Malignant Lymphomas Ifosfamide, epirubicin and etoposide (IEV) regimen as salvage and research paper mobilizing therapy for haematologica 2002; 87:816-821 relapsed/refractory lymphoma http://www.haematologica.ws/2002_08/816.htm patients PIER LUIGI ZINZANI, MONICA TANI, ANNA LIA MOLINARI,* VITTORIO STEFONI, ELIANA ZUFFA,* LAPO ALINARI, ANNALISA GABRIELE, FRANCESCA BONIFAZI, Institute of Hematology and Medical Oncology PATRIZIA ALBERTINI, MARZIA SALVUCCI,* SANTE TURA, “L. e A. Seràgnoli”, University of Bologna; MICHELE BACCARANI *Division of Hematology, Ravenna Hospital, Ravenna, Italy Background and Objectives. Therapy for relapsed/refrac- lthough advanced stage Hodgkin’s disease tory lymphomas should be based only on drugs not (HD) and some aggressive non-Hodgkin’s included in the front-line chemotherapy regimens. We Alymphomas (NHL) are potentially curable adopted the strategy of using salvage chemotherapy to with standard chemotherapy, many patients either debulk disease and simultaneously mobilize stem cells, relapse or never achieve remission.1,2 One way of using a regimen based on ifosfamide and etoposide, improving this situation could be to intensify (drugs not usually used for front-line treatment). front-line chemotherapy, either by dose-escala- tion of conventional therapy3 or by adding high- Design and Methods. A three-drug combination of ifos- famide, epirubicin and etoposide (IEV) was used to treat dose chemotherapy with peripheral blood stem cell 4,5 62 patients with relapsing or refractory aggressive non- (PBSC) rescue. Whereas treatment of relapsing Hodgkin’s lymphoma (NHL; n=51) or Hodgkin’s disease disease with conventional chemo- and/or radiation (HD; n=11). Forty-five of the patients were studied for the therapy is unsatisfactory, especially in those feasibility of peripheral blood stem cell (PBSC) harvest. patients who have had an early relapse,6,7 high- dose chemotherapy and stem cell rescue may Results. The overall and complete response (CR) rates improve prognosis.8,9 Although high-dose chemo- were, respectively, 77% and 32% in the NHL subset and therapy can also be effective as a salvage strate- 81% and 45% in the HD subset. Among the 17 patients gy for HD patients who do not respond to induc- who achieved CR after IEV but did not have a subsequent tion treatment,10 the approach fails with many transplantation, the median duration of the response was 11 9 months (range, 2 to 14 months). Mobilization was suc- refractory primary lymphomas. So, despite our cessful in 33 of 45 (71%) patients. Among the 45 who current ability to cure almost half of all aggressive proceeded to autotransplantation, 27 (60%) were in CR NHL and the majority of HD, effective second-line status after the autograft; 23/45 (51%) patients are cur- therapies are needed for both resistant and relaps- rently in continuous CR with a median follow-up of 25 ing disease. These second-line therapies could months (range, 10-68 months); the relapse-free survival serve both for re-induction prior to high-dose curve shows 83% in this state at 60 months. Twenty- chemotherapy with PBSC rescue, and for patients three (37%) patients are currently in continuous CR with who are not candidates for transplantation. a median follow-up of 25 months. Clinical and hemato- Ideally, second-line therapy should not share any logic toxic effects were mild. mechanism of action or toxicity with the initial induction regimen. In pratical terms, since most Interpretation and Conclusions. Our results indicate the efficacy of the IEV regimen in inducing a good remission primary induction chemotherapy regimens contain rate. IEV is a predictable and highly effective mobilization anthracyclines and tend to be myelosuppressive, regimen in relapsed/refractory patients with aggressive second-line combinations that avoid cardiac tox- NHL or HD. icity and excessive stem cell damage would be par- ©2002, Ferrata Storti Foundation ticularly useful. In multiple trials in which combi- nation chemotherapy has been used to treat Key words: IEV regimen, HD, aggressive NHL, relapsed lymphoma patients following treatment relapse/refractory patients, PBSC mobilization. with CHOP, most of the regimens have included cisplatin, methotrexate, mitoxantrone, and ifos- 12-14 Correspondence: Pier Luigi Zinzani, M.D., Istituto di Ematologia famide. The MINE (ifosfamide, mitoxantrone, e Oncologia Medica “L. e A. Seràgnoli”, Policlinico S.Orsola, etoposide) regimen was one of the first to include via Massarenti 9, 40138 Bologna, Italy. Phone: international +39.051.6363680. Fax: international ifosfamide, and several investigators have used +39.051.6364037. E-mail: [email protected] variants of this combination to treat patients with haematologica vol. 87(8):august 2002 IEV regimen in pretreated lymphomas 817 relapsed lymphomas.15-23 All these studies have stage II to IV according to the Ann Arbor staging indicated that ifosfamide-based regimens incor- system;25 Eastern