Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma

Transcription

1 Bone Marrow Transplantation, (1999) 23, Stockton Press All rights reserved /99 $ Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma J Mayer 1, Z Kořístek 1,IVášová 1, J Vorlίček 1 and P Vodvářka 2 1 Department of Internal Medicine Hematooncology, Masaryk University Hospital, Brno; and 2 Department of Radiotherapeutic Medicine, Faculty Hospital, Ostrava, Czech Republic Summary: We treated 40 patients with poor prognosis lymphomas. Patients with non-hodgkin s lymphoma (NHL, n = 14) received MINE chemotherapy (mesna, ifosfamide 1330 mg/m 2 and etoposide 65 mg/m 2 by i.v. infusions on days 1 3, mitoxantrone 8 mg/m 2 i.v. on day 1), and those with Hodgkin s disease (HD, n = 26) received VIM chemotherapy (mesna, ifosfamide 1200 mg/m 2 by i.v. infusion on days 1 5, etoposide 90 mg/m 2 by i.v. infusion on days 1, 3 and 5, and methotrexate 30 mg/m 2 i.v. on days 1 and 5). Chemotherapy was followed by G-CSF (10 or 16 g/kg in two divided doses daily) to mobilize PBSC. We performed 134 aphereses (median three leukaphereses per patient) starting on either day 13 (median; VIM) or day 12 (median; MINE). The median yield was CD34 + cells/kg and CFU- GM/kg for VIM, and CD34 + cells/kg and CFU-GM/kg for MINE. Except for predictable myelosuppression, no serious toxicity was seen. Response rate using MINE was 63% (18% CR, 45% PR) and using VIM 50% (17% CR, 33% PR). We conclude that VIM and MINE are effective and well-tolerated salvage regimens in patients with lymphomas and, followed by G-CSF, they also exhibit good capacity to mobilize stem cells in a predictable time interval. Keywords: MINE; VIM; mobilization; lymphoma; salvage chemotherapy; G-CSF Aggressive non-hodgkin s lymphomas (NHL) and Hodgkin s disease (HD) are neoplasias curable with standard chemoradiotherapy, but refractory or early relapsing lymphomas are not considered to be satisfactorily treatable by conventional salvage chemotherapy. High-dose chemotherapy followed by autologous haematopoietic stem cell transplantation has achieved better results than conventional salvage chemotherapies in patients with relapsed or refractory disease. 1,2 The use of peripheral blood stem cells (PBSC) offers an advantage over bone marrow because the period of neutropenia and thrombocytopenia is shorter and the procedure can be less expensive. Correspondence: J Mayer, Department of Internal Medicine Hematooncology, Masaryk University Hospital, Brno, Jihlavska 20, , Czech Republic Received 9 April 1998; accepted 26 September 1998 Growth factors (G-CSF or GM-CSF, granulocyte or granulocyte macrophage colony-stimulating factors) and/or a higher dose of cyclophosphamide are standard for adequate mobilization of PBSC, although other combinations of polychemotherapy and growth factors can be used. A combination of chemotherapy and growth factors is more effective than growth factors and chemotherapy alone and intensity of chemotherapy correlates with the degree of PBSC mobilization. 3 8 In lymphoma patients, PBSC can be mobilized with growth factors alone or by a combination of highdose cyclophosphamide and growth factors, but these regimens have little or no activity against malignant disease. The best option is to use a regimen that embodies proven mobilization ability and adequate anti-neoplastic activity, combining PBSC mobilization with tumor mass cytoreduction prior to administration of the conditioning regimen. HD patients with chemosensitive disease and/or minimal tumor burden before high-dose therapy have a better prognosis Similarly, NHL patients with a smaller tumor mass before transplantation also have a better prognosis. 12,13 While it remains unclear whether minimizing tumor mass before high-dose therapy provides better results, recent data support this hypothesis. 14,15 Few salvage regimens have been examined in combination with growth factor-stimulated PBSC mobilization, and a number of these studies have been published only in the form of meeting abstracts. In our study, we used the VIM regimen (VP-16, ifosfamide, methotrexate) 28 for HD patients and MINE (mesna, ifosfamide, mitoxantrone Novatrone, etoposide) 29 for NHL patients. VIM is similar to the IMVP-16 regimen. 30 To date, there are no reports examining the efficacy of VIM or MINE regimens for PBSC mobilization. Patients and methods Patients From May 1995 to August 1997, we treated 40 patients; 22 female and 18 male, age 18 to 56 years (median 34), who were primarily refractory, partial responders to firstline therapy (usually ABVD/COPP and CHOP) or early relapses. Patient characteristics are shown in Tables 1 and 2.

