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

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Ifosfamide and Etoposide-Based Chemotherapy As Salvage and Mobilizing Regimens for Poor Prognosis Lymphoma 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 gra- nulocyte–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 lym- phomas are not considered to be satisfactorily treatable by conventional salvage chemotherapy. High-dose chemo- therapy 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. 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 × 106/kg × 104/kg 1 F 47 IV A – 2 – F MR 3 12 23.5 138.9 Ifosfamide and etoposide for poor prognosis lymphoma 2 F 47 III A – 4.5 – F F 3 13 20.8 124.8 3 F 35 III A – 6 E R MR 1 12 8.1 7.8 4 M 24 IV B – 7 L R F 3 11 8.2 64.7 5 M 24 IV B – 32 L R MR 3 13 6.2 36.7 6 M 19 II B – 7 – R CR 3 12 13.9 86.8 7 F 24 III A – 6 L R N 3 12 5.7 24.9 8 M 19 IV B – 10 L F MR 4 13 1.4 48.7 9 F 48 III B – 12 E R CR 6 12 2.1 12.3 10 M 24 II B – 6 – F F 4 11 15.3 47.0 11 F 24 II B – 8 L MR MR 3 13 4.8 19.1 12 M 20 III B + 6 L R PR 4 13 6.7 62.6 13 M 22 IV B + 4.5 – PR PR 2 13 38.8 216.0 14 M 47 III(S) B – 6 – F F 5 13 8.6 27.9 15 F 32 II A – 2 E MR PR 2 12 7.5 57.2 J Mayer 16 M 29 III(S) B – 12 E R CR 2 12 7.7 56.5 17 F 28 IV B – 27 E R PR 6 14 2.4 26.9 18 F 41 II B – 11 E R CR 7 19 3.2 17.0 et al 19 M 26 II A – 2 E F PR 5 13 0.0 49.5 20 F 41 III A – 8 E R PR 3 14 3.7 10.2 21 F 25 II A – 6 L R PR 4 13 5.3 45.2 22 M 21 II A – 7 L R PR 3 14 8.7 38.6 23 M 28 II A – 6 L R PR 2 12 9.5 23.2 24 F 28 II A – 4 – R MR 4 12 12.7 41.4 25 M 50 IV B – 5 – PR CR 2 11 15.8 70.7 26 M 35 II A – 6 E R N 2 12 7.7 24.3 CR = complete remission; PR = partial remission; MR = minor response; F = failure (no response or progression); R = relapse; N = not evaluated; L = low-dose radiotherapy (Ͻ40 Gy); E = extensive radiotherapy (Ͼ40 Gy); Start of harvesting = day of the first leukapheresis (start of the stimulating regimen = day 1). 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 × 106/kg × 104/kg 1 M 56 IV B + IM 8 – PR PR 4 11 5.0 37.2 2 M 33 III A − HG 7 L R PR 5 12 48.1 129.3 3 F 20 II B − HG 7 L PR N 2 12 8.2 74.1 4 F 50 IV A − HG 4 – PR PR 1 12 17.8 38.1 5 F 54 II B − HG 15 – F MR 4 11 16.7 51.6 6 F 18 IV B + HG 2 – F PR 5 13 0.8 4.2 J Mayer Ifosfamide and etoposide for poor prognosis lymphoma 7 F 54 III B − IM 8 – R CR 5 10 7.6 27.1 8 M 40 III B − HG 10 L R PR 2 12 13.4 20.7 et al 9 F 46 IV A − IM 9 – F F 4 13 32.7 96.4 10 M 41 IV B + LG 16 – R N 4 12 5.2 49.3 11 F 44 III B − IM 8 – R PR 2 12 11.4 35.4 12 F 43 III A − LG 8 – R CR 3 12 16.7 78.3 13 F 49 III B − HG 13 L R PR 2 10 9.0 63.2 14 F 46 III A − IM 7 L R F 2 13 9.5 5.0 CR = complete remission; PR = partial remission; MR = minor response; F = failure (no response or progression); R = relapse; N = not evaluated; L = low-dose radiotherapy (Ͻ40 Gy); Start of harvesting = day of the first leukapheresis (start of the stimulating regimen = day 1). 415 Ifosfamide and etoposide for poor prognosis lymphoma J Mayer et al 416 + Table 3 Chemotherapy VIM (salvage and/or mobilization) back-up).
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