ESHAP Plus G-CSF As an Effective Peripheral Blood

ESHAP plus G-CSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin’s lymphoma: comparison with high-dose cyclophosphamide plus G-CSF

J-L Lee1,4, S Kim1, SW Kim1, E-K Kim1, S-B Kim1, Y-K Kang1, J Lee1, MW Kim1, CJ Park2, H-S Chi2, J Huh3, S-H Kim1 and C Suh1

1Department of Medicine, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 2Department of Diagnostic Laboratory Medicine, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 3Department of Pathology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; and 4Department of Medicine, Yeungnam University College of Medicine, Daegu, Korea

Summary: High-dose chemotherapy along with autologous peripheral blood hematopoietic stem cell transplantation is The ESHAP (etoposide, methylprednisolone, high-dose widely used for relapsed or primary refractory non- cytarabine, and cisplatin) regimen has been shown to be Hodgkin’s lymphoma (NHL).1–3 The use of chemotherapy effective as an active salvage therapyfor lymphoma. and G-CSF in this setting should be directed to the Mobilizing stem cells following ESHAP should decrease dual objectives of good antilymphoma activity and time to transplantation bymaking separate mobilizing mobilization of an adequate number of peripheral blood chemotherapy(MC) unnecessary,while controlling a progenitor cells (PBPC). Although the regimen of cyclo- patient’s lymphoma. We therefore assessed the mobiliza- phosphamide and G-CSF is good for PBPC mobilization potential of ESHAP plus G-CSF in 26 patients tion in various diseases and situations,4 it is less effective (ESHAP group) with non-Hodgkin’s lymphoma (NHL) in cases of primary refractory or relapsed lymphoma and compared these results with those of 24 patients with after cyclophosphamide-containing combination chemo- NHL who received high-dose (4 g/m2l) cyclophosphamide therapy. In these patients, where potent antilymphoma (HDCY) as MC (HDCY group). The age, sex, and activity is needed, the regimen of cyclophosphamide plus radiotherapyto the axial skeleton were well matched G-CSF theoretically loses most of its utility. The ESHAP between groups, but the number of patients with poor (etoposide, methylprednisolone, high-dose cytarabine, mobilization predictors was higher in the ESHAP group. and cisplatin) regimen has been shown to be effective as Significantlyhigher numbers of CD34 þ cells ( Â 106/kg) active salvage therapy for lymphoma.5,6 Mobilization of (17.1718.8 vs 5.875.0, P ¼ 0.03) and apheresis day1 stem cells following ESHAP chemotherapy is attractive, CD34 þ cells ( Â 106/kg) (5.576.6 vs 1.772.0, P ¼ as it should decrease the time to transplant by making 0.014) were collected from the ESHAP group than from separate mobilizing chemotherapy (MC) unnecessary the HDCY group, and the number of patients who while controlling a patient’s lymphoma. However, ESHAP achieved an optimal CD34 þ cell target of 5 Â 106/kg plus G-CSF has been utilized only to a limited extent for was higher in the ESHAP group (81 vs 50%, P ¼ 0.022). MC in NHL.7–9 Log-rank test revealed that time to target peripheral blood We report here the results of MC using ESHAP progenitor cell collection (X5 Â 106/kg) was shorter in the plus G-CSF in 26 patients with NHL. In addition, we ESHAP group (P ¼ 0.007). These results indicate that compare the mobilizing potential of ESHAP plus G-CSF ESHAP plus G-CSF is an excellent mobilization regimen with that of a high-dose cyclophosphamide (HDCY) in patients with relapsed and poor-risk aggressive NHL. regimen. Bone Marrow Transplantation (2005) 35, 449–454. doi:10.1038/sj.bmt.1704798 Published online 17 January 2005 Patients and methods Keywords: ESHAP; mobilization; lymphoma; cyclophosphamide Patients The autologous stem cell transplantation (ASCT) data registry of Asan Medical Center (AMC) and Yeungnam Correspondence: Dr C Suh, Department of Medicine, University of University Medical Center (YUMC) revealed that 26 Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap- patients with aggressive NHL received ESHAP chemo- dong, Songpa-gu, Seoul 138-040, South Korea; E-mail: [email protected] therapy followed by G-CSF prior to collection of PBPC Received 13 May 2004; accepted 14 October 2004 between July 1998 and March 2004. During the same Published online 17 January 2005 period, 24 patients with NHL received HDCY with G-CSF ESHAP mobilization in NHL J-L Lee et al 450 as the mobilization regimen. We collected the demographic continued until the absolute neutrophil count (ANC) was characteristics, harvest results, post-ASCT