Bone Marrow Transplantation (2001) 27, Suppl. 2, S23–S29  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim

CH Weaver, KA Schulman and CD Buckner

CancerConsultants.com Inc., Ketchum, ID; and Clinical Economics Research Unit, Duke University Medical Center, Durham, NC, USA

Summary: the sequential regimen received higher numbers of CD34 cells and had faster platelet recovery with fewer Myelosuppressive chemotherapy is frequently used for patients requiring platelet transfusions than patients mobilization of autologous CD34+ progenitor cells into receiving peripheral blood stem cells mobilized by GM- the peripheral blood for subsequent collection and sup- CSF. In summary, G-CSF alone is superior to GM-CSF port of high-dose chemotherapy. The administration of alone for the mobilization of CD34+ cells and reduction myelosuppressive chemotherapy is typically followed by of toxicities following myelosuppressive chemotherapy. a myeloid growth factor and is associated with variable An economic analysis evaluating the cost-effectiveness CD34 cell yields and morbidity. The two most com- of these three effective schedules is ongoing at the time monly used myeloid growth factors for facilitation of of this writing. Bone Marrow Transplantation (2001) 27, CD34 cell harvests are granulocyte colony-stimulating Suppl. 2, S23–S29. factor (G-CSF) and granulocyte–macrophage colony- Keywords: filgrastim; sargramostim; stem cell mobiliz- stimulating factor (GM-CSF). We performed a ran- ation domized phase III clinical trial comparing G-CSF, GM- CSF, and sequential administration of GM-CSF and G- CSF following administration of myelosuppressive chemotherapy. We evaluated CD34 yields, morbidity, The two most commonly used myeloid growth factors for and cost-effectiveness of the three cytokine schedules. facilitation of peripheral blood stem cell (PBSC) harvests One hundred and fifty-six patients with multiple myel- in the USA are recombinant human granulocyte colony- 1–11 oma, breast cancer, or lymphoma received cyclophos- stimulating factor (rHuG-CSF; filgrastim) and recombi- phamide with either paclitaxel or etoposide and were nant human granulocyte–macrophage colony-stimulating randomized to receive G-CSF 6 ␮g/kg/day s.c., GM- factor (rHuGM-CSF; sargramostim). Sargramostim is a CSF 250 ␮g/m2/day s.c., or GM-CSF for 6 days followed glycosylated form of rHuGM-CSF derived from yeast and 12–15 by G-CSF until completion of the stem cell harvest. marketed in the USA and molgramostim is an unglyco- Compared with patients who received GM-CSF, sylated form of rHuGM-CSF derived from Escherichia coli 16–24 patients who received G-CSF had faster recovery of and only available for experimental use in the USA. absolute neutrophil count to 0.5 × 109 per liter (median It has not been determined in randomized prospective = trials whether there are major differences between myeloid of 11 vs 14 days, P 0.0001) with fewer patients requir- + ing red blood cell transfusions (P = 0.008); fewer growth factor regimens and CD34 cell yields and mor- patients with fever (18% vs 52%, P = 0.001); fewer hos- bidity following myelosuppressive chemotherapy (MC). pital admissions (20% vs 42%, P = 0.13); and less intra- There are reports of harvesting PBSC with MC followed 4–11,25 14,15,26 venous antibiotic therapy (24% vs 59%, P = 0.001). by filgrastim, sargramostim or the combination 12 Patients who received G-CSF also yielded more CD34 of sargramostim and filgrastim, but there have been no cells (median 7.1 vs 2.0 × 106 kg per apheresis, P = prospective, randomized studies comparing relative effec- 0.0001) and a higher percentage achieved 2.5 × 106 tiveness. A prospective randomized trial was performed to CD34 cells per kilogram (94% vs 78%, P = 0.21) and 5 compare the effects of filgrastim alone, sargramostim alone, × 6 = or the sequential administration of sargramostim and fil- 10 CD34 cells per kilogram (88% vs 53%, P 0.01) + or more CD34 cells per kilogram with fewer aphereses grastim on CD34 cell yields, hematological recovery, mor- (median 2 vs 3, P = 0.002) and fewer days of growth bidity, and resource utilization after the administration of factor treatment (median 12 vs 14, P = 0.0001). There MC. were no significant differences in outcomes between groups receiving G-CSF alone and the sequential regi- men. After high-dose chemotherapy, patients who had Patients and methods peripheral blood stem cells mobilized with G-CSF or This was a randomized, open-label trial of three schedules of myeloid growth factors administered after MC for the + Correspondence: Dr CH Weaver, CancerConsultants.com collection of CD34 PBSC. The MC regimen – cyclophos- Filgrastim and sargramostim for stem cell mobilization CH Weaver et al S24 phamide and etoposide (CE) or paclitaxel and cyclophos- Hematopoietic recovery and resource utilization phamide (PC) – was determined by the primary treatment protocol. The following three groups of patients were The effects of growth factor regimen on hematopoietic evaluated: (1) filgrastim alone: daily administration until recovery and resource utilization after MC are shown in PBSC harvests were completed; (2) sargramostim alone: Table 2. Four patients died of treatment-related causes 9 to 15 days after the first dose of MC without recovery of neutro- daily administration until PBSC harvests were completed; = = (3) sargramostim followed by filgrastim: daily adminis- phils or platelets (infection 2, multi-organ failure 2). tration of sargramostim for 5 days followed by daily filgra- stim until PBSC harvests were completed. CD34+ cell harvests and growth factor administration One hundred and fifty-six patients were evaluable for + toxicity of MC, 150 were evaluable for efficiency of PBSC The median number of CD34 cells collected for all 150 × 6 harvests, and 126 were evaluable for engraftment para- patients was 8.5 10 /kg (range, 0.02 to 96) in a median meters after a single course of high-dose chemotherapy of two aphereses (range, 1 to 9), with a median of 13 days of growth factor administration (range, 9 to 22). The results (HDC) and PBSC infusion. + Patients were treated in one of 39 medical centers in the of CD34 cell yields for the three groups of patients are USA under the care of 88 medical oncologists affiliated shown in Table 3. with the Clinical Trials Division of Response Oncology, Inc. (ROI), Memphis, TN.27 Chemotherapy for all phases CD34+ cell yields following PC or CE of treatment was administered and PBSC harvested in an Tables 4 and 5 summarize the differences observed in outpatient facility. Patients who required admission were + admitted to hospitals meeting the criteria of the American CD34 cell harvests between patients receiving MC Society of Clinical Oncology/American Society of Hema- consisting of PC or CE. tology Guidelines for Stem Cell Transplantation.28 2 MC consisted of cyclophosphamide (4 g/m ) on day 1 Hematological recovery following HDC and etoposide (200 mg/m2) on days 1 to 3 (CE, n = 75),29 or paclitaxel (200 mg/m2) on day 1 and cyclophosphamide Treatment regimens, hematological recovery, and resource (3 g/m2) on day 2 (PC, n = 81).29 utilization after HDC are shown in Table 6. Myeloid growth factor administration was begun on the day after the completion of MC. The regimens evaluated were: filgrastim 6 ␮g/kg/day (Amgen, Thousand Oaks, CA, Discussion USA), sargramostim 250 ␮g/m2/day (Immunex, Seattle, WA, USA), or sargramostim 250 ␮g/m2/day for 5 days A major finding in this study was that patients receiving followed by filgrastim 6 ␮g/kg/day. All myeloid growth filgrastim after MC yielded more CD34+ cells than patients factors were administered daily until the final day of receiving sargramostim. There were differences in CD34+ apheresis.29 cell yields between the two MC regimens as shown in The following HDC regimens were administered to 126 Tables 4 and 5. Twice as many CD34+ cells were collected patients: cyclophosphamide, thiotepa, and carboplatin following CE as following PC. For patients receiving CE, (CTCb, n = 87),27 carmustine, etoposide, cytarabine, and more CD34+ cells were collected following filgrastim alone cyclophosphamide (BEAC, n = 25),30 busulfan, melphalan, or sequential sargramostim and filgrastim than following and thiotepa (BuMelTT, n = 13),31 or a single high dose sargramostim alone. However, 82% of patients receiving of melphalan (n = 1).32 All patients received filgrastim 6 sargramostim yielded у2.5 ϫ 106 CD34+ cells/kg and 77% ␮g/kg/day beginning on day 1 after PBSC infusion and yielded у5.0 ϫ 106 CD34+ cells/kg, which was not sig- continuing until the absolute neutrophil count (ANC) was nificantly different than patients receiving filgrastim alone Ͼ0.5 ϫ 109/l for 3 consecutive days. or sequential sargramostim and filgrastim (Table 4). Thus, The optimal dose for support of HDC was considered to sargramostim and filgrastim following CE were equally be у5.0 ϫ 106 CD34+ cells/kg and the minimal dose to effective for achieving target CD34+ cell numbers. The proceed with HDC was 1.0 ϫ 106 CD34+ cells/kg.33 major differences in achieving target CD34+ cell yields Patients who yielded Ͻ2.5 but Ͼ1.0 ϫ 106 CD34+ cells/kg were observed in patients receiving PC (Table 5). In gen- could elect to have HDC supported by less than optimal eral, PC was associated with less toxicities and more rapid CD34+ cell numbers or undergo a second mobilization hematological recovery than CE. It has been previously procedure.34 observed that more intensive chemotherapy regimens are Patients received MC and HDC in an outpatient treat- associated with a better CD34+ cell yield than less intensive ment facility with daily surveillance for complications war- regimens; this would probably explain the current obser- ranting hospital admission.35 vations.1,5,36 There have been no previous randomized trials compar- ing the prophylactic administration of filgrastim to sargra- Results mostim after MC. However, one randomized trial compared filgrastim to molgramostim in 26 patients with Hodgkin’s Characteristics of the 156 evaluable patients receiving MC disease receiving MC.16 Twenty-one patients completed are shown in Table 1. There were no statistically significant PBSC collections and there were no differences in CD34+ differences between the three groups. cell yields or toxicities between the two groups.16 Bregni