2 414 Table 1 Hodgkin s disease UPN Sex Age Stage Bone marrow No. of previous Previous Why salvage Effect of VIM No. of Start of Cells collected infiltration chemotherapy radiotherapy therapy aphereses harvesting (day) CD34 + CFU-GM 10 6 /kg 10 4 /kg 1 F 47 IV A 2 F MR F 47 III A 4.5 F F F 35 III A 6 E R MR M 24 IV B 7 L R F M 24 IV B 32 L R MR M 19 II B 7 R CR F 24 III A 6 L R N M 19 IV B 10 L F MR F 48 III B 12 E R CR M 24 II B 6 F F F 24 II B 8 L MR MR M 20 III B + 6 L R PR M 22 IV B PR PR M 47 III(S) B 6 F F F 32 II A 2 E MR PR M 29 III(S) B 12 E R CR F 28 IV B 27 E R PR F 41 II B 11 E R CR M 26 II A 2 E F PR F 41 III A 8 E R PR F 25 II A 6 L R PR M 21 II A 7 L R PR M 28 II A 6 L R PR F 28 II A 4 R MR M 50 IV B 5 PR CR M 35 II A 6 E R N CR = complete remission; PR = partial remission; MR = minor response; F = failure (no response or progression); R = relapse; N = not evaluated; L = low-dose radiotherapy ( 40 Gy); E = extensive radiotherapy ( 40 Gy); Start of harvesting = day of the first leukapheresis (start of the stimulating regimen = day 1).

3 Table 2 Non-Hodgkin s lymphoma UPN Sex Age Stage Bone marrow Grade No. of previous Previous Why salvage Effect of No. of Start of Cells collected infiltration chemotherapy radiotherapy therapy MINE aphereses harvesting (day) CD34 + CFU-GM 10 6 /kg 10 4 /kg 1 M 56 IV B + IM 8 PR PR M 33 III A HG 7 L R PR F 20 II B HG 7 L PR N F 50 IV A HG 4 PR PR F 54 II B HG 15 F MR F 18 IV B + HG 2 F PR F 54 III B IM 8 R CR M 40 III B HG 10 L R PR F 46 IV A IM 9 F F M 41 IV B + LG 16 R N F 44 III B IM 8 R PR F 43 III A LG 8 R CR F 49 III B HG 13 L R PR F 46 III A IM 7 L R F CR = complete remission; PR = partial remission; MR = minor response; F = failure (no response or progression); R = relapse; N = not evaluated; L = low-dose radiotherapy ( 40 Gy); Start of harvesting = day of the first leukapheresis (start of the stimulating regimen = day 1). 415

4 416 Table 3 Chemotherapy VIM (salvage and/or mobilization) Etoposide 90 mg/m 2 i.v. once daily on (Vepesid, Bristol-Myers Squibb, infusion days 1, 3, 5 Regensburg, Germany) Ifosfamide 1200 mg/m 2 i.v. once daily on (Holoxan, Asta Medica, Frankfurt, infusion days 1 5 Germany) Methotrexate 30 mg/m 2 i.v. once daily on (Methotrexate Lachema, Lachema, days 1 and 5 Brno, Czech Republic) Filgrastim (Neupogen, Amgen Roche) 10 or 16 g/kg s.c. in two divided doses daily to mobilize PBSC from day 7 until aphereses were finished. Table 4 Chemotherapy MINE used for mobilization Ifosfamide 1700 mg/m 2 i.v. once daily on (Holoxan, Asta Medica) infusion days 1 3 Mitoxantrone 10 mg/m 2 i.v. on day 1 (Refador, Spofa, Praha, Czech Republic) Etoposide 175 mg/m 2 i.v. once daily on (Vepesid, Bristol-Myers Squibb) infusion days 1 3 Filgrastim (Neupogen, Amgen Roche, Basel, Switzerland) 10 or 16 g/kg s.c. in two divided doses daily from day 5 until aphereses were finished. Chemotherapy VIM and MINE Details are shown in Tables 3, 4 and 5. Continuous hydration (250 ml/h) and mesna (in 100% of ifosfamide dose) were started 3 h prior to starting ifosfamide infusions. The higher dose of filgrastim (16 g/kg) for mobilization was given only in highly pretreated patients (previous extensive radiotherapy and/or intensive polychemotherapy). We usually administered the first course of VIM for mobilization (n = 24). Using MINE, PBSC were mobilized by the first (n = 7) or the second course (n = 7) of this regimen without significant differences in yields. Leukaphereses and cryopreservation Aphereses began during recovery from myelosuppression when