The ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) regimen has been shown to be effective as an active salvage therapy for lymphoma. Mobilizing stem cells following ESHAP should decrease time to transplantation by making separate mobilizing chemotherapy (MC) unnecessary, while controlling a patient's lymphoma. We therefore assessed the mobilization potential of ESHAP plus G-CSF in 26 patients (ESHAP group) with non-Hodgkin's lymphoma (NHL) and compared these results with those of 24 patients with NHL who received high-dose (4 g/m2l) cyclophosphamide (HDCY) as MC (HDCY group). The age, sex, and radiotherapy to the axial skeleton were well matched between groups, but the number of patients with poor mobilization predictors was higher in the ESHAP group. Significantly higher numbers of CD34+ cells (× 106/kg) (17.1±18.8 vs 5.8±5.0, P=0.03) and apheresis day 1 CD34+ cells (× 106/kg) (5.5±6.6 vs 1.7±2.0, P=0.014) were collected from the ESHAP group than from the HDCY group, and the number of patients who achieved an optimal CD34+ cell target of 5 × 106/kg was higher in the ESHAP group (81 vs 50%, P=0.022). Log-rank test revealed that time to target peripheral blood progenitor cell collection (⩾5 × 106/kg) was shorter in the ESHAP group (P=0.007). These results indicate that ESHAP plus G-CSF is an excellent mobilization regimen in patients with relapsed and poor-risk aggressive NHL.
High-dose chemotherapy along with autologous peripheral blood hematopoietic stem cell transplantation is widely used for relapsed or primary refractory non-Hodgkin's lymphoma (NHL).1,2,3 The use of chemotherapy and G-CSF in this setting should be directed to the dual objectives of good antilymphoma activity and mobilization of an adequate number of peripheral blood progenitor cells (PBPC). Although the regimen of cyclophosphamide and G-CSF is good for PBPC mobilization in various diseases and situations,4 it is less effective in cases of primary refractory or relapsed lymphoma after cyclophosphamide-containing combination chemotherapy. In these patients, where potent antilymphoma activity is needed, the regimen of cyclophosphamide plus G-CSF theoretically loses most of its utility. The ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) regimen has been shown to be effective as active salvage therapy for lymphoma.5,6 Mobilization of stem cells following ESHAP chemotherapy is attractive, as it should decrease the time to transplant by making separate mobilizing chemotherapy (MC) unnecessary while controlling a patient's lymphoma. However, ESHAP plus G-CSF has been utilized only to a limited extent for MC in NHL.7,8,9
We report here the results of MC using ESHAP plus G-CSF in 26 patients with NHL. In addition, we compare the mobilizing potential of ESHAP plus G-CSF with that of a high-dose cyclophosphamide (HDCY) regimen.
Patients and methods
The autologous stem cell transplantation (ASCT) data registry of Asan Medical Center (AMC) and Yeungnam University Medical Center (YUMC) revealed that 26 patients with aggressive NHL received ESHAP chemotherapy followed by G-CSF prior to collection of PBPC between July 1998 and March 2004. During the same period, 24 patients with NHL received HDCY with G-CSF as the mobilization regimen. We collected the demographic characteristics, harvest results, post-ASCT hematologic recovery, and adverse event data from those groups of patients. There were no preset criteria or patient characteristics that determined whether patients received ESHAP or HDCY for MC.