Bone Marrow Transplantation Filgrastim and sargramostim for stem cell mobilization CH Weaver et al S25 Table 1 Patient characteristics (n = 156)

Filgrastim Sargramostim Sargramostim + P value alone alone filgrastim

Number of patients 51 52 53 Median age, years (range) 50 (23–68) 46 (28–61) 48 (29–61) 0.480 Male gender 8 (16%) 8 (15%) 10 (19%) 0.869 ECOG performance status = 0 40 (78%) 40 (77%) 47 (89%) 0.242 Diagnosis Stage II–III breast cancer 15 (29%) 20 (38%) 18 (34%) 0.979 Metastatic breast cancer 22 (43%) 19 (37%) 21 (40%) Malignant lymphoma 11 (22%) 11 (21%) 11 (21%) Multiple myeloma 3 (6%) 2 (4%) 3 (6%) Prior radiation therapy 11 (22%) 4 (8%) 8 (15%) 0.139 Number of chemotherapy regimens р1 38 (75%) 42 (81%) 36 (68%) 0.321 у2 13 (25%) 10 (19%) 17 (32%) CE mobilization 24 (47%) 25 (48%) 26 (49%) 0.979 PC mobilization 27 (53%) 27 (52%) 27 (51%)

CE = cyclophosphamide and etoposide; ECOG = Eastern Cooperative Group; PC = paclitaxel and cyclophosphamide.