leukocytes exceeded at least cells/l and the peripheral blood CD34 + cell count approached 20 cells/ l. Collections were performed with a COBE Spectra cell separator (COBE, Lakewood, CO, USA) (software version 3.6, later 5.1) with collection pump speed 0.9 ml/min. We chose as the threshold for satisfactory harvest CD34 + cells/kg (when achieved in one procedure, we collected at least CD34 + cells/kg in the second apheresis as a Table 5 Chemotherapy MINE used as salvage only Ifosfamide 1330 mg/m 2 i.v. once daily on (Holoxan, Asta Medica) infusion days 1 3 Mitoxantrone 8 mg/m 2 i.v. on day 1 (Refador, Spofa, Czech Republic) Etoposide 65 mg/m 2 i.v. once daily on (Vepesid, Bristol-Myers Squibb) infusion days 1 3 back-up). When CD34 + cell estimation was not available (on weekends, breakdown of the flowcytometer), we performed more leukaphereses and thereby some total yields were relatively higher than the threshold. Cells were cryopreserved with a Sy-Lab Glacier (SY- LAB, Parkersdorf, Austria) device in a mixture of autologous plasma, Hank s balanced salt solution (without Ca and Mg; Sigma-Aldrich, Irvine, UK) and DMSO (Sigma; final concentration of 10%), and were stored in liquid nitrogen. CD34 + cell estimation A well-mixed aliquot of 20 l of leukapheresis product was incubated with 5 l of the monoclonal antibody anti- HPCA-2 conjugated with phycoerythrin (Becton Dickinson, San Jose, CA, USA) at 4 C for 20 min and then at 20 C for an additional 10 min. Red cells were lysed in the Q- Prep unit (Coulter, Hialeah, FL, USA). Samples incubated with mouse IgG 1 antibody conjugated with phycoerythrin (Immunotech, Marseilles, France) were used as the isotypic control. Flow cytometry was performed using an Epics XL (Coulter) software System II. The samples were diluted (when necessary) with phosphate-buffered saline, ph 7.4, to keep the flow rate between 200 and 400 cells/s and to avoid artifacts. Debris was gated out using the forward scatter discriminator, and leukocytes were gated on the basis of forward/side scattering characteristics. CD34 + cells were identified on a dot-plot of log fluorescence vs side scatter as a distinct population positioned above isotypic controlstained cells, and exhibited the same side scatter intensity as mononuclear cells. Usually 10 5 cells were evaluated. Results were expressed as the percentage of CD34 + cells in all analyzed cells. CFU-GM assay The number of CFU-GM was evaluated in a standard colony assay system WBCs were plated per 35 mm Petri dish (Sarstedt, Newton, NC, USA) in 1 ml of culture medium containing IMDM (Sigma) supplemented with 0.33% agar (Difco, Detroit, MI, USA), 20% FCS (VFU, Brno, Czech Republic), penicillin (100 IU/ml), streptomycin (100 g/ml) and 5% conditioned medium 5637 (human bladder carcinoma; ÚHKT, Praha, Czech Republic) as a source of growth factors. All cultures were plated in triplicate. Cultures were scored using an inverted microscope after 14 days of incubation at 37 C in 5% CO 2 humidified atmosphere and aggregates with more than 40 cells were considered colonies. Response criteria Response to therapy was assessed by clinical and radiologic examination. Complete remission (CR) was defined as disappearance of any evident disease for at least 1 month, partial remission (PR) as at least a 50% decrease in tumor burden for at least 1 month. Minor response (MR) was defined as a 25 50% decrease in tumor burden for at least 1 month. Any other condition was considered a non-response. Toxicity of VIM and MINE was evaluated by WHO criteria.

