Progenitor Cell Mobilisation Cyclophosphamide, Etoposide and G-CSF to Mobilize Peripheral Blood Stem Cells for Autologous Stem C

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Bone Marrow Transplantation (2002) 30, 273–278  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Progenitor cell mobilisation Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma

P Mollee, D Pereira, T Nagy, K Song, R Saragosa, A Keating and M Crump

University of Toronto Autologous Blood and Marrow Transplant Service, Princess Margaret Hospital, Toronto, Canada

Summary: in patients with lymphoma. Engraftment following transplantation of PBSCs is more rapid than with bone marrow1 We aimed to assess the effectiveness of cyclophospham- and has been demonstrated to correlate best with the num- ide, etoposide and G-CSF (C+E) to mobilize peripheral ber of CD34+ cells in the graft. With standardization of blood stem cells for autologous stem cell transplantation CD34+ enumeration,2 у5 ϫ 106/kg CD34+ cells has been in patients with lymphoma. A matched cohort study was suggested as a reasonable target for PBSC collection, as performed comparing patients mobilized with C+Eto this allows optimal engraftment in nearly all patients.3–5 patients mobilized with cyclophosphamide and G-CSF Alternatively, transplantation of Ͻ1to2ϫ 106/kg CD34+ (C alone). Patients were matched for disease, prior cells has been associated with delayed and failed radiotherapy and a chemotherapy score reflecting the engraftment,6–10 leading to the concept of a minimum thres- amount and type of prior chemotherapy. Thirty-eight hold CD34+ count in order to safely proceed with ASCT. consecutive patients mobilized with C+E were com- Optimizing PBSC collection remains an important goal pared with 38 matched controls. C+E was equivalent for several reasons: to increase the proportion of patients to C alone in terms of numbers of patients achieving a who can proceed to ASCT; to reduce the time to hematopo- 6 + minimum threshold of у2 ؋ 10 /kg CD34 cells (82% ietic recovery post transplant; to maximize the efficiency = + vs 79%, P 0.74). C E was superior, however, in terms of the PBSC collection process given the morbidity and ؋ 6 Ͻ + of total CD34 yield (6.35 vs 3.3 10 /kg, P 0.01), costs of apheresis; and to reduce the need for second mobil- у ؋ 6 achieving a target graft of 5 10 /kg (55% vs 34%, izations and bone marrow harvests. Several studies5,11–14 = P 0.04) and obtaining both a minimum (61% vs 32%, have described factors influencing the yield of PBSCs, Ͻ Ͻ P 0.01) and target (45% vs 13%, P 0.01) graft in including age, diagnosis, marrow involvement, prior radi- one apheresis. This superiority was largely confined to ation and time from prior chemotherapy therapy, but patients with lower chemotherapy scores. There was no amount of previous chemotherapy seems to be the most difference in neutrophil and platelet recovery or trans- consistent. The prior use of stem cell toxic regimens or fusion requirements for those who subsequently agents such as nitrogen mustard, procarbazine, melphalan, received high-dose therapy and stem cell transplan- carmustine, high-dose cytarabine,15 Dexa-BEAM16 and tation. Thus, C+E improves the efficiency of peripheral mini-BEAM17,18 result in poor and unpredictable mobiliz- blood stem cell collection, but does not increase the 19,20 number of patients who can proceed to transplantation. ation. Chemotherapy scoring systems can predict Most of the benefit of the regimen was confined to patients at risk of mobilization failure for whom new patients who had not received extensive prior therapy. strategies are required. While several mobilization regimens have been reported, Novel strategies are required to increase the collection 2 efficiency of ‘hard to mobilize’ patients. single agent cyclophosphamide (1–7 g/m ) followed by Bone Marrow Transplantation (2002) 30, 273–278. filgrastim (G-CSF) remains one of the most common. It has doi:10.1038/sj.bmt.1703653 been reported that combination chemotherapy with cyclo- + Keywords: stem cell mobilization; cyclophosphamide; phosphamide, etoposide and G-CSF (C E) is superior to etoposide; lymphoma cyclophosphamide and G-CSF (C alone), and may add an additional anti-lymphoma effect.21 We explored the use of C+E given the difficulty with mobilization in heavily pretreated lymphoma patients using C alone, the more predict- Peripheral blood stem cells (PBSCs) are currently the graft able timing of mobilization following C+E than with of choice for autologous stem cell transplantation (ASCT) ESHAP or DHAP chemotherapy, and the ability to deliver C+E as an out-patient. Here, we report our experience with the C+E mobilizing regimen. To overcome some of the Correspondence: Dr M Crump, Princess Margaret Hospital, 610 University Avenue, Suite 5-108, Toronto, ON M5G 2M9, Canada biases associated with historic comparisons, we have per- Received 22 January 2002; accepted 24 April 2002 formed a matched cohort analysis comparing patients mobi- Cyclophosphamide and VP-16 to mobilize stem cells P Mollee et al 274 lized with C+E versus C alone, matched for factors likely received cyclophosphamide 2.5 g/m2 i.v. on day 1. Both to influence PBSC collection efficiency. regimens were followed by G-CSF 10 ␮g/kg once daily s.c., starting on day 4 for C alone patients and day 6 for C+E patients, until harvesting was complete. PBSC collec- Materials and methods tion commenced on day 13 (C+E) or day 11 (C alone) pro- vided that the peripheral blood CD34+ count was у5 Patients cells/␮l. PBSCs were collected by continuous apheresis, processing three blood volumes, using the Cobe Spectra Consecutive patients undergoing their first PBSC mobiliz- (Lakewood, CO, USA). ation with C+E were identified from the ASCT database. Patients undergoing autologous transplantation received Only patients with Hodgkin’s disease and non-Hodgkin’s etoposide 60 mg/kg i.v. over 5 or 32 h day Ϫ4 and mel- lymphoma were considered. Matched controls were selec- phalan 180 mg/m2 over 30 min on day Ϫ3. Peripheral blood ted with a cohort of all lymphoma patients mobilized with stem cells were infused on day 0. Routine transfusion trig- C alone from January 1999 to December 2000. This gers included platelets Ͻ10 ϫ 109/l and hemoglobin Ͻ80 allowed comparison with a cohort of patients with identical g/l. G-CSF 300 ␮g s.c. was commenced on day 7. PBSC collection techniques (CD34+ enumeration, com- mencement of apheresis depending on peripheral blood CD34+ count, apheresis procedure). Data abstracted Statistical analysis included patient demographics, disease status and prior therapy, daily CD34+ yields and days of apheresis, and if In validating the modified chemotherapy score in the 1999/2000 cohort, the score was categorized as a binary transplanted, time to hematopoietic recovery, transfusion Ͻ у requirements and days of hospitalization. variable ( 42 vs 42), the cutoff corresponding to the 50th percentile for this group of patients. The chi-square test was used to determine the effect of the chemotherapy score on Matching of patients the proportion of patients achieving a CD34+ yield of у2 ϫ 6 Patients were matched for diagnosis (Hodgkin’s disease vs 10 /kg. In the matched cohort analysis, study endpoints included: non-Hodgkin’s lymphoma), prior radiotherapy to the axial у ϫ skeleton and a previously validated chemotherapy score the proportion of patients achieving minimum ( 2 6 + у ϫ 6 + (within a limit of Ϯ3).19 If more than one patient potentially 10 /kg CD34 ) and target ( 5 10 /kg CD34 ) collections; the proportion of patients achieving these thresholds matched, the patient with the most recent mobilization date + was chosen. Matching was performed in a manner blinded in one apheresis; total CD34 yield; time to recovery of neutrophils Ͼ0.5 ϫ 109/l and platelets Ͼ20 ϫ 109/l, and to all potential outcomes. + The chemotherapy score, as outlined in Table 1, was days of hospitalization. The impact of C E on these end- slightly modified from that reported by Drake et al,19 with points was assessed using McNemar’s test for categorical the addition of a score of two for cytarabine, which was variables and the sign-rank test for continuous variables. not included in the original scoring system. This was in All analyses were performed using the STATA (University order to accommodate the majority of non-Hodgkin’s lym- of Texas) statistical software package. Summary statistics phoma patients salvaged with ESHAP or DHAP, both cyta- use median values with ranges in brackets. rabine-containing regimens. The modified score was then applied to the 1999/2000 cohort of patients mobilized with C alone to validate its utility as a predictor of PBSC mobil- Results ization with that regimen. Patient characteristics and matching Mobilization and transplantation Forty-eight consecutive lymphoma patients were mobilized with C+E between July 2000 and October 2001. Of these, + Patients mobilized with C E received cyclophosphamide 38 could be successfully matched as detailed in the 2 2 2.5 g/m i.v. on day 1 and etoposide 200 mg/m once daily