hematologic at least 1.0 Â 109/l on 2 consecutive days. Platelet transfu- recovery, and adverse event data from those groups of sions were administered empirically for patients with patients. There were no preset criteria or patient character- platelet counts of 2.0 Â 109/l or lower or for clinical istics that determined whether patients received ESHAP or bleeding. HDCY for MC. Definitions MC, PBPC harvest and CD34 cell quantitation After MC, days to first apheresis were measured from the The ESHAP regimen consisted of etoposide (40 mg/m2, first day of chemotherapy administration (day 0). CD34 þ days 1–4), methylprednisolone (500 mg, days 1–5), cytar- cells X2.0 Â 106 and X5.0 Â 106/kg were defined as abine (2 g/m2, day 5), and cisplatin (25 mg/m2, days 1–4), as ‘adequate’ and ‘optimal’ PBPC for ASCT, respectively, described previously.5 HDCY (4 g/m2) was given in a whereas CD34 þ cells o1.0 Â 106/kg was regarded as 90 min infusion with intravenous hydration and MESNA mobilization failure. Days to adequate or optimal PBPC (2-mercaptoethane sulfonate).4,10 In the early phase of collection were measured from the first day of apheresis. study period, G-CSF (10 mg/kg/day; Lenograstim, Neutro- After high-dose chemotherapy, hematopoietic recovery was gint, Choongwae, Seoul, South Korea) was given sub- measured from the day of PBPC infusion (day 0). cutaneously, starting on the day the WBC first rose after the nadir after ESHAP or HDCY had ended and Statistics continuing until the day before the last apheresis. Since July 2002, G-CSF (10/kg/day) was started on day 6 for Patient characteristics, apheresis components, and post- ESHAP and on day 2 for HDCY and continued until the ASCT hematologic recovery data are described using completion of apheresis. CBC was monitored daily from 3 summary statistics as median values and ranges, or as days after the end of ESHAP and from 7 days after the means and standard deviations. All continuous variables were analyzed using the Mann–Whitney test. Proportions completion of HDCY. The criteria for apheresis com- 2 mencement differed in the participating centers. In AMC, were compared using the w test or Fisher’s exact test, as from July 1998 to July 2002, the first PBPC harvest was appropriate. Sessions of apheresis needed to achieve initiated on the day when the first of the following adequate or optimal PBPC collection were estimated using occurred: (1) WBC count exceeded 10.0 Â 109/l; (2) MNC the product-limit method according to Kaplan and Meier count exceeded 1.0 Â 109/l; or (3) hematopoietic progenitor and were compared using the log-rank test. Statistical cell (HPC) count, as assessed by an automated hematology analysis was performed with SPSS for Windows V. 10.0 analyzer (SE-9000, Sysmex, Kobe, Japan), exceeded 5/ (SPSS Inc., Chicago, IL, USA) and significance levels were ml.11,12 Since July 2002, apheresis was started only if the set at 0.05. peripheral blood (PB) HPC count exceeded 5/ml.13 In YUMC, PBPC collection was started when PB CD34 þ cell count exceeded 10/ml. In both centers, PBPC were collected Results with a continuous-flow large-volume blood cell separator (Fenwal CS3000 plus, Baxter healthcare, Deerfield, IL, Patient characteristics USA). Each apheresis procedure was performed for The characteristics of the 50 patients who received either approximately 2–4 h, processing 10–14 l of blood. Leuka- ESHAP or HDCY are summarized in Table 1. The two pheresis was continued for up to 9 days, until analysis groups were well matched with respect to participating confirmed the collection of X5 Â 106/cells/kg, regarded as center, age, sex, and prior radiotherapy involving the axial the criterion for ‘optimal’ PBPC collection in our institu- skeleton. However, the number of prior chemotherapy tions. PBPC harvest was discontinued after at least 2 days regimens and the number of patients who had been exposed from the initiation of leukapheresis when a single apheresis to both cyclophosphamide and cisplatin, which predict resulted in fewer than 0.2 Â 106 cells/kg and the apheresis poor mobilization,14 were significantly higher in the CD34 þ cell count declined. The quantities of CD34 þ ESHAP group (P ¼ 0.001 and 0.01, respectively). In cells in PB and leukapheresis components were determined addition, more patients in the ESHAP group had bone as described previously.11,12 marrow involvement at the time of diagnosis and patients in the HDCY group tended to have received fewer cycles of High-dose chemotherapy with PBPC support conventional chemotherapy prior to MC.

