Bone Marrow Transplantation (2010) 45, 1147–1153 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00 www.nature.com/bmt ORIGINAL ARTICLE Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study M Musso1, R Scalone1, G Marcacci2, F Lanza3, N Di Renzo4, N Cascavilla5, P Di Bartolomeo6, A Crescimanno1, T Perrone7 and A Pinto2 1Department of Oncology, Oncohematology and Bone Marrow Transplantation Unit, ‘La Maddalena’, Palermo, Italy; 2Hematology- Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione ‘G Pascale’, IRCCS, Naples, Italy; 3Section of Hematology, University Hospital, St Anna Hospital, Ferrara, Italy; 4Hematology Unit, ‘Vito Fazi’ Hospital, Lecce, Italy; 5Hematology Unit and Bone Marrow Transplantation, IRCSS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo (FG), Italy; 6Department of Hematology, Bone Marrow Transplant Centre, Ospedale Civile, Pescara, Italy and 7Scientific Department, Italfarmaco S.p.A, Cinisello Balsamo (MI), Italy BEAM is a widely used conditioning regimen for Introduction relapsed/refractory lymphoma patients undergoing auto- SCT. We conducted a multicenter study with an alter- BEAM is a widely adopted conditioning regimen for native regimen (fotemustine plus etoposide, cytarabine autologous hemopoietic SCT (ASCT) in patients with and melphalan (FEAM)) in which BCNU was substituted Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL), by the chloroethylnitrosourea fotemustine (FTM). Eighty- and has an acceptable toxicity and high efficacy.1 Adverse four patients with relapsed/refractory Hodgkin’s (n ¼ 20) events associated with carmustine-containing conditioning and non-Hodgkin’s lymphoma (n ¼ 64) were conditioned regimens (that is, BEAM, BEAC) are partly related to with a FEAM regimen (FTM 150 mg/m2 on days –7, –6, BCNU and most commonly include severe mucositis, etoposide 200 mg/m2 and cytarabine 400 mg/m2 on days chemotherapy-induced nausea and vomiting, diarrhea, –5, –4, –3, –2 and melphalan 140 mg/m2 on day –1). hepatotoxicity and nephrotoxicity.1–4 In addition, non- Patients were evaluated for toxicity and engraftment infective toxic pulmonary complications have been repor- parameters. Median times to neutrophil (4500 Â 109/l) ted in 16–64% of patients after carmustine-containing and plt (420 000 Â 109/l) engraftment were 11 and high-dose regimens.5 Post transplant lung toxicity in 13 days, respectively. Grade 3 mucositis occurred in patients receiving carmustine-based conditioning has been 19 patients (23%), while G3 nausea/vomiting and G3 related to the fact that BCNU inhibits the glutathione diarrhea were observed in 13 (15%) and 6 (7%) patients, reductase tissue detoxification system.6 As BCNU-related respectively. No severe hepatic, renal or pulmonary major pulmonary toxicity represents an invalidating and toxicity was detected. Seven patients (7%) experienced sometimes fatal complication of ASCT, accurate monitoring G4 mucositis, while no other G4 toxicities or unexpected of respiratory functions, prompt initiation of steroid therapy adverse events of any grade were recorded. Transplant- and even carmustine dose reductions, especially in BCNU related mortality was 2.4%. We conclude that a FEAM plus CY-containing regimens, have been suggested.5,7 regimen is feasible and safe. Although toxicity and Fotemustine (FTM) is a third-generation chloroethyl- engraftment times compared favorably with BEAM, nitrosourea containing a phosphoalanine carrier group longer follow-up is needed to evaluate fully its efficacy attached to the nitrosourea radical.8 The phosphoalanine and long-term safety. group makes the drug highly lipophilic, as shown by the Bone Marrow Transplantation (2010) 45, 1147–1153; octanol/water partition coefficient, which is in the optimal doi:10.1038/bmt.2009.318; published online 9 November 2009 range compared with other nitrosoureas such as BCNU Keywords: fotemustine; carmustine; FEAM; BEAM; and CCNU.9,10 This characteristic allows FTM to cross the conditioning; auto-SCT blood-brain barrier (BBB), as shown by experimental studies in animals.11,12 In addition, as FTM does not significantly alter glutathione reductase activity, a more favorable pulmonary toxicity profile for this agent can be predicted compared with BCNU.13 In fact, several clinical Correspondence: Dr M Musso, Department of Oncology, Oncohema- trials have confirmed that FTM, unlike other nitrosoureas, tology and BMT Unit ‘La Maddalena’, Via San Lorenzo Colli 312/D, shows no significant pulmonary toxicity.14–16 I-90146, Palermo, Italy. E-mail: [email protected] With regards to antitumor activity, a phase II study by 17 Received 14 April 2009; revised 17 September 2009; accepted 29 Jacquillat et al., showed