MC, PBPC harvest and CD34 cell quantitation
The ESHAP regimen consisted of etoposide (40 mg/m2, days 1–4), methylprednisolone (500 mg, days 1–5), cytarabine (2 g/m2, day 5), and cisplatin (25 mg/m2, days 1–4), as described previously.5 HDCY (4 g/m2) was given in a 90 min infusion with intravenous hydration and MESNA (2-mercaptoethane sulfonate).4,10 In the early phase of study period, G-CSF (10 μg/kg/day; Lenograstim, Neutrogin™, Choongwae, Seoul, South Korea) was given subcutaneously, starting on the day the WBC first rose after the nadir after ESHAP or HDCY had ended and continuing until the day before the last apheresis. Since July 2002, G-CSF (10/kg/day) was started on day 6 for ESHAP and on day 2 for HDCY and continued until the completion of apheresis. CBC was monitored daily from 3 days after the end of ESHAP and from 7 days after the completion of HDCY. The criteria for apheresis commencement differed in the participating centers. In AMC, from July 1998 to July 2002, the first PBPC harvest was initiated on the day when the first of the following occurred: (1) WBC count exceeded 10.0 × 109/l; (2) MNC count exceeded 1.0 × 109/l; or (3) hematopoietic progenitor cell (HPC) count, as assessed by an automated hematology analyzer (SE-9000, Sysmex, Kobe, Japan), exceeded 5/μl.11,12 Since July 2002, apheresis was started only if the peripheral blood (PB) HPC count exceeded 5/μl.13 In YUMC, PBPC collection was started when PB CD34+ cell count exceeded 10/μl. In both centers, PBPC were collected with a continuous-flow large-volume blood cell separator (Fenwal CS3000 plus, Baxter healthcare, Deerfield, IL, USA). Each apheresis procedure was performed for approximately 2–4 h, processing 10–14 l of blood. Leukapheresis was continued for up to 9 days, until analysis confirmed the collection of ⩾5 × 106/cells/kg, regarded as the criterion for ‘optimal’ PBPC collection in our institutions. PBPC harvest was discontinued after at least 2 days from the initiation of leukapheresis when a single apheresis resulted in fewer than 0.2 × 106 cells/kg and the apheresis CD34+ cell count declined. The quantities of CD34+ cells in PB and leukapheresis components were determined as described previously.11,12
High-dose chemotherapy with PBPC support
The carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC) regimen was used for 35 patients, whereas the carmustine, etoposide, cytarabine, and melphalan (BEAM) regimen was used for the remaining 15 patients. There were no between-group differences in high-dose chemotherapy regimens (P=0.87). In each institution, patients were cared for in a single room, which may have been equipped with a HEPA filter system, and with reverse isolation. G-CSF (5 μg/kg) was begun the day after PBPC infusion and was continued until the absolute neutrophil count (ANC) was at least 1.0 × 109/l on 2 consecutive days. Platelet transfusions were administered empirically for patients with platelet counts of 2.0 × 109/l or lower or for clinical bleeding.
After MC, days to first apheresis were measured from the first day of chemotherapy administration (day 0). CD34+ cells ⩾2.0 × 106 and ⩾5.0 × 106/kg were defined as ‘adequate’ and ‘optimal’ PBPC for ASCT, respectively, whereas CD34+ cells <1.0 × 106/kg was regarded as mobilization failure. Days to adequate or optimal PBPC collection were measured from the first day of apheresis. After high-dose chemotherapy, hematopoietic recovery was measured from the day of PBPC infusion (day 0).
Patient characteristics, apheresis components, and post-ASCT hematologic recovery data are described using summary statistics as median values and ranges, or as means and standard deviations. All continuous variables were analyzed using the Mann–Whitney test. Proportions were compared using the χ2 test or Fisher's exact test, as appropriate. Sessions of apheresis needed to achieve adequate or optimal PBPC collection were estimated using the product-limit method according to Kaplan and Meier and were compared using the log-rank test. Statistical analysis was performed with SPSS for Windows V. 10.0 (SPSS Inc., Chicago, IL, USA) and significance levels were set at 0.05.
The characteristics of the 50 patients who received either ESHAP or HDCY are summarized in Table 1. The two groups were well matched with respect to participating center, age, sex, and prior radiotherapy involving the axial skeleton. However, the number of prior chemotherapy regimens and the number of patients who had been exposed to both cyclophosphamide and cisplatin, which predict poor mobilization,14 were significantly higher in the ESHAP group (P=0.001 and 0.01, respectively). In addition, more patients in the ESHAP group had bone marrow involvement at the time of diagnosis and patients in the HDCY group tended to have received fewer cycles of conventional chemotherapy prior to MC.