5 Results Toxicity of VIM and MINE therapy A total of 119 courses of salvage regimens were administered, 46 courses of MINE (median three per patient; range 1 5) and 51 courses of VIM (median two per patient; range 1 4). Tolerance to chemotherapy was excellent; sideeffects were not serious. For better outcome of salvage therapy or when VIM and MINE failed, we administered a total of 22 courses of other regimens (DHAP, mini-dexa- BEAM). Microscopic hematuria (grade I) occurred in a total of 16 (MINE) and nine (VIM) cases. No cases of higher grade renal or bladder toxicity occurred. Transient vomiting (grade II) occurred in a total of five (MINE) and two (VIM) cases despite antiemetic therapy. Vomiting requiring additional therapy (grade III) occurred in a total of four (MINE) and two (VIM) cases. The vast majority of patients reported no, or only minimal nausea. In a total of five cases, we observed a mild transient increase in the serum SGOT/SGPT level (grades 1 and 2). We observed oral and oesophageal mucositis (grade 3) associated with VIM (methotrexate) and oral candidiasis in only one case. The transience and intensity of leukopenia was predictable (1 3 days). Infectious complications associated with leukopenia were rare; one patient with tumor-associated bronchial obstruction developed pneumonia. Grade IV thrombocytopenia was seen in only two patients. Thrombocytopenia was never associated with bleeding and no problems with thrombocytopenia occurred during aphereses. The median time to hematologic recovery corresponded to the median time to the first leukapheresis. Outcome of salvage therapy The disease status of patients before and after salvage therapy is shown in Tables 1 and 2. Eleven patients were treated with MINE for relapse or first-line therapy nonresponse; two patients (18%) attained CR, five patients (45%) PR, one MR; two patients were refractory to any salvage therapy and one patient was not evaluated. Response rate was 63%. Three patients were treated with only one course of MINE chemotherapy as priming and were not included in the analysis of response to salvage chemotherapy. Twenty-four patients were treated with VIM for relapse or first-line therapy non-response; four patients (17%) attained CR, eight patients (33%) PR, six MR; four patients were refractory to any salvage therapy and two patients were not evaluated. Response rate was 50%. Two patients were treated with only one course of VIM chemotherapy as priming and were not included in the analysis of response to salvage chemotherapy. Patients were treated by high-dose chemotherapy within 6 weeks of completion of salvage chemotherapy (30 patients up to August 1997), except patients with a hopeless prognosis. In this study we did not investigate any prognostic factors which might be associated with response to salvage chemotherapy. Leukaphereses and yields We performed 134 leukaphereses (median three per patient; range 1 7), processing a median blood volume of ml per leukapheresis (range volumes of the patient s total blood volume). In 25 patients primed with VIM + G- CSF, we started to collect PBSC between days +11 and +14 (on day +12 in 10 patients). In only one patient primed with VIM, aphereses were performed later (on day +19). The timing of aphereses using VIM was advantageously predictable. The mean collection yield was CD34 + cells/kg (range ) and CFU-GM/kg (range ). We started to collect PBSC between days +11 and +13 (usually on day +12) in 12 patients primed with MINE + G-CSF. In two patients primed with MINE, aphereses were performed on day +10. Again, the timing of aphereses using MINE was easily predictable. The mean collection yield