous treatments: 7 PTS had surgery, 4 PTS had radiotherapy, all PTS had received previously a median of 4. 5 chemotherapy courses (4–12). CB-CTX-VP combination was administered over 3 days. Each patient, received two courses of the same CT, followed, randomly, either by 14 days of GCSF (arm A) or by 7 days of GCSF and 7 days of GMCSF (arm B) with cross over in the second CT course. Both growth factors were given sq at the dose of 5μg/kg/day. CB dose was calculated according to Calvert et al. (JCO 1989,7:1748) and expressed with the area under the concentration versus time curve (AUC). All patients received an outpatient treatment. The maximum tolerated doses of CTX and Vp, found in a previous work (Ann Oncol 1994, 5:90,), were, respectively, 1500 and 400mg/m2, while CB doses ranged from 5 to 8 AUC. Twenty chemotherapy courses over 20 are evaluable. Absolute neutrophil count (ANC)<1000μL for 54 days in arm A versus 68 days in arm B (<i>P</i>=0.02); platelets (PLT) count<25.000μL: 57 days arm A versus 30 days in arm B (<i>P</i>=0.03); days of hospitalisation 35 in arm Aversus 16 in arm B (<i>P</i>=0.75); platelets transfusion: 107 Vs 58 (<i>P</i>=0.02); PRBCS 15 vs 5 (<i>P</i>=0.25). No treatment related death occurred. At the present time, eight patients had responses and are alive. These data indicate that dose intensified CT may be delivered safely; GCSF alone shortens days of neutropenia, the combination of the 2 cytokines shortens the time of thrombocytopenia and decreases the number of platelets transfusions.

Concomitant Granulocyte Colony-Stimulating Factor and Induction Chemoradiotherapy in Adult Acute Lymphoblastic Leukemia: A Randomized Phase III Trial

This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count < 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P < .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.