The carmustine, etoposide, cytarabine, and cyclophospha- PBPC harvest yields for the ESHAP and HDCY groups mide (BEAC) regimen was used for 35patients, whereas the carmustine, etoposide, cytarabine, and melphalan (BEAM) The apheresis yields for the ESHAP and HDCY groups are regimen was used for the remaining 15patients. There were shown in Table 2. There were no between-group differences no between-group differences in high-dose chemotherapy in apheresis initiation criteria and days of G-CSF use. regimens (P ¼ 0.87). In each institution, patients were cared Aphereses were started on day 16 (median) in the ESHAP for in a single room, which may have been equipped with a (range 13–22) and on day 14 (median) in the HDCY group HEPA ﬁlter system, and with reverse isolation. G-CSF (range 12–22) (P ¼ 0.002). The number of total MNCs (5 mg/kg) was begun the day after PBPC infusion and was collected was signiﬁcantly greater in the HDCY group

Bone Marrow Transplantation ESHAP mobilization in NHL J-L Lee et al 451 Table 1 Patient characteristics (N ¼ 50)

ESHAP (N ¼ 26) HDCY (N ¼ 24) P-value

No.% No.%

Participating centers 1.0 AMC 24 92 22 92 YUMC 2 8 2 8

Age (years) Median (range) 45(17–64) 45(16–63) 0.915

Male sex 19 73 19 79 0.745

WHO type 0.872 DLBL 14 54 12 50 NK/TL 2 8 1 4 PTCL 519 521 LBL 3 12 521 Others 2 8 1 4

Bone marrow involvement 10 39 3 13 0.057

Disease status 0.042 CR/PR to ﬁrst-line therapy 9 3516 70 CR/PR to second-line therapy 16 62 6 26 Refractory to second-line therapy 1 4 1 4 Prior radiotherapy 6 23 4 17 0.728

No.of chemotherapy regimens 0.001 1 7 27 14 58 2 3 12 8 33 3124628 441500

Prior chemotherapy regimen 0.01 Cy containing 9 3518 75 DDP containing 4 17 0 0 Both Cy and DDP containing 13 48 6 25

No.of prior chemotherapy cycles 0.151 Median (range) 6 (3–13) 5(3–10) Mean7s.d. 7.273.1 5.972.4

HDCY ¼ high-dose cyclophosphamide; AMC ¼ Asan Medical Center; YUMC ¼ Yeungnam University Medical Center; DLBL ¼ diffuse large B-cell lymphoma; NK/TL ¼ extranodal NK/T-cell lymphoma; PTCL ¼ peripheral T-cell lymphoma; LBL ¼ lymphoblastic lymphoma; DDP ¼ cisplatin.

Table 2 Results of CD34+ cell harvest

ESHAP (N ¼ 26) HDCY (N ¼ 24) P-value

Apheresis initiation criteria 1.0 AMC PB WBC 410K/ml, MNC 41K/ml, or HPC 45/ml1010 PB HPC 45/ml alone 14 12 YUMC PB CD34 410/ml22

Days of G-CSF usage 8 (3–13)a 8 (3–18) 0.32 No. of days to ﬁrst apheresis 16 (13–22) 14 (12–22) 0.002 No. of aphereses 2 (2–5) 4 (2–5) o0.001 Total no. of MNC Â 108/kg 3.63 (1.22–13.26) 6.99 (2.20–17.38) 0.002 Total no. of CD34+ cells Â 106/kg 12.0 (0.9–83.4) 5.0 (0.1–18.1) 0.003 % CD34+ cells in apheresis MNC 2.08 (0.29–19.00) 0.68 (0.02–5.16) 0.001 No. of CD34+ cells/kg/apheresis 6.0 (0.3–27.8) 1.9 (0.2–7.6) 0.001 First harvest CD34+ cells/kg 2.0 (0.1–22.0) 1.8 (0.0–7.4) 0.014 No. of patients with X2 Â 106 CD34+ cells/kg 24 (92%) 18 (75%) 0.132 No. of patients with X5 Â 106 CD34+ cells/kg 21 (81%) 12 (50%) 0.022 No. of patients with o1 Â 106 CD34+ cells/kg 1 (4%) 5(21%) 0.09

HDCY ¼ high-dose cyclophosphamide; AMC ¼ Asan Medical Center; YUMC ¼ Yeungnam University Medical Center; PB ¼ peripheral blood; HPC ¼ hematopoietic progenitor cell. aMedian (range).