was CD34 + cells/kg (range ) and CFU-GM/kg (range ). We found bone marrow involvement in five patients before mobilization. The yield of leukapheresis was negatively affected in only one patient (UPN 6; Table 2). We did not find bone marrow involvement in the other four patients after the course of mobilizing therapy. Discussion Our data show that VIM and MINE are low toxicity, effective regimens for therapy of relapsed or refractory lymphoma and have excellent PBSC mobilization capacity in a predictable time interval. Rodriguez et al 29 reported a response rate of 48% (CR 21%) in NHL patients treated with MINE. The main toxicity was myelosuppression; nephrotoxicity and neurotoxicity were also reported. Nowrousian et al 28,31 observed 18% CR and 64% PR in HD patients treated with VIM. In 6% of patients the authors observed stomatitis, and septic complications in 5%. The response rate to MINE in the present study was 63% (CR 18%, PR 45%). We also observed myelosuppression as the main form of toxicity. The response rate to VIM was 50%, 17% CR, and 33% PR; as with MINE, myelosuppression was the dominant form of toxicity. We also observed urotoxicity, nausea, vomiting and occasionally a transient increase in serum SGOT/SGPT levels. Several previous publications have demonstrated the PBSC mobilization capacity of salvage regimens; some regimens were rather toxic, however, while others failed to show sufficient mobilizing capacity. The poor predictability of the harvest window after mobilization chemotherapy observed in other studies presents logistic problems. Fermé et al 16 administered MIME (mitoguazon, ifosfamide, mesna and etoposide) and GM-CSF to 30 patients with HD. The authors reported thrombocytopenia (grades III IV) with 53% of courses, neutropenia (grade IV) with 85% 417

6 418 of courses, and febrile neutropenia with 32% of courses. Collections started on days Weaver et al 17 administered CE or CEP (cyclophosphamide with mesna, etoposide and cisplatin) with subsequent administration of G-CSF (6 g/kg/day) in 38 HD patients. The collection yield was higher than CD34 + cells/kg in 74% of patients. The neutrophil count decreased below /l during a median of 5 days (range 0 19). The median number of platelet transfusions was two (0 11) per patient. Febrile neutropenia occurred in 42% of patients. Stamatoullas et al 18 administered IVAM (ifosfamide, mesna, etoposide, Ara-C and methotrexate with leucovorin) with subsequent administration of G-CSF 5 g/kg/day in 31 NHL patients. The neutrophil count decreased below /l for a median of 7 days (range 2 10) and platelet count below /l for a median of one day (0 7). Collections started on day 16 on average (14 31). The rate of CR was 61%, and 26% of patients achieved PR. Aurlien et al 19 treated 49 NHL patients with MIME (Metyl-Gag, ifosfamide with mesna, methotrexate and etoposide) and G-CSF 5 g/kg/day. Leukaphereses usually began on days Febrile neutropenia occurred in six patients. Baars et al 20 administered ifosfamide plus etoposide with subsequent administration of G-CSF (5 or 10 g/kg/day) in 17 lymphoma patients and in 24 patients with solid tumors. Thirty-two percent of patients did not reach a threshold yield of CD34 + cells/kg. The authors reported lower yields in patients treated with a dose of 5 g/kg/day of filgrastim and pretreated with radiotherapy. Several studies were performed with the DexaBEAM regimen. 