Ifosfamide and Etoposide-Based Chemotherapy As Salvage and Mobilizing Regimens for Poor Prognosis Lymphoma

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Bone Marrow Transplantation, (1999) 23, 413–419  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma

J Mayer1, Z Korˇ´ıstek1,IVa´sˇova´1, J Vorlι´cˇek1 and P Vodva´rˇka2

1Department of Internal Medicine – Hematooncology, Masaryk University Hospital, Brno; and 2Department of Radiotherapeutic Medicine, Faculty Hospital, Ostrava, Czech Republic

Summary: Growth factors (G-CSF or GM-CSF, granulocyte or granulocyte–macrophage colony-stimulating factors) and/or a We treated 40 patients with poor prognosis lymphomas. higher dose of cyclophosphamide are standard for adequate Patients with non-Hodgkin’s lymphoma (NHL, n = 14) mobilization of PBSC, although other combinations of received MINE chemotherapy (mesna, ifosfamide polychemotherapy and growth factors can be used. A com- 1330 mg/m2 and etoposide 65 mg/m2 by i.v. infusions on bination of chemotherapy and growth factors is more effec- days 1–3, mitoxantrone 8 mg/m2 i.v. on day 1), and those tive than growth factors and chemotherapy alone and inten- with Hodgkin’s disease (HD, n = 26) received VIM sity of chemotherapy correlates with the degree of PBSC chemotherapy (mesna, ifosfamide 1200 mg/m2 by i.v. mobilization.3–8 In lymphoma patients, PBSC can be mobil- infusion on days 1–5, etoposide 90 mg/m2 by i.v. infusion ized with growth factors alone or by a combination of high- on days 1, 3 and 5, and methotrexate 30 mg/m2 i.v. on dose cyclophosphamide and growth factors, but these regi- days 1 and 5). Chemotherapy was followed by G-CSF mens have little or no activity against malignant disease. (10 or 16 ␮g/kg in two divided doses daily) to mobilize The best option is to use a regimen that embodies proven PBSC. We performed 134 aphereses (median three leu- mobilization ability and adequate anti-neoplastic activity, kaphereses per patient) starting on either day 13 combining PBSC mobilization with tumor mass cytoreduc- (median; VIM) or day 12 (median; MINE). The median tion prior to administration of the conditioning regimen. yield was 9.9 × 106 CD34+ cells/kg and 53.2 × 104 CFU- HD patients with chemosensitive disease and/or minimal GM/kg for VIM, and 13.5 × 106 CD34+ cells/kg and tumor burden before high-dose therapy have a better prog- 53.4 × 104 CFU-GM/kg for MINE. Except for predict- nosis.9–12 Similarly, NHL patients with a smaller tumor able myelosuppression, no serious toxicity was seen. mass before transplantation also have a better prog- Response rate using MINE was 63% (18% CR, 45% nosis.12,13 While it remains unclear whether minimizing PR) and using VIM 50% (17% CR, 33% PR). We con- tumor mass before high-dose therapy provides better clude that VIM and MINE are effective and well-toler- results, recent data support this hypothesis.14,15 ated salvage regimens in patients with lymphomas and, Few salvage regimens have been examined in combination followed by G-CSF, they also exhibit good capacity to with growth factor-stimulated PBSC mobilization,16–27 and a mobilize stem cells in a predictable time interval. number of these studies have been published only in the Keywords: MINE; VIM; mobilization; lymphoma; sal- form of meeting abstracts. In our study, we used the VIM vage chemotherapy; G-CSF 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 Aggressive non-Hodgkin’s lymphomas (NHL) and Hodg- examining the efficacy of VIM or MINE regimens for kin’s disease (HD) are neoplasias curable with standard PBSC mobilization. 