materials and methods section. Ten could not be matched i.v. on days 1–3 on an outpatient basis. The C alone group due mainly to the recent use of a gemcitabine-based salvage regimen that precluded the assignment of a chemotherapy score to these patients. The characteristics of these 38 Table 1 Derivation of chemotherapy score (modified from Drake et al19) patients and their matched controls along with the entire 1999/2000 cohort mobilized with C alone are detailed in + Toxicity grade Drugs Table 2. When C E patients were compared with their matched C alone recipients, there was no difference in age, 0 Prednisone, dexamethasone sex, disease status, marrow involvement or number of prior 1 Vincristine, vinblastine, bleomycin, interferon chemotherapy regimens. 2 Cyclophosphamide, anthracyclines, cisplatin, etoposide, cytarabine 3 Chlorambucil, procarbazine Validation of ‘modified’ chemotherapy score 4 Melphalan, carmustine, mechlorethamine, lomustine Of the 98 patients in the entire C-mobilized cohort, 45% Score = (number of cycles of each drug) ϫ (toxicity grade). had a chemotherapy score Ͻ42 (low score) and 55% scored

Bone Marrow Transplantation Cyclophosphamide and VP-16 to mobilize stem cells P Mollee et al 275 Table 2 Patient characteristics appears to have improved with the use of C+E compared to the previous C-mobilized cohort (70% vs 82%, P = 0.18), C+E C C (all the matched analysis demonstrates no difference in this (matched 1999/2000) regard. Thus, the matching process is likely to be correcting controls) for the lower chemotherapy score in C+E patients compared to patients mobilized with C alone (see Table 2). n 38 38 98 Significantly more patients obtained the minimum threshold Tumor type + HD (%) 34% 34% 34% number of CD34 cells after a single apheresis when mobil- NHL (%) 66% 66% 68% ized with C+E (61% vs 32%, P Ͻ 0.01). In subgroup analy- Disease status (%) sis C+E was not superior to C alone according to tumor First remission 3% 8% 10% Chemosensitive primary non- 16% 18% 16% type or chemotherapy score in achieving a minimum thres- responder hold. The chemotherapy score was predictive of mobiliz- Untested first relapse 15% 6% 4% ation failure for all patients in the matched cohorts (9% if Chemosensitive first relapse 63% 63% 56% score Ͻ42 vs 32% if score у42, P = 0.01). Patients with у Second relapse 3% 5% 14% Hodgkin’s disease mobilized better than patients with non- Prior radiotherapy 37% 37% 34% Chemotherapy score 38 (24– 39 (24– 42 (15– Hodgkin’s lymphoma, likely reflecting the type of prior 61) 60) 84) treatment given to these patients (median score 34 for Prior chemotherapy regimens 2 (1–3) 2 (1–3) 2 (1–7) Hodgkin’s disease vs 42 for non-Hodgkin’s lymphoma; Median age (years) 46 47 50 Table 3). Sex (% male) 58% 53% 59% Bone marrow involvement (%) 3% 3% 10% Target threshold (у5 ϫ 106/kg CD34+): C+E was superior + C+E = cyclophosphamide + etoposide; C = cyclophosphamide alone; HD to C alone in obtaining an optimal CD34 yield (56% vs = Hodgkin’s disease; NHL = non-Hodgkin’s lymphoma. 34%, P = 0.04), and this target could be collected with a single leukapheresis in significantly more patients (45% vs Ͻ у 13%, P 0.01). This improved collection efficiency, how- 42 (high score). This score was able to identify patients ever, appears to be confined to those patients with low at increased risk of mobilization failure; a graft of у2 ϫ chemotherapy scores, and does not appear to benefit those 106/kg was obtained in 88% of patients with a score Ͻ42, with a score у42 (Table 3). у P Ͻ compared to 56% of patients with a score 42 ( 0.01). Of the 10 patients who could not be matched, nine achieved a minimum threshold of у2 ϫ 106/kg CD34+ cells PBSC collections using C+E as a mobilizing regimen. Eight of these had received gemcitabine-based salvage chemotherapy and Mobilization results for the matched patients and the entire + their median CD34 yield was 17.5 ϫ 106/kg (range, 1.6– C-mobilized cohort are shown in Table 3. Detailed is the 37.7 ϫ 106/kg). total CD34+ yield and the proportion of patients obtaining both minimum and target PBSC numbers. The total CD34+ yield was significantly greater for C+E compared to C alone Engraftment vs ϫ 6 P Ͻ (6.35 3.3 10 /kg, 0.01). Days to platelet and neutrophil engraftment, transfusion requirements and length of hospital stay are detailed in Minimum threshold (у2 ϫ 106/kg CD34+): While the pro- + Table 4. The C+E mobilization regimen was not superior portion of patients achieving a minimum CD34 threshold to C alone for any of these parameters.