PBPC harvest yields for the ESHAP and HDCY groups
The apheresis yields for the ESHAP and HDCY groups are shown in Table 2. There were no between-group differences in apheresis initiation criteria and days of G-CSF use. Aphereses were started on day 16 (median) in the ESHAP (range 13–22) and on day 14 (median) in the HDCY group (range 12–22) (P=0.002). The number of total MNCs collected was significantly greater in the HDCY group (P=0.002), but the number of total CD34+ cells was significantly higher in the ESHAP group (P=0.003). The average number of aphereses per patient was significantly lower in the ESHAP group (2.6) than in the HDCY group (3.8, P<0.001). As expected, the number of CD34+ cells collected per apheresis was much greater in the ESHAP group (P=0.001, Figure 1). When we assessed the effects of 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 of both adequate and optimal PBPC collection (P=0.012, and P=0.007, respectively; Figure 2).
The proportion of patients who achieved optimal PBPC collection was greater in the ESHAP group (P=0.022). Although not statistically significant, the proportion of patients who were regarded as mobilization failures was smaller in the ESHAP group (P=0.09).
Engraftment characteristics in the ESHAP and HDCY groups
In all, 19 of the ESHAP-mobilized patients and 15 of the HDCY-mobilized patients underwent high-dose chemotherapy and were evaluable for hematologic recovery (Table 3). The median time to engraftment was similar for both groups.
Comparison of toxicity and need for supportive care
Toxicity after ESHAP and HDCY was evaluable for all patients. HDCY was associated with higher toxicity, as assessed by frequency of neutropenic fever and need for supportive care (Table 4). In addition, grade 1 hematuria (WHO) was observed in four patients in the HDCY group, but none in the ESHAP group. Grade 1 nausea and vomiting was present in seven and nine patients in the ESHAP and HDCY groups, respectively. Grade 1 neurosensory complications and grade 1 creatinine elevation occurred in one and two patients in the ESHAP group, 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.
PBPCs can be collected after the administration of G-CSF 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 regimen to mobilize PBPCs,4 and most patients with myeloma or lymphoma undergo a course of variable cyclophosphamide doses to mobilize PBPCs. In the setting of relapsed or primary refractory lymphoma after cyclophosphamide-containing combination chemotherapy, however, the MC should be directed toward the dual objectives of good antilymphoma activity and adequate PBPC mobilization, conditions under which HDCY may lose most of its utility. ESHAP has been shown to be effective as an active salvage therapy for lymphoma.5,6 ESHAP has been reported to be superior to DHAP (dexamethasone, high-dose cytarabine, and cisplatin) in response rate, survival, and time to treatment failure, with fewer toxicities.6 Furthermore, DHAP was not superior to HDCY in mobilization potential.16 Mobilization of stem cells following ESHAP should decrease the time to transplant by making separate MC unnecessary while controlling the patient's lymphoma. To date, however, ESHAP plus G-CSF has been utilized only to a limited extent for mobilization chemotherapy in NHL,7,8,9 and there have been no comparisons between ESHAP and HDCY in terms of mobilization efficacy.
