Ifosfamide is an alkylating agent with a broad spectrum of activity in solid tumors and hematological malignancies. In this review we will illustrate its use in the treatment of lymphomas and Hodgkin’s disease and the results of the principal studies which have investigated ifosfamide-containing regimens. Ifosfamide has been mainly used, in combination with other drugs, as a component of salvage regimens for relapsed or primarily refractory lymphoma. These regimens induced a variable clinical response rate (complete remissions ranging from 6 up to 73% and overall response rate from 24 to 72%). High-dose ifosfamide, in combination with etoposide or mitoxantrone, showed a good potential for mobilization of peripheral stem cells while reducing the tumor burden. Ifosfamide-based regimens are also being evaluated in the treatment of newly diagnosed patients in sequential, response-based protocols, using many non-cross-resistant drugs.

1.
Sarosy G: Ifosfamide pharmacologic overview. Semin Oncol 1989;16(suppl 3):2–8.
2.
Von Kalle AK, Schaadt M, Diehl V: European experience with ifosfamide in lymphomas. Semin Oncol 1989;16(suppl 3):73–77.
3.
Creaven PJ, Allen LM, Cohen MH, Nelson RL: Studies on the clinical pharmacology and toxicology of isophosphamide (NSC-109724). Cancer Treat Rep 1976;60:445–449.
4.
Rodriguez V, McCredie KB, Keating MJ, Valdivieso M, Bodey GP, Freireich EJ: Isophosphamide therapy for hematologic malignancies in patients refractory to prior treatment. Cancer Treat Rep 1978;62:493–497.
5.
Magrath I, Adde M, Sandlund J, Jain V: Ifosfamide in the treatment of high-grade recurrent non-Hodgkin lymphomas. Hematol Oncol 1991;9:267–274.
6.
King K, Younes A: Ifosfamide- and paclitaxel-based treatment of relapsed and refractory lymphoma. Semin Oncol 2000;27(suppl 1):14–22.
7.
Moskowitz CH, Bertino JR, Glassman JR, Hedrick EE, Hunte S, Coady-Lyons N, Agus DB, Goy A, Jurcic J, Noy A, O’Brien J, Portlock CS, Straus DS, Childs B, Frank R, Yahalom J, Filippa D, Louie D, Nimer SD, Zelenetz AD: Ifosfamide, carboplatin and etoposide: A highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:3776–3785.
8.
Joyce RM, Kraser CN, Tetrealt JC, Giallombardo N, McDermott D, Levine J, Umiel T, Regan M, Hurley D, Uhl L, Avigan D: Rituximab and ifosfamide, mitoxantrone, etoposide (RIME) with Neupogen® support for B-cell non-Hodgkin’s lymphoma prior to high-dose chemotherapy with autologous hematopoietic transplant. Eur J Haematol 2001;66(suppl 64):56–62.
9.
Cabanillas F: Experience with ifosfamide combinations in malignant lymphomas. Semin Oncol 1989;16(suppl 3):78–81.
10.
Rodriguez MA, Cabanillas FC, Hagemeister FB, McLaughlin P, Romaguera JE, Swan F, Velasquez W: A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol 1995;6:609–611.
11.
Rodriguez MA, Cabanillas FC, Velasquez W, Hagemeister FB, McLaughlin P, Swan F, Romaguera JE: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 1995;13:1734–1741.
12.
Romaguera JE, Rodriguez MA, Hagemeister FB, McLaughlin P, Rodriguez J, Preti A, Younes A, Sarris AH, Cabanillas F: Phase II study of paclitaxel in combination with mitoxantrone and ifosfamide/mesna for patients with relapsed or refractory non-Hodgkin’s lymphoma after failure to cytarabine/cispatin combination. Invest New Drugs 1999;17:187–192.
13.
Donato ML, Champlin RE, Van Besien KW, Korbling M, Cabanillas F, Anderlini P, Gajewski JG, Lauppe J, Durett A, Andersson B, Giralt S, Khouri I, Hagemeister F, Romaguera JE, Sarris A, McLaughlin P, Younes A, Ippoliti C, Blamble DA, Hester J, Gee A, Rodriguez MA: Intensive dose ifosfamide and etoposide with G-CSF for stem cell mobilization in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 1999;35:317–324.
14.
Van Besien K, Rodriguez A, Tomany S, Younes A, Donato M, Sarris A, Giralt S, Mehra R, Andersson B, Gajewski, Champlin R, Cabanillas F: Phase II study of a high-dose ifosfamide-based chemotherapy regimen with growth factor rescue in recurrent aggressive NHL. High response rates and limited toxicity, but limited impact on long-term survival. Bone Marrow Transplant 2001;27:397–404.