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 conven- Patients and methods tional 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 Patients period of neutropenia and thrombocytopenia is shorter and the procedure can be less expensive. 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 first- Correspondence: J Mayer, Department of Internal Medicine – Hematoon- cology, Masaryk University Hospital, Brno, Jihlavska 20, 639 00, line therapy (usually ABVD/COPP and CHOP) or early Czech Republic relapses. Patient characteristics are shown in Tables 1 Received 9 April 1998; accepted 26 September 1998 and 2. Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 414 /kg 4 extensive 10 = × CFU-GM + /kg 6 40 Gy); E Ͻ 10 CD34 × (day) low-dose radiotherapy ( = not evaluated; L = relapse; N = day 1). = failure (no response or progression); R = 6 L R PR 4 13 6.7 62.6 4.5 – PR PR 2 13 38.8 216.0 minor response; F + + = infiltration chemotherapy radiotherapy therapy aphereses harvesting day of the first leukapheresis (start of the stimulating regimen = partial remission; MR = 40 Gy); Start of harvesting Ͼ Hodgkin’s disease complete remission; PR = 12345 F6 F7 F8 M9 47 M 47 M 35 F 24 IV M A 24 III A F 19 III A 24 IV B 19 IV B 48 II – B III – A IV B – – III B – – – 2 – 4.5 – 6 7 32 7 – 6 10 – 12 E L L – F L F L E R R R R MR F R F MR R F MR CR 3 MR N 3 1 CR 3 3 3 12 4 3 13 12 6 13 11 23.5 12 20.8 13 12 8.1 12 6.2 138.9 8.2 124.8 13.9 1.4 7.8 5.7 36.7 64.7 2.1 86.8 48.7 24.9 12.3 Table 1 UPN Sex Age Stage Bone marrow No. of previous Previous Why salvage Effect of VIM No. of Start of Cells collected CR 10111213 M F M M 24 24 20 22 II B II B III B IV B – – 6 8 – L F MR MR F 3 4 13 11 4.8 15.3 19.1 47.0 1415161718 M19 F20 M21 F 4722 F23 32 M 2924 III(S) F B25 28 F26 41 II III(S) M 26 A B M 41 IV B F 25 – II M 21 B II A M 28 – III A – 28 II 50 A II A – 35 II A – – II 6 A IV B – 12 II A – 2 – – 27 – 11 – – 2 – 8 E E 6 7 E 6 E 4 F 5 E R E 6 MR L L R L R F – – F CR PR R E R PR R R CR 5 PR R 2 PR 2 PR R PR 6 PR PR 7 13 CR MR 5 12 12 3 N 4 14 3 2 19 8.6 4 2 7.7 13 7.5 14 2 13 2.4 14 27.9 3.2 12 56.5 57.2 0.0 12 11 3.7 26.9 5.3 12 17.0 8.7 9.5 49.5 12.7 15.8 10.2 45.2 38.6 7.7 23.2 41.4 70.7 24.3 radiotherapy ( Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 415 /kg 4 10 × CFU-GM + /kg 40 Gy); Start of 6 Ͻ 10 CD34 × (day) low-dose radiotherapy ( = not evaluated; L = relapse; N = failure (no response or progression); R day 1). = = IM 9 – F F 4 13 32.7 96.4 IMIM 8 8 – – R R CR PR 5 2 10 12 7.6 27.1 11.4 35.4 IM 7 L R F 2 13 9.5 5.0 IM 8 – PR PR 4 11 5.0 37.2 LG 16 – R N 4 12 5.2 49.3 LG 8 – R CR 3 12 16.7 78.3 HG 10 L R PR 2 12 13.4 20.7 HG 2HG – 13 F L PR R 5 PR 13 2 0.8 10 4.2 9.0 63.2 HG 15 – F MR 4 11 16.7 51.6 HG 4 – PR PR 1 12 17.8 38.1 HG 7 L PR N 2 12 8.2 74.1 HG 7 L R PR 5 12 48.1 129.3 minor response; F = − − − + − + − − − − − − + − infiltration chemotherapy radiotherapy therapy MINE aphereses harvesting partial remission; MR = day of the first leukapheresis (start of the stimulating regimen Non-Hodgkin’s lymphoma = complete remission; PR = 9 F 46 IV A 78 F M 54 40 III B III B 6 F 18 IV B 5 F 54 II B 4 F 50 IV A 3 F 20 II B 12 M M 56 33 IV B III A 1011 M F 41 44 IV B III B 121314 F F F 43 49 46 III A III B III A Table 2 UPN Sex Age Stage Bone marrow Grade No. of previous Previous Why salvageCR harvesting Effect of No. of Start of Cells collected Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al