Bone Marrow Transplantation ESHAP mobilization in NHL J-L Lee et al 452 (P ¼ 0.002), but the number of total CD34 þ cells was Engraftment characteristics in the ESHAP and HDCY significantly higher in the ESHAP group (P ¼ 0.003). The groups average number of aphereses per patient was significantly In all, 19 of the ESHAP-mobilized patients and 15of the lower in the ESHAP group (2.6) than in the HDCY group HDCY-mobilized patients underwent high-dose chemo- (3.8, Po0.001). As expected, the number of CD34 þ cells therapy and were evaluable for hematologic recovery collected per apheresis was much greater in the ESHAP (Table 3). The median time to engraftment was similar group (P ¼ 0.001, Figure 1). When we assessed the effects of for both groups . MC on the time to adequate and optimal PBPC collection using the log-rank test, we found that ESHAP was associated with a higher probability of faster achievement Comparison of toxicity and need for supportive care of both adequate and optimal PBPC collection (P ¼ 0.012, Toxicity after ESHAP and HDCY was evaluable for all and P ¼ 0.007, respectively; Figure 2). The proportion of patients who achieved optimal PBPC patients. HDCY was associated with higher toxicity, as assessed by frequency of neutropenic fever and need for collection was greater in the ESHAP group (P ¼ 0.022). Although not statistically significant, the proportion of supportive care (Table 4). In addition, grade 1 hematuria patients who were regarded as mobilization failures was (WHO) was observed in four patients in the HDCY group, but none in the ESHAP group. Grade 1 nausea and smaller in the ESHAP group (P ¼ 0.09). vomiting was present in seven and nine patients in the ESHAP and HDCY groups, respectively. Grade 1 neuro- sensory complications and grade 1 creatinine elevation 100 occurred in one and two patients in the ESHAP group, P = 0.001 respectively. All of these nonhematologic complications were mild and reversible within 2–3 days in all cases. Treatment-related death was not observed in either group. 10

Discussion /kg/apheresis 6 1 PBPCs can be collected after the administration of G-CSF 10

× alone or in combination with myelosuppressive chemotherapy, with more PBPCs collected following the latter.15 HDCY (4–7 g/m2) plus G-CSF is the most commonly used 0.1 regimen to mobilize PBPCs,4 and most patients with

CD34+ cells myeloma or lymphoma undergo a course of variable cyclophosphamide doses to mobilize PBPCs. In the setting

0.01 ESHAP HDCY Table 3 Hematopoietic recovery after high-dose chemotherapy

Figure 1 Number of CD34 þ cells collected per apheresis following ESHAP HDCY P-value ESHAP or HDCY mobilization. (N ¼ 26) (N ¼ 24)

No. of patients without 7 (27%) 9 (38%) 0.423 ASCT No. of CD34+ cells Â 106/kg 7.6 (1.9–48.6)a 5.2 (3.0–12.5) 0.024 infused 100 ESHAP No. of days to an ANC 11 (10–24) 12 (10–22) 0.511 X 9 90 0.5 Â 10 /l No. of days to a platelet 16 (9–60+) 14 (11–47+) 0.102 80 HDCY count X20 Â 109/l 70 aMedian (range). 60 50 40 Table 4 Toxicities and supportive care after mobilization chemo- 30 therapy

20 ESHAP HDCY P-value Cumulative percentage (%) P = 0.007 10 (N ¼ 26) (N ¼ 24) 0 Neutropenic fever 5(19%) 12 (50%) 0.04 012345678Documented infection 2 (8%) 5(21%) 0.23 Days of apheresis Platelet transfusion 2 (8%) 7 (29%) 0.07 RBC transfusion 11 (42%) 13 (54%) 0.40 Figure 2 Days to achieve CD34 cells X5 Â 106/kg.