15.
Hagemeister FB, Donato M: Ifosfamide-based chemotherapy regimens in treatment of lymphoma: The M.D. Anderson experience. Eur J Haematol 2001;66(suppl 64):8–13.
16.
Cabanillas F, Burgess MA, Bodey GP, Freireich EJ: Sequential chemotherapy and late intensification for malignant lymphomas of aggressive histologic type. Am J Med 1983;74:382–388.
17.
Cabanillas F, Rodriguez DP, Hagemeister FB, McLaughlin P, Rodriguez MA, Romaguera JE, Dong K, Moon T: Alternating triple therapy for the treatment of intermediate grade and immunoblastic lymphoma. Ann Oncol 1998;9:511–518.
18.
Fridrik MA, Hausmaninger H, Lang A, Greil R, Drach J, Krieger O, Geissler D, Michlmayr G, Ulsperger E, Oberaigner W, Chott A: Sequential alternating chemotherapy with cyclophosphamide, epirubicin, vincristine, prednisolone, ifosfamide, etoposide, methotrexate, dexamethasone and filgrastim (CEOP/IMVP-Dexa) vs. standard cyclophosphamide, vincristine doxorubicin, prednisolone (CHOP) in untreated aggressive non-Hodgkin’s lymphoma. A prospective study (NHL-5) of the AGMT. Blood 2002;100:775, abstr 3065.
19.
Retsas S: Treatment of refractory malignant neoplasms with ifosfamide as single agent and in combination chemotherapy. Cancer Treat Rev 1983;10(suppl A):151–157.
20.
Nowrousian MR, Schoetensack B, Pfeiffer R: Combination chemotherapy with etoposide (VP-16), ifosfamide, methotrexate and bleomycin (VIM(B)) for refractory or recurrent lymphomas; in Brade W, Nagel GA, Seeber S (eds): Contributions to Oncology. Basel, Karger, 1987, vol 26, pp 414–422.
21.
Hagemeister FB, Tannir N, McLaughlin P, Salvador P, Riggs S, Velasquez WS, Cabanillas F: MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin’s disease. J Clin Oncol 1987;5:556–561.
22.
Bonfante V, Viviani S, Santoro A, Devizzi L, Di Russo A, Zanini M, Soncini F, Soto Parra H, Valagussa P, Bonadonna G: Ifosfamide and vinorelbine: An active regimen for patients with relapsed or refractory Hodgkin’s disease. Br J Haematol 1998;103:533–535.
23.
Ribrag V, Nasr F, Bouhris JH, Bosq J, Brault P, Girinsky T, Cosset JM, Munck JN, Corti C, Decaudin D, Pico JL, Hayat M, Cardle P: VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensification program in relapsed or refractory Hodgkin’s disease. Bone Marrow Transplant 1998;21:69–74.
24.
Magagnoli M, Sarina B, Balzarotti M, Castagna L, Timofeeva I, Nozza A, Bertuzzi A, Siracusano L, Sinnone A, Santoro A: Mobilizing potential of ifosfamide/vinorelbine-based chemotherapy in pretreated malignant lymphoma. Bone Marrow Transplant 2001;28:923–927.
25.
Bonfante V, Viviani S, Devizzi L, Di Russo A, Di Nicola M, Magni M, Matteucci P, Grisanti S, Valagussa P, Bonadonna G, Gianni AM: High-dose ifosfamide and vinorelbine as salvage therapy for relapsed or refractory Hodgkin’s disease. Eur J Haematol Suppl 2001;64:51–55.
26.
Proctor SJ, Taylor PR, Angus B, Wood K, Lennard AL, Lucraft H, Carey PJ, Stark A, Iqbal A, Haynes A, Russel N, Leonard RC, Culligan D, Conn J, Jackson GH: High-dose ifosfamide in combination with etoposide and epirubicin (IVE) in the treatment of relapsed/refractory Hodgkin’s disease and non-Hodgkin’s lymphoma: A report on toxicity and efficacy. Eur J Haematol Suppl 2001;64:28–32.
27.
Sieber M, Tesch H, Pfistner B, Rueffer U, Lathan B, Brosteanu O, Paulus U, Koch T, Pfreundschuh M, Loeffler M, Engert A, Josting A, Wolf J, Hasenclever D, Franklin J, Duehmke E, Georgii A, Schalk KP, Kirchner H, Doelken G, Munker R, Koch P, Herrmann R, Greil R, Anselmo AP, Diehl V: Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin’s lymphoma: final results of the German Hodgkin’s Lymphoma Study Group Trial HD5. J Clin Oncol 2002;20:476–484.