416 + Table 3 Chemotherapy VIM (salvage and/or mobilization) back-up). When CD34 cell estimation was not available (on weekends, breakdown of the flowcytometer), we perfor- Etoposide 90 mg/m2 i.v. once daily on med more leukaphereses and thereby some total yields were (Vepesid, Bristol-Myers Squibb, infusion days 1, 3, 5 relatively higher than the threshold. Regensburg, Germany) Cells were cryopreserved with a Sy-Lab Glacier (SY- 2 Ifosfamide 1200 mg/m i.v. once daily on LAB, Parkersdorf, Austria) device in a mixture of autolog- (Holoxan, Asta Medica, Frankfurt, infusion days 1–5 Germany) ous plasma, Hank’s balanced salt solution (without Ca and Methotrexate 30 mg/m2 i.v. once daily on Mg; Sigma-Aldrich, Irvine, UK) and DMSO (Sigma; final (Methotrexate Lachema, Lachema, days 1 and 5 concentration of 10%), and were stored in liquid nitrogen. Brno, Czech Republic) CD34+ cell estimation 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. A well-mixed aliquot of 20 ␮l of leukapheresis product was incubated with 5 ␮l of the monoclonal antibody anti- Table 4 Chemotherapy MINE used for mobilization HPCA-2 conjugated with phycoerythrin (Becton Dickinson, San Jose, CA, USA) at 4°C for 20 min and then at 20°C Ifosfamide 1700 mg/m2 i.v. once daily on for an additional 10 min. Red cells were lysed in the Q- (Holoxan, Asta Medica) infusion days 1–3 Prep unit (Coulter, Hialeah, FL, USA). Samples incubated Mitoxantrone 10 mg/m2 i.v. on day 1 with mouse IgG1 antibody conjugated with phycoerythrin (Refador, Spofa, Praha, Czech (Immunotech, Marseilles, France) were used as the isotypic Republic) control. Flow cytometry was performed using an Epics XL Etoposide 175 mg/m2 i.v. once daily on (Coulter) software System II. The samples were diluted (Vepesid, Bristol-Myers Squibb) infusion days 1–3 (when necessary) with phosphate-buffered saline, pH 7.4, to keep the flow rate between 200 and 400 cells/s and to Filgrastim (Neupogen, Amgen Roche, Basel, Switzerland) 10 or 16 ␮g/kg avoid artifacts. Debris was gated out using the forward scat- s.c. in two divided doses daily from day 5 until aphereses were finished. ter discriminator, and leukocytes were gated on the basis of forward/side scattering characteristics. CD34+ cells were Chemotherapy VIM and MINE identified on a dot-plot of log fluorescence vs side scatter as a distinct population positioned above isotypic control- Details are shown in Tables 3, 4 and 5. Continuous stained cells, and exhibited the same side scatter intensity hydration (250 ml/h) and mesna (in 100% of ifosfamide as mononuclear cells. Usually 105 cells were evaluated. dose) were started 3 h prior to starting ifosfamide infusions. Results were expressed as the percentage of CD34+ cells ␮ The higher dose of filgrastim (16 g/kg) for mobilization in all analyzed cells. was given only in highly pretreated patients (previous extensive radiotherapy and/or intensive polychemotherapy). We usually administered the first course of VIM for mobil- CFU-GM assay = ization (n 24). Using MINE, PBSC were mobilized by The number of CFU-GM was evaluated in a standard col- = = the first (n 7) or the second course (n 7) of this regimen ony assay system. 2.0 × 105 WBCs were plated per 35 mm without significant differences in yields. Petri dish (Sarstedt, Newton, NC, USA) in 1 ml of culture medium containing IMDM (Sigma) supplemented with Leukaphereses and cryopreservation 0.33% agar (Difco, Detroit, MI, USA), 20% FCS (VFU, Brno, Czech Republic), penicillin (100 IU/ml), strepto- Aphereses began during recovery from myelosuppression mycin (100 ␮g/ml) and 5% conditioned medium 5637 × 9 when leukocytes exceeded at least 1 10 cells/l and the (human bladder carcinoma; U´ HKT, Praha, Czech Republic) + ␮ peripheral blood CD34 cell count approached 20 cells/ l. as a source of growth factors. All cultures were plated in Collections were performed with a COBE Spectra cell sep- triplicate. Cultures were scored using an inverted micro- arator (COBE, Lakewood, CO, USA) (software version 3.6, ° scope after 14 days of incubation at 37 Cin5%CO2 later 5.1) with collection pump speed 0.9 ml/min. We chose humidified atmosphere and aggregates with more than 40 × 6 + as the threshold for satisfactory harvest 5 10 CD34 cells were considered colonies. cells/kg (when achieved in one procedure, we collected at least 2.5 × 106 CD34+ cells/kg in the second apheresis as a Response criteria