21,22 Knauf et al 22 treated 16 HD and NHL patients with DexaBEAM followed by G-CSF. The leukocyte count decreased below /l for a median of 6 days (range 5 8) and leukaphereses began on days Some studies also describe the efficacy of the ESHAP regimen Watts et al 24,25 concluded that ESHAP is more effective than 1.5 g/m 2, of cyclophosphamide, based on higher yields of progenitor cells and better anti-lymphoma effect. Two studies described salvage and PBSC mobilizing efficacy of the DHAP regimen. Hansen et al 26 treated 20 HD and NHL patients with DHAP and G-CSF (5 g/kg/day). Leukaphereses began on days Profound myelosuppression (grades III IV) was observed in each patient. Similar results were published by Olivieri et al, 27 where thrombocytopenia /l, occurred in 33% of patients. In summary, VIM and MINE are well-tolerated regimens providing significant anti-lymphoma effect and low toxicity. VIM and MINE in combination with g/kg/day of filgrastim also provide good PBSC mobilizing capability at a predictable time interval. These regimens are also advantageous because of short-term leukopenia and mild thrombocytopenia, which is critical for ensuring uneventful apheresis. Compared with other regimens, VIM and MINE seem to offer multiple advantages. Acknowledgements We thank Jayesh Mehta and Seema Singhal for critically reviewing the manuscript, colleagues from our department for the excellent care for patients, L Bourkova for CFU-GM assays, and J Adler for cooperation with progenitor cell cryopreservation. References 1 Linch DC, Winfield D, Goldstone AH et al. Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin s disease: results of a BNLI randomised trial. Lancet 1993; 341: Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin s lymphoma. New Engl J Med 1995; 333: Demirer T, Buckner CD, Bensinger WI. Optimization of peripheral blood stem cell mobilization. Stem Cells 1996; 14: Desikan KR, Jagannath S, Vesole D et al. Collection of peripheral blood stem cells (PBSC) in multiple myeloma following G-CSF with or without high-dose cyclophosphamide. Blood 1995; 86 (Suppl. 1): Abstr Janssen WE, Hiemenz J, Zorsky J et al. Mobilization of peripheral blood stem cells: comparing cell collections from cyclophosphamide and growth factor based regimens. Exp Hematol 1993; 21: Abstr Vahdat L, Raptis G, Fennelly D et al. Superiority of high dose cyclophosphamide + G-CSF versus either lower dose cyclophosphamide + G-CSF or G-CSF alone in mobilization of peri- pheral blood progenitor cells. Blood 1993; 82 (Suppl. 1): Abstr Weaver CH, Hazelton B, Palmer PA et al. A randomized dose finding study of filgrastim for mobilization of peripheral blood progenitor cells (PBSCs). Proc ASCO 1996; 15: Abstr Zeller W, Gutensohn K, Stockschlader M et al. Increase of mobilized CD34-positive peripheral blood progenitor cells in patients with Hodgkin s disease, non-hodgkin s lymphoma, and cancer of testis. Bone Marrow Transplant 1996; 17: Burns LJ, Daniels KA, McGlave PB et al. Autologous stem cell transplantation for refractory and relapsed Hodgkin s disease: factors predictive of prolonged survival. Bone Marrow Transplant 1995; 16: Goldstone AH, McMillan AK. The place of high-dose therapy with haemopoietic stem cell transplantation in relapsed and refractory Hodgkin s disease. Ann Oncol 1993; 4 (Suppl. 1): S21 S Poen JC, Hoppe RT, Horning SJ. High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin s disease: the impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 1996; 36: Rapoport AP, Rowe JM, Kouides PA. One hundred autotransplants for relapsed or refractory Hodgkin s disease and lymphoma: value of pretransplant disease status for predicting outcome. J Clin Oncol 1993; 11: Vose JM, Anderson JR, Kessinger A et al. High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-hodgkin s lymphoma. J Clin Oncol 1993; 11: Bosly A, Sonet A, Salles G et al. Late intensification is superior to early intensification in relapsing/refractory aggressive non-hodgkin s lymphoma. A randomized study from the GELA: LNH RP 93. Exp Hematol 1997; 25: Abstr Prince HM, Imrie K, Crump M et al. The role of intensive therapy and autologous blood and marrow transplantation for chemotherapy-sensitive relapsed and primary refractory non-

