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.