Table 5 Chemotherapy MINE used as salvage only Response to therapy was assessed by clinical and radiologic examination. Complete remission (CR) was deﬁned as dis- Ifosfamide 1330 mg/m2 i.v. once daily on appearance of any evident disease for at least 1 month, par- (Holoxan, Asta Medica) infusion days 1–3 tial remission (PR) as at least a 50% decrease in tumor Mitoxantrone 8 mg/m2 i.v. on day 1 burden for at least 1 month. Minor response (MR) was (Refador, Spofa, Czech Republic) deﬁned as a 25–50% decrease in tumor burden for at least 1 Etoposide 65 mg/m2 i.v. once daily on month. Any other condition was considered a non-response. (Vepesid, Bristol-Myers Squibb) infusion days 1–3 Toxicity of VIM and MINE was evaluated by WHO criteria. Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 417 Results In this study we did not investigate any prognostic factors which might be associated with response to salvage Toxicity of VIM and MINE therapy chemotherapy.

A total of 119 courses of salvage regimens were adminis- Leukaphereses and yields tered, 46 courses of MINE (median three per patient; range We performed 134 leukaphereses (median three per patient; 1–5) and 51 courses of VIM (median two per patient; range range 1–7), processing a median blood volume of 12 000 1–4). Tolerance to chemotherapy was excellent; side- ml per leukapheresis (range 2.5–3 volumes of the patient’s effects were not serious. For better outcome of salvage ther- total blood volume). In 25 patients primed with VIM + G- apy or when VIM and MINE failed, we administered a total CSF, we started to collect PBSC between days +11 and of 22 courses of other regimens (DHAP, mini-dexa- +14 (on day +12 in 10 patients). In only one patient primed BEAM). with VIM, aphereses were performed later (on day +19). Microscopic hematuria (grade I) occurred in a total of The timing of aphereses using VIM was advantageously 16 (MINE) and nine (VIM) cases. No cases of higher grade predictable. The mean collection yield was 9.9 × 106 CD34+ renal or bladder toxicity occurred. cells/kg (range 1.4–38.8 × 106) and 53.2 × 104 CFU-GM/kg Transient vomiting (grade II) occurred in a total of five (range 7.8–216.0 × 104). (MINE) and two (VIM) cases despite antiemetic therapy. We started to collect PBSC between days +11 and +13 Vomiting requiring additional therapy (grade III) occurred (usually on day +12) in 12 patients primed with MINE + in a total of four (MINE) and two (VIM) cases. The vast G-CSF. In two patients primed with MINE, aphereses were majority of patients reported no, or only minimal nausea. performed on day +10. Again, the timing of aphereses using In a total of five cases, we observed a mild transient MINE was easily predictable. The mean collection yield increase in the serum SGOT/SGPT level (grades 1 and 2). was 13.5 × 106 CD34+ cells/kg (range 0–48.1 × 106) and We observed oral and oesophageal mucositis (grade 3) 53.4 × 104 CFU-GM/kg (range 4.2–129.3 × 104). associated with VIM (methotrexate) and oral candidiasis in We found bone marrow involvement in five patients only one case. before mobilization. The yield of leukapheresis was nega- The transience and