Table 2 Resource utilization and hematopoietic recovery after myelosuppressive mobilization chemotherapy

F P value S P value S + F P value FvsS SvsSF FvsSF

Number of patients 51 52 53 Days to ANC у0.5 × 109/la,b 11 (0–19) 0.0001 14 (10–19) 0.0001 12 (10–15) 0.001 No. with temp Ͼ38.5°C 9 (18%) 0.001 27 (52%) 0.001 8 (15%) No. febrile daysa 1 (1–4) 1 (1–8) 1 (1–4) No. with bacteremia 2 (4%) 3 (6%) 2 (4%) No. i.v. antibiotics 12 (24%) 0.001 36 (69%) 0.001 13 (25%) Days i.v. antibioticsa 4.5 (1–8) 5 (1–11) 4 (2–13) No. adm to hospital 10 (20%) 0.013 22 (42%) 0.017 11 (21%) Days in hospitala 5 (3–16) 4.5 (3–14) 6 (4–27) No. with platelets у20 × 109/l 15 (29%) 18 (35%) 20 (38%) No. receiving platelets 13 (25%) 0.072 22 (42%) 0.086 14 (26%) Days platelets infuseda 2 (1–7) 1 (1–6) 1 (1–8) No. with hemoglobin у8.0 mg/dl 18 (35%) 0.058 28 (54%) 0.040 18 (34%) No. receiving RBCs 11 (22%) 0.008 24 (46%) 17 (32%) No. days RBCs infuseda 1 (1–4) 1 (1–3) 1 (1–3) No. not apheresed 2 3 1 Treatment deaths 2 2 0 Poor clinical condition 1 (infection) 1 (CHF) aMedian (range). bExcludes four patients with early death. P values reported if р0.10. CHF = congestive heart failure; F = filgrastim; RBCs = red blood cells; S = sargramostim. et al,18 in a non-randomized trial, compared filgrastim to schedule of growth factor administration, or to the rela- molgramostim administered by continuous intravenous tively small number of patients evaluated.16,18 infusion in 49 patients with malignant lymphoma receiving Filgrastim has been compared to sargramostim or the cyclophosphamide 7 g/m2.18 These investigators found combination of sargramostim and filgrastim in normal indi- more rapid recovery of neutrophils following filgrastim (P viduals.13,37–39 These studies demonstrated that filgrastim = 0.01), more rapid recovery of platelets following molgra- alone or sequential sargramostim and filgrastim mobilized mostim (P = 0.01), and more CD34+ cells/kg/apheresis fol- more CD34+ cells than sargramostim alone in normal per- lowing molgramostim (the latter difference not being stat- sons.13,37–39 These studies also suggested that sequential istically significant, P = 0.132).18 This study also found no sargramostim and filgrastim mobilized more primitive hem- differences in yields of undifferentiated hematopoietic pro- atopoietic cells (CD23+/CD38−/HLA-DR+) than either drug genitors as defined by the CD34+/CD33− surface pheno- alone.13,37–39 The practical significance of these obser- type.18 Differences between these two studies and the cur- vations for PBSC transplantation is unknown. However, the rent study could be due to differences in the rHuGM-CSF lack of reports of late graft failure following autologous or molecule, in the myelosuppressive regimens, in dose and allogeneic transplantation with filgrastim-mobilized PBSC

Bone Marrow Transplantation Filgrastim and sargramostim for stem cell mobilization CH Weaver et al S26 Table 3 Results of CD34+ cell harvests and growth factor administration (n = 150)

F P value S P value S + F P value FvsS SvsSF FvsSF

Number of patients 49 49 52 Day to first apheresisa 12 (10–20) 0.0001 14 (10–19) 0.0004 13 (11–20) 0.008 Days of growth factora 12 (9–21) 0.0001 14 (11–22) 0.0001 12 (10–20) 0.037 Number of apheresesa 2 (1–6) 0.002 3 (1–9) 0.004 2 (1–6) CD34+ cells/kg/apheresisa 7.1 0.0001 2.0 0.0002 5.5 (0.03–27) (0.01–31) (0.12–48) Total CD34+ cells × 106/kga 12.0 0.0001 5.4 0.0003 10.5 (0.10–54) (0.02–62) (0.40–96) No. у2.5 × 106 CD34+ cells/kg 46 (94%) 0.021 38 (78%) 0.015 49 (94%) No. у5.0 × 106 CD34+ cells/kg 43 (88%) 0.001 26 (53%) 0.003 42 (81%) No. р1.0 × 106 CD34+ cells/kg 2 4 1 No. with second mobilization 1 5b 0.018 0

aMedian (range). bOne patient had second mobilization after first harvesting 1.2 × 106 CD34+ cells/kg. P values reported if р0.10. F = filgrastim; S = sargramostim.