28.
Fermé C, Mounier N, Divine M, Brice P, Stamatoullas A, Reman O, Voillat L, Jaubert J, Lederlin P, Colin P, Berger F, Salles G: Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: Results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 Trial. J Clin Oncol 2002;20:467–475.
29.
Reiter A, Schrappe M, Ludwig WD, Lampert F, Harbott J, Henze G, Niemeyer CM, Gadner H, Müller-Weihrich S, Ritter J, Odenwald E, Riehm H: Favourable outcome of B-cell acute lymphoblastic leukemia in childhood: A report of three consecutive studies of the BFM group. Blood 1992;80:2471.
30.
Hoelzer D, Ludwig WD, Thiel E, Gassmann W, Loffler H, Fonatsch C, Rieder H, Heil G, Heinze B, Arnold R, Hossfeld D, Buchner T, Koch P, Freund M, Hiddemann W, Maschmeyer G, Heyll A, Aul C, Faak T, Kuse R, Ittel TH, Gramatzki M, Diedrich H, Kolbe K, Uberla K et al: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 1996;87:495–508.
31.
Magrath I, Adde M, Shad A, Venzon D, Seibel N, Gootenberg J, Neely J, Arndt C, Nieder M, Jaffe E, Wittes RA, Horak ID: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14:925–934.
32.
Mead GM, Sydes MR, Walewski J, Grigg A, Hatton CS, Pescosta N, Guarnaccia C, Lewis MS, McKendrick J, Stenning SP, Wright D, Norbert P; the UKLG LY06 collaborators: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: Results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 2002;13:264–274.
33.
Rodriguez V, McCredie KB, Keating MJ, Valdivieso M, Bodey GP, Freireich EJ: Isophosphamide therapy for hematologic malignancies in patients refractory to prior treatment. Cancer Treat Rep 1978;62:493–497.
34.
Case DC Jr, Anderson J, Ervin TJ, Gottlieb A: Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin’s lymphoma: Cancer and Leukemia Group B Study 8552. Med Pediatr Oncol 1988;16:182–186.
35.
Cabanillas F, Rodriguez V, Bodey GP: Ifosfamide, methotrexate and vincristine (IMV) combination chemotherapy as secondary treatment for patients with malignant lymphoma. Cancer Treat Rep 1980;64:933–937.
36.
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;60:693–697.
37.
Cabanillas F, Hagemeister FB, McLaughlin P, Velasquez WS, Riggs S, Fuller L, Smith T: Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 1987;5:407–412.
38.
Bush FW, Kruger HU, Kraft A: Combination of ifosfamide, methotrexate, VP-16 and bleomycin (IMV-Bleo) as salvage therapy for non-Hodgkin’s lymphoma; in Brade W, Nagel GA, Seeber S (eds): Contributions to Oncology. Basel, Karger, 1987, vol 26, pp 425–430.
39.
Retsas S: Preliminary results of the BMV-VIP regimen in the treatment of refractory lymphomas. Chemioterapia 1985;4(suppl):1129–1131.
40.
Steinke B, Kraft A, Busch FW: Etoposide, ifosfamide, methotrexate and bleomycin (VIM-Bleo) in CHOP-resistant non-Hodgkin’s lymphomas. Abstracts 4th European Conference on Clinical Oncology and Cancer Nursing, Madrid, Nov 1987, p 117.
41.
Bremer D, Bauer G: Salvage chemotherapy with ifosfamide, bleomycin, etoposide, and procarbazine (IBEP) in CHOP-resistant non-Hodgkin’s lymphomas; in Brade W, Nagel GA, Seeber S (eds): Contributions to Oncology. Basel, Karger, 1987, vol 26, pp 431–437.
42.
Lorusso V, Paradiso A, Guida M, Berardi F, De Lena M: Ifosfamide plus mitoxantrone as salvage treatment in non-Hodgkin’s lymphomas. Am J Clin Oncol 1991;14:492–495.
43.
Case DC Jr, Santarelli MT, Carey RW, Anderson J, Gottlieb A: Phase II trial of ifosfamide/mesna and mitoxantrone in previously treated patients with non-Hodgkin’s lymphoma: Cancer and leukemia group B study 8753. Med Pediatr Oncol 1992;20:325–329.
44.
Hickish T, Roldan A, Cunningham D, Mansi J, Ashley S, Nicolson V, Gore ME, Catovsky D, Smith IE: EPIC: An effective low toxicity regimen for relapsing lymphoma. Br J Cancer 1993;68:599–604.
45.