intensity of leukopenia was pre- tively affected in only one patient (UPN 6; Table 2). We dictable (1–3 days). Infectious complications associated did not find bone marrow involvement in the other four with leukopenia were rare; one patient with tumor-asso- patients after the course of mobilizing therapy. ciated bronchial obstruction developed pneumonia. Grade IV thrombocytopenia was seen in only two patients. Thrombocytopenia was never associated with Discussion bleeding and no problems with thrombocytopenia occurred during aphereses. The median time to hematol- Our data show that VIM and MINE are low toxicity, effec- ogic recovery corresponded to the median time to the tive regimens for therapy of relapsed or refractory lym- first leukapheresis. phoma and have excellent PBSC mobilization capacity in a predictable time interval. Rodriguez et al29 reported a Outcome of salvage therapy response rate of 48% (CR 21%) in NHL patients treated with MINE. The main toxicity was myelosuppression; The disease status of patients before and after salvage ther- nephrotoxicity and neurotoxicity were also reported. apy is shown in Tables 1 and 2. Eleven patients were Nowrousian et al28,31 observed 18% CR and 64% PR in treated with MINE for relapse or first-line therapy non- HD patients treated with VIM. In 6% of patients the authors response; two patients (18%) attained CR, five patients observed stomatitis, and septic complications in 5%. The (45%) PR, one MR; two patients were refractory to any response rate to MINE in the present study was 63% (CR salvage therapy and one patient was not evaluated. 18%, PR 45%). We also observed myelosuppression as the Response rate was 63%. Three patients were treated with main form of toxicity. The response rate to VIM was 50%, only one course of MINE chemotherapy as priming and 17% CR, and 33% PR; as with MINE, myelosuppression were not included in the analysis of response to salvage was the dominant form of toxicity. We also observed uro- chemotherapy. toxicity, nausea, vomiting and occasionally a transient Twenty-four patients were treated with VIM for relapse increase in serum SGOT/SGPT levels. or first-line therapy non-response; four patients (17%) Several previous publications have demonstrated the attained CR, eight patients (33%) PR, six MR; four patients PBSC mobilization capacity of salvage regimens; some were refractory to any salvage therapy and two patients regimens were rather toxic, however, while others failed were not evaluated. Response rate was 50%. Two patients to show sufficient mobilizing capacity. The poor pre- were treated with only one course of VIM chemotherapy dictability of the harvest window after mobilization as priming and were not included in the analysis of chemotherapy observed in other studies presents logis- response to salvage chemotherapy. tic problems. Patients were treated by high-dose chemotherapy within Ferme´ et al16 administered MIME (mitoguazon, ifosfam- 6 weeks of completion of salvage chemotherapy (30 ide, mesna and etoposide) and GM-CSF to 30 patients with patients up to August 1997), except patients with a hope- HD. The authors reported thrombocytopenia (grades III– less prognosis. IV) with 53% of courses, neutropenia (grade IV) with 85% Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 418 of courses, and febrile neutropenia with 32% of courses. excellent care for patients, L Bourkova for CFU-GM assays, and Collections started on days 11–22. J Adler for cooperation with progenitor cell cryopreservation. Weaver et al17 administered CE or CEP (cyclophosphamide with mesna, etoposide and cisplatin) with subsequent administration