Table 4 Results of CD34+ cell harvests and growth factor administration after cyclophosphamide and etoposide (n = 70)

F P value S P value S + F P value FvsS SvsSF FvsSF

Number of patients 22 23 25 Day to first apheresisa 13 (11–20) 0.022 14 (13–18) 0.026 13 (12–20) Days of growth factora 12 (9–21) 0.031 14 (11–19) 0.026 12 (10–20) Number of apheresesa 2 (1–4) 2 (1–5) 2 (1–5) CD34+ cells/kg/apheresisa 12.6 0.042 3.2 0.035 6.7 (0.03–24) (0.01–31) (0.12–48) Total CD34+ cells × 106/kga 20.7 0.018 6.6 0.091 13.0 (0.10–47) (0.02–61) (0.35–96) No. у2.5 × 106 CD34+ cells/kg 20 (91%) 18 (82%) 19 (95%) No. у5.0 × 106 CD34+ cells/kg 19 (86%) 17 (77%) 17 (85%) No. р1.0 × 106 CD34+ cells/kg 1 2 1 No. with second mobilization 1 2 0

aMedian (range). P values reported if р0.10. F = filgrastim; S = sargramostim.

Table 5 Results of CD34+ cell harvests and growth factor administration after paclitaxel and cyclophosphamide (n = 80)

F P value S P value S + F P value FvsS SvsSF FvsSF

Number of patients 27 26 27 Day to first apheresisa 12 (10–14) 0.0001 13.5 (10–19) 0.004 12 (11–15) 0.005 Days of growth factora 12 (10–15) 0.0001 15 (11–22) 0.0004 13 (11–18) 0.030 Number of apheresesa 2 (1–6) 0.0002 4 (2–9) 0.005 2 (1–6) CD34+ cells ×106/kg/apheresisa 5.6 0.0001 1.1 0.0003 5.3 (0.12–27) (0.11–8) (0.34–22) Total CD34+ cells × 106/kga 10.6 0.0001 4.2 0.0002 8.7 (0.37–54) (0.57–15) (1.70–26) No. у2.5 × 106 CD34+ cells/kg 26 (96%) 0.024 19 (73%) 0.076 25 (93%) No. у5.0 × 106 CD34+ cells/kg 24 (89%) 0.001 8 (31%) 0.002 20 (74%) No. р1.0 × 106 CD34+ cells/kg 1 2 0 No. with second mobilization 0 3b 0

aMedian (range). bOne patient had second mobilization after first harvesting 1.2 × 106 CD34+ cells/kg. P values reported if р0.10. F = filgrastim; S = sargramostim.

Bone Marrow Transplantation Filgrastim and sargramostim for stem cell mobilization CH Weaver et al S27 Table 6 Hematopoietic recovery and resource utilization after high-dose chemotherapy (n = 126)