Our retrospective analysis shows that ESHAP is a highly effective mobilization regimen. This finding is in contrast to a previous report, which showed that a high-dose cytarabine-containing regimen was associated with poor mobilization of PBPC.17,18 Although the majority of the patients in the ESHAP group could be regarded as having characteristics that predicted poor mobilization, including exposure to cyclophosphamide and cisplatin, the presence of bone marrow involvement, and greater numbers of previous chemotherapy regimens and cycles,14,19 the median number of CD34+ cells collected per apheresis in the ESHAP group was 6.0 × 106/kg, and 92% of these patients achieved a threshold value of 2 × 106/kg. Moreover, in this group, the median number of aphereses required to achieve adequate PBPC collection was 1, which is superior to the result for the HDCY group. The engraftment kinetics was similar between the two groups, indicating that the quality of ESAHP-mobilized PBPC was satisfactory. In our study, the patients in the ESHAP group had a significantly longer interval between the initiation of mobilization chemotherapy and the start of apheresis, suggesting that ESHAP is more myelosuppressive than HDCY.9 However, ESHAP is administered over 5 days, which may explain the longer interval to initiation of apheresis. Compared with HDCY, the ESHAP regimen was better tolerated, with no serious adverse events including treatment-related mortality.
In agreement with a previous study,9 our results confirm that ESHAP plus G-CSF resulted in a higher CD34+ cell yield with a lower MNC harvest, resulting in a significantly higher proportion of CD34+ cells in the apheresis (P=0.001). This is advantageous in terms of the final purity and enrichment of CD34+ cells,9,20 as well as for CD34+ selection or tandem transplantation. This may be more effective than current single high-dose chemotherapy in appropriately selected patients, such as those with refractory or early relapsed high-grade NHL.21 Furthermore, CD34+ cell dose is important because of the correlation between the number of CD34+ cells infused and the speed and durability of engraftment.22
Although several combination chemotherapy regimens have been used for PBPC mobilization in lymphoma patients,18,23,24,25 few studies have compared harvest and efficacy. The use of dexa-BEAM is hindered by stem cell toxicity caused by carmustine and melphalan, which reduce the quantity and quality of harvested cells.26 The IVE (ifosfamide 9 g/m2, etoposide 600 mg/m2, and epirubicin 50 mg/m2) regimen has been reported to result in good mobilization, with a median CD34+ cell yield of 1.94 × 106 cells/kg/apheresis.24 The IVE regimen, however, seems to be more toxic than ESHAP, and the dose of epirubicin is not good for patients with NHL refractory to adriamycin-containing regimens.27 The ICE (Ifosfamide 5 g/m2, carboplatin AUC of 5, and etoposide 300 mg/m2 every 2 weeks) regimen has been found to have a good mobilization efficacy, with a median CD34+ cell yield of 8.4 × 106 cells/kg in a median of 3 aphereses,18 as well as favorable antilymphoma activity, with a response rate of 72% in patients with relapsed aggressive NHL. Although we did not compare ESHAP with other combination MC regimens, our results indicate that ESHAP may be comparable to or better than the IVE or ICE regimen in mobilization potential.
Our analysis has limitations inherent to retrospective studies. Although we did not identify any preset patient characteristics determining the use of ESHAP or HDCY for MC, differences in patient characteristics may have influenced the mobilization efficacy of these regimens. This is counteracted by our finding that, despite more patients in the ESHAP group having characteristics of poor mobilizers, ESHAP was superior to HDCY in mobilization efficacy. Another potential limitation of our study was in regard to the criteria for initiating apheresis, which varied with time and by participating center. We observed no difference between regimens, however, in starting times for PBPC collection (P=1.0). Finally, the schedules for administration of G-CSF after MC varied during the study period as the reimbursement policy of medical insurance changed with time, which may have caused a relatively high incidence of neutropenic fever in the HDCY group. Thus, no meaningful conclusions regarding the relative toxicities of these regimens with those of regimens with scheduled early G-CSF administration can be drawn from our data.
In conclusion, we have shown here that the ESHAP regimen is effective as a combined mobilization and second-line regimen for patients with pretreated lymphoma. Prospective randomized trials, including a larger number of patients stratified for pre-mobilization predictors known to influence PBPC harvest, are needed to draw firm conclusions on the best mobilization regimens with powerful antilymphoma activities.
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Lee, J., Kim, S., Kim, S. et al. 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. Bone Marrow Transplant 35, 449–454 (2005) doi:10.1038/sj.bmt.1704798
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