of G-CSF (6 ␮g/kg/day) in 38 References HD patients. The collection yield was higher than 2.5 × 106 + 1 Linch DC, Winfield D, Goldstone AH et al. Dose intensifi- CD34 cells/kg in 74% of patients. The neutrophil count cation with autologous bone marrow transplantation in × 9 decreased below 0.5 10 /l during a median of 5 days relapsed and resistant Hodgkin’s disease: results of a BNLI (range 0–19). The median number of platelet transfusions randomised trial. Lancet 1993; 341: 1051–1054. was two (0–11) per patient. Febrile neutropenia occurred 2 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone in 42% of patients. marrow transplantation as compared with salvage chemo- Stamatoullas et al18 administered IVAM (ifosfamide, therapy in relapses of chemotherapy-sensitive non-Hodgkin’s mesna, etoposide, Ara-C and methotrexate with leucovorin) lymphoma. New Engl J Med 1995; 333: 1540–1545. with subsequent administration of G-CSF 5 ␮g/kg/day in 3 Demirer T, Buckner CD, Bensinger WI. Optimization of peri- 31 NHL patients. The neutrophil count decreased below pheral blood stem cell mobilization. Stem Cells 1996; 14: 0.5 × 109/l for a median of 7 days (range 2–10) and platelet 106–116. 4 Desikan KR, Jagannath S, Vesole D et al. Collection of peri- × 9 count below 20 10 /l for a median of one day (0–7). Col- pheral blood stem cells (PBSC) in multiple myeloma follow- lections started on day 16 on average (14–31). The rate of ing G-CSF with or without high-dose cyclophosphamide. CR was 61%, and 26% of patients achieved PR. Blood 1995; 86 (Suppl. 1): Abstr. 1594. Aurlien et al19 treated 49 NHL patients with MIME 5 Janssen WE, Hiemenz J, Zorsky J et al. Mobilization of peri- (Metyl-Gag, ifosfamide with mesna, methotrexate and pheral blood stem cells: comparing cell collections from etoposide) and G-CSF 5 ␮g/kg/day. Leukaphereses usually cyclophosphamide and growth factor based regimens. Exp began on days 12–13. Febrile neutropenia occurred in six Hematol 1993; 21: Abstr. 567. patients. 6 Vahdat L, Raptis G, Fennelly D et al. Superiority of high dose 20 cyclophosphamide + G-CSF versus either lower dose cyclo- Baars et al administered ifosfamide plus etoposide with + subsequent administration of G-CSF (5 or 10 ␮g/kg/day) in phosphamide G-CSF or G-CSF alone in mobilization of peripheral blood progenitor cells. Blood 1993; 82 (Suppl. 17 lymphoma patients and in 24 patients with solid tumors. 1): Abstr. 2558. Thirty-two percent of patients did not reach a threshold 7 Weaver CH, Hazelton B, Palmer PA et al. A randomized dose 6 + yield of 3 × 10 CD34 cells/kg. The authors reported lower finding study of filgrastim for mobilization of peripheral blood yields in patients treated with a dose of 5 ␮g/kg/day of progenitor cells (PBSCs). Proc ASCO 1996; 15: Abstr. 990. filgrastim and pretreated with radiotherapy. 8 Zeller W, Gutensohn K, Stockschlader M et al. Increase of Several studies were performed with the DexaBEAM mobilized CD34-positive peripheral blood progenitor cells in regimen.21,22 Knauf et al22 treated 16 HD and NHL patients patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, with DexaBEAM followed by G-CSF. The leukocyte count and cancer of testis. Bone Marrow Transplant 1996; 17: decreased below 1.0 × 109/l for a median of 6 days (range 709–713. 5–8) and leukaphereses began on days 18–22. Some studies 9 Burns LJ, Daniels KA, McGlave PB et al. Autologous stem cell transplantation for refractory and relapsed Hodgkin’s dis- also describe the efficacy of the ESHAP regimen.23–25 24,25 ease: factors predictive of prolonged survival. Bone Marrow Watts et al concluded that ESHAP is more effective Transplant 1995; 16: 13–18. 