Fields KK, Zorsky PE, Hiemenz JW, Kronish LE, Elfenbein GJ: Ifosfamide, carboplatin, and etoposide: A new regimen with a broad spectrum of activity. J Clin Oncol 1994;12:544–552.
46.
Buzzoni R, Colleoni M, Nelli P, Nole F, Bajetta E: Results of a salvage regimen in refractory or relapsed non-Hodgkin’s lymphoma. Leuk Lymphoma 1994;14:121–128.
47.
Hopfinger G, Heinz R, Koller E, Schneider B, Pittermann E: Ifosfamide, mitoxantrone and etoposide (VIM) as salvage therapy of low toxicity in non-Hodgkin’s lymphoma. Eur J Haematol 1995;55:223–227.
48.
Rodriguez J, Van Besien K, Swan F, Mehra R, Romaguera J, McLaughlin P, Andersson B, Hagemeister F, Gajewski J, Sarris A, Przepiorka D, Younes A, Cabanillas F, Champlin R: MINE-ESHAP-BEAC: An induction-consolidation program for relapsed intermediate grade lymphomas. Proc ASCO 1995;14:397, abstr 1247.
49.
Enblad G, Hagberg H, Glimelius B: Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for non-Hodgkin’s lymphomas: a Swedish national prospective study. Swedish Lymphoma Study Group. Acta Oncol 1996;35:165–170.
50.
Garay G, Dupont J, Dragosky M, Nucifora E, Cacchione R, Schnidrig P, Fernandez J, Abel-Alzueta, Riveros D, Noviello V, Beguelin R, Campestri R, Albera C, Nicastro M, Triguboff E: Combination salvage chemotherapy with MIZE (ifosfamide-mesna, idarubicin and etoposide) for relapsing or refractory lymphoma. Leuk Lymphoma 1997;26:595–602.
51.
Haim N, Ben-Shahar M, Faraggi D, Tsuri-Etzioni A, Leviov M, Epelbaum R: Dexamethasone, etoposide, ifosfamide and cisplatin as second-line therapy in patients with aggressive non-Hodgkin’s lymphoma. Cancer 1997;80:1989–1996.
52.
Engert A, Schnell R, Kupper F, Reiser M, Engelhard M, Wilhelm M, Lathan B, Baltes-Engler S, Winterhalter B, Scheulen ME, Dederichs B, Tesch H, Wormann B, Diehl V: A phase II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high-grade non-Hodgkin’s lymphoma. Leuk Lymphoma 1997;24:513–522.
53.
Romaguera JE, Hagemeister FB, McLaughlin P, Rodriguez MA, Bachier C, Preti H, Sarris AH, Weber D, Younes A, Cabanillas F: Ninety-six-hour paclitaxel infusion with mitoxantrone and ifosfamide/mesna and consolidation with ESHAP for refractory and relapsed non-Hodgkin’s lymphoma. Leuk Lymphoma 1998;32:97–106.
54.
Reiser M, Schnell R, Straub G, Borchmann P, Wilhelm M, Ubelacker R, Wormann B, Munch R, Diehl V, Engert A: DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): An effective and well-tolerated new regimen for patients with relapsed lymphoma. Leuk Lymphoma 1998;31:359–366.
55.
Plantier-Colcher I, Dupriez B, Simon M, Detourmignies L, Jouet JP, Fenaux P, Bauters F, Morel P: The VIM3-AraC regimen followed by autologous stem cell transplantation in refractory or relapsing aggressive non-Hodgkin’s lymphoma. A prospective study of 71 consecutive cases. Leukemia 1999;13:282–288.
56.
O’Connell N, Gardiner N, Duggan C, Enright H, Kennedy MJ, McCann SR, Daly PA, Browne PV: Effective progenitor cell mobilization in lymphoproliferative disorders using ifosfamide, epirubicin and etoposide (IEV). Eur J Haematol Suppl 2001;64:33–36.
57.
Sawada M, Tsurumi H, Yamada T, Kasahara S, Goto H, Hara T, Oyama M, Takami T, Moriwaki H: Combination chemotherapy consisting of methylprednisolone, ifosfamide, methotrexate, etoposide, carboplatin (P-IMVP16/CBDCA) and G-CSF efficiently mobilize peripheral blood progenitor cells in aggressive non-Hodgkin’s lymphoma patients who received CHOP. Blood 2002;100:472b, abstr 5466.
58.
Arland M, Leuner S, Lange S, Bartsch R, Kahl C, Florschutz A, Franke A, Hoffkes HG: Ifosfamide, epirubicin and granulocyte colony-stimulating factor: A regimen for successful mobilization of peripheral blood progenitor cells in patients with multiple myeloma. Hematol Oncol 2001;19:59–66.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.