Table 3 Peripheral blood stem cell collections Discussion C+E C (matched C (all controls) 1999/2000) The collection of adequate numbers of PBSCs is a critical step in the management of lymphoma patients requiring Total CD34+ ϫ 106/kg 6.35 3.3* 3.4 + autotransplantation. The combination of cyclophosphamide CD34 у2 ϫ 106/kg All patients 82% 79% 70% Score у42 69% 67% 56% Ͻ Score 42 91% 90% 88% Table 4 Engraftment and hospitalization HD 92% 92% 77% NHL 76% 72% 67% + Obtained in 1 apheresis 61% 32%* 30% C E C (matched CD34+ у5 ϫ 106/kg controls) All patients 58% 34%* 34% Score у42 25% 22% 25% Platelets Ͼ20 (days) 10 (8–15) 11.5 (8–20) Score Ͻ42 82% 45%* 43% Neutrophils Ͼ0.5 (days) 10 (9–14) 11 (9–15) Obtained in 1 apheresis 45% 13%* 9% Platelet transfusion episodes 1 (0–6) 1.5 (0–8) Packed cell units transfused 2 (0–6) 2 (0–11) C+E= cyclophosphamide + etoposide; C = cyclophosphamide alone; HD Length of hospital stay (days) 18 (16–24) 20 (16–35) = Hodgkin’s disease; NHL = non-Hodgkin’s lymphoma. *P Ͻ 0.05 by matched pairs analysis (C+E vs C). C+E = cyclophosphamide + etoposide; C = cyclophosphamide alone.

Bone Marrow Transplantation Cyclophosphamide and VP-16 to mobilize stem cells P Mollee et al 276 and G-CSF is a well tolerated outpatient regimen that has lar CD34+ yields, but improved neutrophil engraftment and been used extensively for stem cell mobilization.17,22–25 It less toxicity with cyclophosphamide. Only one randomized is successful in the majority of patients, but a significant controlled trial has compared a chemotherapy-based regi- proportion cannot attain an adequate graft, especially those men (cyclophosphamide 5g/m2 + G-CSF) with a cytokine predicted to be ‘hard to mobilize’. Similarly, improvements alone (G-CSF alone).36 This demonstrated no difference in in the efficiency of the mobilization procedure could lead engraftment or CD34+ yields, although the number of to cost savings and reduced morbidity. We have demon- patients was small, and no patients progressed on salvage strated in this matched cohort study that C+E is more chemotherapy, suggesting a somewhat atypical lymphoma efficient, with increased progenitor yields and reduced days population. This trial highlighted the importance of con- of apheresis, compared to C alone. There was, however, no sidering engraftment rather than CD34+ yield as the clinical improvement in the proportion of patients who obtained a endpoint of interest. minimum threshold (у2 ϫ 106/kg CD34+) harvest in order Our study is limited by not being a randomized compari- to proceed safely to ASCT. Patients mobilized with C alone son, but uses a matched-pairs analysis based on factors required more aphereses compared to C+E, but were still known to influence mobilization efficiency to help over- able to eventually reach the minimum threshold and had come some of the biases associated with historical cohort similar hematopoietic recovery following high-dose chemo- comparisons. The difference in PBSC yields between the therapy. matched controls and the entire cohort from which they The use of cyclophosphamide and etoposide has been were selected illustrates the importance of appropriate reported in a randomized study by Schwartzberg et al26 matching in such comparisons of new mobilizing regimens. comparing different two doses of cyclophosphamide (2 vs While a chemotherapy score19 was primarily used in our 4 g/m2), given in combination with etoposide (600 mg/m2) study to match patients for prior chemotherapy exposure, and G-CSF. Both arms resulted in excellent progenitor it was also able to predict those at increased risk of mobiliz- yields, but the study population consisted of breast cancer ation failure. Furthermore, it was those patients predicted patients without extensive prior chemotherapy. The same to be ‘hard to mobilize’ who benefited least from the authors have reported a randomized trial comparing cyclo- addition of etoposide