Bone Marrow Transplantation ESHAP mobilization in NHL J-L Lee et al 453 of relapsed or primary refractory lymphoma after cyclo- efficacy. The use of dexa-BEAM is hindered by stem cell phosphamide-containing combination chemotherapy, how- toxicity caused by carmustine and melphalan, which reduce ever, the MC should be directed toward the dual objectives the quantity and quality of harvested cells.26 The IVE of good antilymphoma activity and adequate PBPC (ifosfamide 9 g/m2, etoposide 600 mg/m2, and epirubicin mobilization, conditions under which HDCY may lose 50 mg/m2) regimen has been reported to result in good most of its utility. ESHAP has been shown to be effective as mobilization, with a median CD34 þ cell yield of 1.94 Â 106 an active salvage therapy for lymphoma.5,6 ESHAP has cells/kg/apheresis.24 The IVE regimen, however, seems to been reported to be superior to DHAP (dexamethasone, be more toxic than ESHAP, and the dose of epirubicin is high-dose cytarabine, and cisplatin) in response rate, not good for patients with NHL refractory to adriamycin- survival, and time to treatment failure, with fewer containing regimens.27 The ICE (Ifosfamide 5g/m 2, carbo- toxicities.6 Furthermore, DHAP was not superior to platin AUC of 5, and etoposide 300 mg/m2 every 2 weeks) HDCY in mobilization potential.16 Mobilization of stem regimen has been found to have a good mobilization cells following ESHAP should decrease the time to efficacy, with a median CD34 þ cell yield of 8.4 Â 106 cells/ transplant by making separate MC unnecessary while kg in a median of 3 aphereses,18 as well as favorable controlling the patient’s lymphoma. To date, however, antilymphoma activity, with a response rate of 72% in ESHAP plus G-CSF has been utilized only to a limited patients with relapsed aggressive NHL. Although we did extent for mobilization chemotherapy in NHL,7–9 and there not compare ESHAP with other combination MC regi- have been no comparisons between ESHAP and HDCY in mens, our results indicate that ESHAP may be comparable terms of mobilization efficacy. to or better than the IVE or ICE regimen in mobilization Our retrospective analysis shows that ESHAP is a highly potential. effective mobilization regimen. This finding is in contrast to Our analysis has limitations inherent to retrospective a previous report, which showed that a high-dose studies. Although we did not identify any preset patient cytarabine-containing regimen was associated with poor characteristics determining the use of ESHAP or HDCY mobilization of PBPC.17,18 Although the majority of the for MC, differences in patient characteristics may have patients in the ESHAP group could be regarded as having influenced the mobilization efficacy of these regimens. This characteristics that predicted poor mobilization, including is counteracted by our finding that, despite more patients in exposure to cyclophosphamide and cisplatin, the presence the ESHAP group having characteristics of poor mobili- of bone marrow involvement, and greater numbers of zers, ESHAP was superior to HDCY in mobilization previous chemotherapy regimens and cycles,14,19 the med- efficacy. Another potential limitation of our study was in ian number of CD34 þ cells collected per apheresis in the regard to the criteria for initiating apheresis, which varied ESHAP group was 6.0 Â 106/kg, and 92% of these patients with time and by participating center. We observed no achieved a threshold value of 2 Â 106/kg. Moreover, in this difference between regimens, however, in starting times for group, the median number of aphereses required to achieve PBPC collection (P ¼ 1.0). Finally, the schedules for adequate PBPC collection was 1, which is superior to the administration of G-CSF after MC varied during the study result for the HDCY group. The engraftment kinetics was period as the reimbursement policy of medical insurance similar between the two groups, indicating that the quality changed with time, which may have caused a relatively high of ESAHP-mobilized PBPC was satisfactory. In our study, incidence of neutropenic fever in the HDCY group. Thus, the patients in the ESHAP group had a significantly longer no meaningful conclusions regarding the relative toxicities interval between the initiation of mobilization chemother- of these regimens with those of regimens with scheduled apy and the start of apheresis, suggesting that ESHAP is early G-CSF administration can be drawn from our data. more myelosuppressive than HDCY.9 However, ESHAP is In conclusion, we have shown here that the ESHAP administered over 5days, which may explain the longer regimen is effective as a combined mobilization and second- interval to initiation of apheresis. Compared with HDCY, line regimen for patients with pretreated lymphoma. the ESHAP regimen was better tolerated, with no serious Prospective randomized trials, including a larger number adverse events including treatment-related mortality. of patients stratified for pre-mobilization predictors known In agreement with a previous study,9 our results confirm to influence PBPC harvest, are needed to draw firm that ESHAP plus G-CSF resulted in a higher CD34 þ cell conclusions on the best mobilization regimens with power- yield with a lower MNC harvest, resulting in a significantly ful antilymphoma activities. higher proportion of CD34 þ cells in the apheresis (P ¼ 0.001). This is advantageous in terms of the final purity and enrichment of CD34 þ cells,9,20 as well as for CD34 þ selection or tandem transplantation. This may be References more effective than current single high-dose chemotherapy in appropriately selected patients, such as those with 1 Vose JM, Zhang MJ, Rowlings PA et al. Autologous refractory or early relapsed high-grade NHL.21 Further- transplantation for diffuse aggressive non-Hodgkin’s lymphoma in patients never achieving remission: a report from the more, CD34 þ cell dose is important because of the Autologous Blood and Marrow Transplant Registry. J Clin correlation between the number of CD34 þ cells infused Oncol 2001; 19: 406–413. 22 and the speed and durability of engraftment. 2 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone Although several combination chemotherapy regimens marrow transplantation as compared with salvage chemother- have been used for PBPC mobilization in lymphoma apy in relapses of chemotherapy-sensitive non-Hodgkin’s patients,18,23–25 few studies have compared harvest and lymphoma. N Engl J Med 1995; 333: 1540–1545.

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