F P value S P value S + F P value FvsS SvsSF FvsSF

Number of patients 43 42 41 HDC regimen CTCb 27 (63%) 30 (71%) 30 (73%) BuMelTT 6 3 4 Melphalan 1 0 0 BEAC 9 9 7 CD34+ cells × 106/kg infusa 11.3 0.0001 5.4 0.001 10.5 (2.2–47) (1.5–31) (1.7–48) No. Ͻ5.0 × 106 CD34+/kg infus 6 (14%) 0.001 22 (52%) 0.032 12 (29%) 0.087 No. Ͻ2.5 × 106 CD34+/kg infus 4 (9%) 0.041 11 (26%) 7 (17%) Day to ANC у0.5 ± 109/la 11 (9–15) 0.006 11.5 (9–41) 11 (8–19) Day platelets у20 × 109/la 9 (5–48+) 0.015 12 (7–139+) 11 (6–35) No receiving platelets 33 (77%) 0.014 40 (95%) 37 (90%) 0.097 No. days platelets transfuseda 2 (1–12) 0.001 3 (1–29) 0.006 2 (1–8) No transfused with RBC 22 (51%) 0.031 31 (74%) 25 (61%) No. days RBC transfuseda 2 (1–4) 2 (1–14) 2 (1–4) No. admitted to hospital 33 (77%) 31 (74%) 31 (76%) Days of hospitalizationa 10 (1–20) 10 (2–22) 12 (1–18) aMedian (range). P values reported if р0.10. BEAC = carmustine, etoposide, cytarabine, and cyclophosphamide; BuMelTT = busulfan, melphalan, and thiotepa; CTCb = cyclophosphamide, thiotepa, and carboplatin; F = filgrastim; S = sargramostim.

suggests that the infusion of inadequate quantities of more to 14% for patients infused with PBSC mobilized with fil- primitive stem cells is not a major clinical problem. grastim alone (P = 0.087). Spitzer et al12 randomized patients to receive filgrastim As shown in Table 2, patients receiving filgrastim or the 10 ␮g/kg/day or the combination of filgrastim 10 ␮g/kg/day sequential regimen had a faster recovery of neutrophils to plus sargramostim 5 ␮g/kg/day without prior chemotherapy 0.5 ϫ 109/l compared to patients receiving sargramostim and found no increase in CD34+ cell yields following the alone (P = 0.0001 and 0.0001, respectively). The increased combination growth factor administration. These obser- incidence of fever in patients receiving sargramostim prob- vations are consistent with those of the current study, ably accounts for the increased frequency of hospital although the schedule of growth factor administration was admissions and intravenous antibiotic usage. Fever in the concurrent rather than sequential as in the present study. sargramostim group was most likely due to the drug itself In the present study, hematopoietic recovery after a sin- and not to infection since the incidence of documented bac- gle course of HDC and PBSC infusion was evaluated in teremia was the same for all three groups. 126 patients (Table 6). Patients who had PBSC mobilized The higher incidence of anemia and more frequent red with CE or PC and sargramostim alone received 50% less blood cell transfusions in the sargramostim group was an CD34+ cells compared to patients receiving cells harvested unexpected finding as neither filgrastim or sargramostim after filgrastim or sequential sargramostim and filgrastim. have a known effect on red blood cell production. The There was a faster recovery by 3 days of platelets in mechanism by which sargramostim-treated patients patients receiving filgrastim-mobilized PBSC than in developed more anemia than patients receiving filgrastim patients receiving sargramostim-mobilized PBSC (day 9 vs or the sequential regimen was not investigated and could day 12, P = 0.015), which was probably due to the large only be speculated upon. There were no differences in the difference in median CD34+ cell dose. This finding lends frequency of patients with a platelet nadir among the three further support to a number of studies which have shown groups. More patients in the sargramostim group received that infusing у5.0 ϫ 106 CD34+ cells/kg is associated with platelet transfusions than patients receiving filgrastim or the a reduction in time to platelet recovery and less supportive sequential regimen, but these differences did not reach stat- care requirements.6,29,40,41 Patients receiving sequential sar- istical significance. gramostim and filgrastim-mobilized PBSC did not recover The current findings are, in general, consistent with the platelets until a median of day 11 compared to day 9 for studies of myeloid growth factors alone (ie without patients receiving comparable median numbers of filgras- chemotherapy) for mobilization of PBSC.12,13,37–39 If the tim-mobilized CD34+ cells (P = 0.101). However, this was goal is to harvest large quantities of CD34+ cells with the probably due to the fact that 29% of patients infused with least morbidity and resource utilization, filgrastim alone PBSC mobilized by sequential sargramostim and filgrastim administered after MC would appear to be the best cur- were transfused with Ͻ5 ϫ 106 CD34+ cells/kg compared rently available myeloid growth factor regimen. Other

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