2 than 1.5 g/m , of cyclophosphamide, based on higher yields 10 Goldstone AH, McMillan AK. The place of high-dose therapy of progenitor cells and better anti-lymphoma effect. Two with haemopoietic stem cell transplantation in relapsed and studies described salvage and PBSC mobilizing efficacy of refractory Hodgkin’s disease. Ann Oncol 1993; 4 (Suppl. 1): the DHAP regimen. Hansen et al26 treated 20 HD and NHL S21–S27. patients with DHAP and G-CSF (5 ␮g/kg/day). Leukapher- 11 Poen JC, Hoppe RT, Horning SJ. High-dose therapy and auto- eses began on days 11–16. Profound myelosuppression logous bone marrow transplantation for relapsed/refractory (grades III–IV) was observed in each patient. Similar Hodgkin’s disease: the impact of involved field radiotherapy results were published by Olivieri et al,27 where thrombocy- on patterns of failure and survival. Int J Radiat Oncol Biol Ͻ × 9 Phys 1996; 36: 3–12. topenia 20 10 /l, occurred in 33% of patients. 12 Rapoport AP, Rowe JM, Kouides PA. One hundred autotrans- In summary, VIM and MINE are well-tolerated regimens plants for relapsed or refractory Hodgkin’s disease and lym- providing significant anti-lymphoma effect and low tox- phoma: value of pretransplant disease status for predicting out- icity. VIM and MINE in combination with 10–16 come. J Clin Oncol 1993; 11: 2351–2361. ␮g/kg/day of filgrastim also provide good PBSC mobilizing 13 Vose JM, Anderson JR, Kessinger A et al. High-dose chemo- capability at a predictable time interval. These regimens therapy and autologous hematopoietic stem-cell transplan- are also advantageous because of short-term leukopenia and tation for aggressive non-Hodgkin’s lymphoma. J Clin Oncol mild thrombocytopenia, which is critical for ensuring 1993; 11: 1846–1851. uneventful apheresis. Compared with other regimens, VIM 14 Bosly A, Sonet A, Salles G et al. Late intensification is and MINE seem to offer multiple advantages. 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: Acknowledgements Abstr. 16. 15 Prince HM, Imrie K, Crump M et al. The role of intensive We thank Jayesh Mehta and Seema Singhal for critically therapy and autologous blood and marrow transplantation for reviewing the manuscript, colleagues from our department for the chemotherapy-sensitive relapsed and primary refractory non- Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 419 Hodgkin’s lymphoma: identification of major prognostic CSF as mobilization regimen for Hodgkin’s disease and non- groups. Br J Haematol 1996; 92: 880–889. Hodgkin’s lymphoma. Bone Marrow Transplant 1997; 19 16 Ferme´ C, Brice P, Gabarre J et al. MINE chemotherapy plus (Suppl. 1): Abstr. P433. rhGM-CSF as salvage and peripheral blood progenitor cell 24 Watts MJ, Sullivan AM, Leverett D. Evaluation of the ESHAP mobilizing regimen for relapsed or refractory Hodgkin’s dis- regimen followed by G-CSF for PBSC mobilization: a ease. Blood 1994; 84 (Suppl. 1): Abstr. 635. matched pairs analysis compared to low dose cyclophospham- 17 Weaver CH, Schwartzberg L, Li W et al. High-dose chemo- ide 1.5 g/m2 plus G-CSF. Br J Haematol 1996; 93 (Suppl. therapy and autologous peripheral blood progenitor cell trans- 1): Abstr. 67. plant for the treatment of Hodgkin’s disease. Bone Marrow 25 Watts MJ, Leverett D, Sullivan AM et al. A comparison of Transplant 1996; 17: 715–731. ESHAP + G-CSF vs cyclophosphamide 1.5 g/m2 for PBSC 18 Stamatoullas A, Fruchart C, Bastit D et al. Ifosfamide, etopo- mobilization in pre-treated lymphoma patients: a matched pair side, cytarabine, and methotrexate as salvage chemotherapy in analysis. 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