Cooperative Oncology Group porating etoposide and other agents can induce (ECOG)26 performance status less than 3; human responses in transplanted patients and, when used immunodeficiency virus negativity; and normal in high doses in combination with growth factors, renal, hepatic, and cardiac functions [including a can act as excellent mobilizers of PBSC. baseline resting left ventricular ejection fraction We previously reported20 on the use of IEV (ifos- (LVEF) greater than 50%]. In all cases, staging eval- famide, epirubicin, and etoposide) alone in a group uation included initial hematologic and chemical of resistant or relapsing lymphoma (HD and aggres- surveys, in addition to chest X-rays, abdominal sive NHL) patients. Herein, we report an extended ultrasonography, computed tomography of the follow-up of a larger series of patients treated with chest and abdomen, and bone marrow biopsy. Oth- IEV either alone or prior to autologous bone mar- er studies included lymphography (in 2 HD row transplantation (ABMT). patients), and liver biopsy when appropriate. No patient underwent staging laparotomy. Bulky Design and Methods disease was defined as a tumor mass ≥6 cm. Twen- ty-three patients had stage II, 15 had stage III, and Patients’ characteristics 24 had stage IV disease. Twenty-two patients pre- The present study regards 62 consecutive, previ- sented bulky disease. Thirty-eight patients had ele- ously treated patients (37 males, 25 females; medi- vated serum lactate dehydrogenase (LDH) level and an age, 42 years, range 14-62) with either NHL 29 patients had at least an extranodal involvement. (n=51) or HD (n=11) diagnosed between January The performance status was 0-1 in 40 patients 1995 and September 2000 (Table 1). and 2 in the remaining 22 patients; according to Eligibility criteria included a confirmed histolog- the stage, 5 patients had stage II, 29 stage III, and ic diagnosis of aggressive or indolent NHL or HD 28 stage IV disease. Histologically, all 51 NHL according to the REAL classification;24 disease patients had aggressive disease. Informed consent was always provided according to the Declaration Table 1. Patients’ characteristics [n=62]. of Helsinki. Treatment protocol Age (years) Median 42 The IEV schedule was as follows: ifosfamide Range 14-62 2,500 mg/m2/day i.v. over 4 hours followed by mes- 2 Sex M/F 37/25 na (3 g/m ) and hydration over 10 h. daily to pro- tect against urothelial toxicity on day 1 to 3, epiru- Histology bicin 100 mg/m2 i.v. on day 1; etoposide 150 mg/m2 Hodgkin’s disease 11 Follicular grade III 3 i.v. on days 1 to 3. Courses were repeated every 21 Peripheral T-cell 2 days, with a target total of three courses; chemo- Diffuse large B-cell 44 therapy was given in an outpatient setting. In the Anaplastic large B-cell 2 45 patients for whom PBSC harvest was feasible only 2 conditioning courses were given in order to Response status at time of treatment: reduce tumor volume before high-dose chemother- PR 12 Relapse 33 apy and PBSC reinfusion. For these patients, sub- Refractory 17 cutaneous administration of granulocyte colony- stimulating factor (G-CSF) (5 g/kg, once daily) Elevated LDH level Yes 38 µ No 24 was commenced on day 6 and continued until completion of the PBSC harvest. The remaining 17 Performance status 0-1 40 222 patients, who were considered unsuitable for mye- loablative therapy, all received 3-4 cycles; G-CSF Extranodal sites Yes 29 was administered at the same dose from day 6 to No 33 14 of each cycle. Stage II 5 Response III 29 IV 28 All patients were restaged after completion of IEV chemotherapy. Clinical and pathologic evalua- IPI 0-2 45 tions were made by repeating radiographic inves- 317 ≥ tigations and bone marrow and/or liver biopsies haematologica vol. 87(8) august 2002 818 P.L. Zinzani et al. whenever previous results had been positive. Com- Table 2. Responses according to disease status prior to IEV plete response (CR) and partial remission (PR) were therapy of all 62 patients. defined according to international criteria.27 No response (NR) was anything less than PR. Standard HD (n=11) NHL (n=51) response response ECOG toxicity criteria were used.26 Statistical methods Disease status No. pts CR PR NR CR PR NR Overall survival was measured from the time of at time of treatment entry into the protocol until death; the relapse- During PR 12 3 1 0 2 3 .3 free interval was calculated from the date of response after autograft until relapse or death; Relapsed 33 2 1 0 12 18 0 event-free survival was measured from the auto- Refractory 17 0 2 2 2 2 9 graft to the first event (resistance to treatment, relapse, death, last follow-up). Overall, relapse-free survival, and event-free survival curves were cal- culated according to the method of Kaplan and PR (a good PR; GPR). Among the patients treated Meier.28 Deaths from lymphoma, secondary to lym- with IEV after relapse, 14 (43%) achieved CR and phoma treatment or to any disease (related or 19 (57%) PR.