that administration of a non- September 2009; published online 9 November 2009 myeloablative schedule of FTM (100 mg/m2 on days 1, 8 Fotemustine-based conditioning for autologous transplant M Musso et al 1148 and 15 (induction), followed after 4–5 weeks by a single Table 1 Dosage and schedule of the FEAM regimen 100 mg/m2 maintenance dose, every 21 days), induced Drug Dose Day objective clinical responses in 7 of 13 heavily pre-treated patients with hematologic malignancies including HL and FTM 150 mg/m2 –7, –6 NHL; thrombocytopenia was the most commonly observed Etoposide 200 mg/m2 –5, –4, –3, –2 2 toxicity. In addition, Rigal-Huguet et al.18 conducted an Ara-C 400 mg/m –5, –4, –3, –2 Melphalan 140 mg/m2 –1 intensification pilot study with autotransplantation of BM in NHL patients in which high-dose FTM was substituted Abbreviations: FEAM ¼ fotemustine plus etoposide, cytarabine and for BCNU in modified BEAM/BEAC-like regimens (FTM, melphalan; FTM ¼ fotemustine. 300 mg/m2; etoposide 500 mg/m2; cytarabine, 400 mg/m2 and melphalan 140 mg/m2 or CY 6.0 g/m2). blood progenitor cells were infused on day 0, followed The aim of this pharmacokinetic study was to show the by s.c. G-CSF (5 mg/kg) from day 1 of ASCT until passage of FTM through the BBB and the feasibility of 2 consecutive days when the ANCs were X1000 Â 109/l. increasing the dose of the drug. Prophylaxis for opportunistic infections and antimicrobial Given the comparable antitumor activity of FTM therapy in cases of febrile episodes as well as standard with respect to BCNU, in addition to a more favorable supportive measures including blood and plt transfusions safety profile, we conducted a multicenter study of a novel were administered according to the standard protocols and FTM-based high-dose regimen (fotemustine plus etoposide, policies of each participating center. Similarly, protocols cytarabine and melphalan (FEAM)) in which BCNU was for antiemetic prophylaxis used during FEAM administra- substituted by an equal dose (300 mg/m2) of FTM without tion, were identical to those currently used for BEAM at further modifications of the BEAM platform. The results, participating centers and consisted of serotonin 5-HT3- in a series of 84 consecutive patients with refractory and receptor antagonists and dexamethasone. relapsed lymphoma, show that FEAM, followed by auto- logous hemopoietic rescue with peripheral blood progeni- tor cells, is a feasible conditioning strategy associated Study definitions, safety and efficacy evaluations with a favorable toxicity profile and timely hemopoietic The primary objectives of the study were to assess the engraftment. feasibility and safety of the FEAM regimen in terms of acute toxicity and hemopoietic engraftment. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria version 3.0 (http://ctep. Patients and methods cancer.gov/protocoldevelopment/electronic_applications/docs/ ctcaev3.pdf). Transplant-related mortality (TRM) was Eligibility criteria defined as any death related to a fatal complication in the In all, 84 eligible patients with relapsed/refractory HL absence of the underlying disease within 100 days from (n ¼ 20) or NHL (n ¼ 64), were consecutively enrolled. transplantation. Secondary end points included evaluation The study was conducted according to the Declaration of of the efficacy of the FEAM regimen in terms of event free Helsinki, and all patients signed a written informed consent survival and overall survival. Disease status at transplant- form before treatment. Eligible patients were required to ation and response to high-dose chemotherapy, assessed 1 have histologically proven relapsed/refractory HL or NHL month after ASCT, were evaluated with standard response after first-line chemotherapy. High-risk patient candidates criteria for lymphoma.19 Event free survival was defined as to upfront high-dose consolidation and ASCT were also the time between ASCT and the occurrence of a serious accrued. Other eligibility criteria included a Karnofsky morbidity (that is, a life-threatening complication requiring Performance Status 460, adequate cardiac, pulmonary, hospitalization or prolonging ongoing hospitalization hepatic and renal function, and no acute or uncontrolled resulting in death or significant disability/incapacity), bacterial or viral infections before transplantation. Patients disease relapse, disease progression or death from any with uncontrolled comorbid conditions or active toxicity cause. Overall survival was defined as the time from ASCT from salvage chemotherapy were considered ineligible. until death or the date of last follow-up when the patient was known to be alive. Conditioning regimen In all of the cases