to the mobilizing regimen. Stiff et phosphamide plus etoposide, with or without cisplatin, in al37 have explored the addition of stem cell factor to G- lymphoma patients. More than 90% of patients in the cyclo- CSF in heavily pretreated lymphoma patients. This pro- phosphamide plus etoposide arm achieved a PBSC harvest duced improved CD34+ yields compared to those mobilized of Ͼ2 ϫ 106/kg CD34+ cells.27 The addition of cisplatin with G-CSF alone, although the proportion who achieved resulted in excessive toxicity with no additional benefitin Ͼ1 ϫ 106/kg CD34+ cells was not significantly different. mobilization. In summary, C+E mobilizing chemotherapy improves One concern with the use of etoposide in the mobiliz- the efficiency of PBSC collection compared to C alone by ation regimen is its potential contribution to an increased reducing days of apheresis and increasing progenitor yields. risk of secondary acute leukemia after ABMT.28,29 We used This effect, however, is largely confined to those patients a relatively low dose of etoposide (total 600 mg/m2), but with less prior chemotherapy and does not appear to benefit the long-term safety and leukemia risk of this lower dose more heavily pre-treated patients predicted to be ‘hard to will require additional follow-up. Ultimately, separating the mobilize’. The chemotherapy scoring system we used can contributions of DNA damaging agents (alkylating agents identify those patients where new strategies are required for such as cyclophosphamide and topoisomerase II inhibitors successful stem cell collection. We are currently prospec- such as etoposide) in salvage and mobilization chemo- tively evaluating the combination of cyclophosphamide, G- therapy, in addition to the high-dose therapy itself, with CSF and stem cell factor as a mobilizing regimen in this regard to this leukemic risk may be problematic. high-risk lymphoma population. It is difficult to compare the results of C+E to other mobilizing regimens because of the heterogeneous nature of the study populations, the lack of randomized trials and, until References recently, the lack of standardization in CD34+ enumer- 1 Schmitz N, Linch DC, Dreger P et al. Randomised trial of ation.2 Improved PBSC mobilization has been reported with 23,26,30 filgrastim-mobilised peripheral blood progenitor cell trans- higher doses of cyclophosphamide, although mor- plantation versus autologous bone-marrow transplantation in bidity from the procedure also rises. In a matched cohort lymphoma patients. Lancet 1996; 347: 353–357. study of ESHAP vs intermediate-dose cyclophosphamide, 2 Sutherland DR, Anderson L, Keeney M et al. The ISHAGE Watts et al31 reported that ESHAP significantly improved guidelines for CD34+ cell determination by flow cytometry. the proportion of patients obtaining a CD34+ yield Ͼ2 ϫ International Society of Hematotherapy and Graft Engineer- 106/kg in one apheresis (72% vs 22%) and improved pro- ing. J Hematother 1996; 5: 213–226. genitor yields on the first day of apheresis. The total num- 3 Weaver CH, Hazelton B, Birch R et al. An analysis of ber of progenitors collected, and median time to platelet engraftment kinetics as a function of the CD34 content of per- and neutrophil engraftment, were similar for both groups. ipheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood A number of chemotherapy-based mobilizing regimens has 32–35 1995; 86: 3961–3969. been reported in lymphoma patients, however, only one 4 Sutherland DR, Filshie R, Nayar R et al. Clinical validation of 32 is a randomized comparison to cyclophosphamide alone. the single platform ISHAGE protocol in the transplant setting: That trial compared ifosfamide 10 g/m2 and GM-CSF to speed of engraftment highly correlates with numbers of cyclophosphamide 4 g/m2 and GM-CSF and reported simi- CD34+ cells infused. Blood 1999; 94: 139a.

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Bone Marrow Transplantation