7 Hodgkin s lymphoma: identification of major prognostic groups. Br J Haematol 1996; 92: Fermé C, Brice P, Gabarre J et al. MINE chemotherapy plus rhgm-csf as salvage and peripheral blood progenitor cell mobilizing regimen for relapsed or refractory Hodgkin s disease. Blood 1994; 84 (Suppl. 1): Abstr Weaver CH, Schwartzberg L, Li W et al. High-dose chemotherapy and autologous peripheral blood progenitor cell transplant for the treatment of Hodgkin s disease. Bone Marrow Transplant 1996; 17: Stamatoullas A, Fruchart C, Bastit D et al. Ifosfamide, etoposide, cytarabine, and methotrexate as salvage chemotherapy in relapsed or refractory aggressive non-hodgkin s lymphoma. Cancer 1996; 77: Aurlien P, Blystad AK, Pharo A. Mobilizing PBSC in lymphomas employing G-CSF and standard dose of methyl-gag, ifosfamide, methotrexate, etoposide (MIME): an efficient and safe procedure. Bone Marrow Transplant 1997; 19 (Suppl. 1): Abstr. P Baars JW, Holtkamp MJ, Nooyen WJ et al. Mobilization of blood progenitor cells with ifosfamide and etoposide (VP-16) in combination with recombinant human G-CSF (filgrastim) in patients with malignant lymphomas or solid tumours. Anticancer Res 1996; 16: Dreger P, Marquardt P, Haferlach T et al. Effective mobilization of peripheral blood progenitor cells with Dexa-BEAM and G-CSF: timing of harvesting and composition of the leukapheresis product. Br J Cancer 1993; 68: Knauf GU, Koenigsmann MP, Notter M et al. Peripheral blood progenitor cell mobilization with Dexa-BEAM/G-CSF, ether lipid purging, and autologous transplantation after highdose CBV treatment: a safe and effective regimen in patients with poor risk malignant lymphomas. Leuk Lymphoma 1996; 23: Petit J, Boqué C, Sarrá J et al. Feasibility of ESHAP and G- CSF as mobilization regimen for Hodgkin s disease and non- Hodgkin s lymphoma. Bone Marrow Transplant 1997; 19 (Suppl. 1): Abstr. P Watts MJ, Sullivan AM, Leverett D. Evaluation of the ESHAP regimen followed by G-CSF for PBSC mobilization: a matched pairs analysis compared to low dose cyclophosphamide 1.5 g/m 2 plus G-CSF. Br J Haematol 1996; 93 (Suppl. 1): Abstr Watts MJ, Leverett D, Sullivan AM et al. A comparison of ESHAP + G-CSF vs cyclophosphamide 1.5 g/m 2 for PBSC mobilization in pre-treated lymphoma patients: a matched pair analysis. Blood 1996; 88 (Suppl. 1): Abstr Hansen KS, Hansen LK, Spurgin PA et al. Simultaneous cytoreduction and peripheral blood stem cell mobilization in malignant lymphomas employing DHAP chemotherapy a two-fer. Blood 1995; 86 (Suppl. 1): Abstr Olivieri A, Offidani M, Ciniero L et al. DHAP regimen plus G-CSF as salvage therapy and priming for blood progenitor cell collection in patients with poor prognosis lymphoma. Bone Marrow Transplant 1995; 16: Nowrousian MR, Schoetensack B, Pfeiffer R et al. Combination chemotherapy with etoposide (VP-16), ifosfamide, methotrexate, and bleomycin (VIM(B)) for refractory or recurrent lymphomas. Contr Oncol 1987; 26: Rodriguez MA, Cabanillas FC, Hagemeister FB et al. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol 1995; 6: Cabanillas F, Hagemeister FB, Bodey GP, Freireich EJ. IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 1982; 60: Nowrousian MR, Anders CH, Niederle N et al. Etoposide, ifosfamide, and methotrexate with or without bleomycin in refractory or recurrent lymphomas. Ann Oncol 1991; 2 (Suppl. 1):