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Busulfan, Cyclophosphamide and Etoposide As High-Dose Conditioning Therapy in Patients with Malignant Lymphoma and Prior Dose-Limiting Radiation Therapy

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Busulfan, Cyclophosphamide and Etoposide As High-Dose Conditioning Therapy in Patients with Malignant Lymphoma and Prior Dose-Limiting Radiation Therapy Bone Marrow Transplantation, (1998) 21, 1171–1175 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Busulfan, cyclophosphamide and etoposide as high-dose conditioning therapy in patients with malignant lymphoma and prior dose-limiting radiation therapy ¨ ¨ ¨ ¨ N Kroger1, M Hoffknecht1,MHanel2, W Kruger1, W Zeller1, M Stockschlader1, M de Wit1, HJ Weh3, H Kabisch1, R Erttmann1 and AR Zander1 1Bone Marrow Transplantation, 3Department of Oncology/Hematology University Hospital Hamburg-Eppendorf and 2Department of Internal Medicine, Hematology Chemnitz, Germany Summary: High-dose chemotherapy and/or radiotherapy with periph- eral blood stem cell support is increasingly used in patients Relapse after transplant for malignant lymphomas with high-risk or relapsed malignant non-Hodgkin’s lym- remains the main cause of treatment failure. Most con- phoma.1–3 Recently, a randomized trial confirmed the ditioning regimens contain total body irradiation (TBI). superiority of high-dose chemotherapy followed by auto- We investigated the toxicity and efficacy of an intensi- logous bone marrow transplantation over standard salvage fied chemotherapy conditioning regimen without TBI in therapy for relapsing chemosensitive non-Hodgkin’s lym- patients with relapsed or high-risk malignant lym- phoma.4 Total body irradiation (TBI) is part of many fre- phoma who had received prior radiation therapy and quently used conditioning regimens. The most frequent sin- were therefore not eligible for TBI. Twenty patients gle cause of treatment failure has been relapse. In an with a median age of 38 (18–56) and relapsed or high- attempt to decrease the relapse rate, etoposide was added to risk malignant non-Hodgkin’s lymphoma (NHL, n = 16) the TBI/cyclophosphamide regimen because of its known or Hodgkin’s disease (HD, n = 4) underwent high-dose activity against lymphoma.5–7 However, patients with prior chemotherapy consisting of busulfan (16 mg/kg), cyclo- dose-limiting radiation therapy need alternative radiation- phosphamide (120 mg/kg) and etoposide 30 mg/kg free preparative regimens. The combination of busulfan (n = 8) or 45 mg/kg (n = 12) followed by peripheral stem plus cyclophosphamide (Bu/Cy) has been widely used in cell support (n = 14), autologous bone marrow (n = 3), patients with hematological malignancies. Initially, studies allogeneic (n = 2) or syngeneic (n = 1) transplantation. using busulfan (16 mg/kg) and cyclophosphamide All but two had chemosensitive disease before high-dose (200 mg/kg) provided an effective alternative to TBI plus chemotherapy. The main toxicity – according to the cyclophosphamide in the treatment of AML.8 Modification Bearman score – was mucositis II in 18 (90%) patients; of this regimen by lowering the cyclophosphamide dose to five patients (25%) suffered a grade I hepatic toxicity. 120 mg/kg appears to be equally effective and less toxic.9 GI toxicity I occurred in three (15%) and renal toxicity Studies with Bu/Cy also demonstrated significant antitumor I in two patients (10%). Sixty percent of the patients activity in patients with lymphoid malignancy10–13 but – developed transient dermatitis with erythema and three similiar to TBI containing therapies – treatment failure was of them (15%) had skin desquamation; one patient mainly due to relapse. We therefore conducted a study to experienced asymptomatic pancreatitis. Toxicity was increase efficacy by adding etoposide (30 or 45 mg/kg) to slightly higher in patients treated with 45 mg/kg etopo- high-dose busulfan, cyclophosphamide in patients with side. One patient (5%) died of treatment-related veno- malignant lymphoma who had received prior radiotherapy occlusive disease. After a median follow-up of 50 months and were not eligible for a TBI containing regimen. We (24–84) the disease-free and overall survival were 50% have previously reported the efficacy of Bu/Cy/etoposide and 55%. One of the nine relapsing patients developed as preparative therapy in allogeneic bone marrow transplan- secondary AML 18 months after transplant. High-dose tation of patients with AML.14 busulfan, cyclophosphamide and etoposide is an effec- tive regimen resulting in long-term disease-free survival in 50% of patients with relapsed malignant lymphoma Patients and methods and prior radiation therapy. The toxicity is moderate with a low treatment-related mortality (5%). Patient selection Keywords: malignant lymphoma; high-dose chemo- therapy; etoposide; busulfan; cyclophosphamide. Between November 1991 and April 1995, 20 patients with non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease ¨ (HD) who had received prior dose-limiting radiotherapy Correspondence: Dr med N Kroger, Bone Marrow Transplantation, Uni- versity Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Ham- received high-dose busulfan, cyclophosphamide and etopo- burg, Germany side followed by peripheral blood stem cell support Received 1 October 1997; accepted 15 January 1998 (n = 14), autologous bone marrow (n = 3) or allogeneic High-dose Bu/Cy/etoposide for malignant lymphoma ¨ N Kroger et al 1172 (n = 2)/syngeneic (n = 1) bone marrow transplantation. Table 1 Patient characteristics (n = 20) Inclusion criteria included prior administration of radio- therapy greater than 20 Gy to the liver or mediastinum or Gender: male/female 10/10 greater than 30 Gy as extended or involved field to other Median age (years) 38 (range 18–56) regions. Histology Further eligibility criteria were age less than 60 years, High grade 12 ECOG performance status 0 or 1, adequate cardiac and pul- Low grade (follicular) 2 monary function and creatinine of less than 2.0 mg/dl. Mantle cell lymphoma 2 NHL was classified according to the Kiel and the REAL Hodgkin’s disease 4 15,16 Disease status classifications. The transplant protocol was approved by CR the local ethics commission and all patients gave written 1st CR 1 informed consent. 2nd CR 4 3rd CR 3 4th CR 1 Patient characteristics 5th CR 1 PR The study included 20 patients with a median age of 38 2nd PR 4 years (range 18–56) and the following histologies: high- 3rd PR 2 grade lymphoma (n = 12), follicular lymphoma (n = 2), 4th PR 2 = 3 Relapse 2 mantle cell lymphoma (n 2) and Hodgkin’s disease Stage at initial diagnosis (n = 4). Before high-dose chemotherapy 10 patients were I1 in complete remission (1st CR: n = 1; 2nd CR: n = 4, 3rd II 7 CR: n = 3; 4th CR: n = 1; 5th CR: n = 1), eight in partial III 2 = = = IV 10 remission (2nd PR: n 4; 3rd PR: n 2; 4th PR n 2;) and Stem cell source two patients were transplanted in 3rd relapse. Ten patients PBSC 14 had had stage IV disease, but none had bone marrow Autologous BM 3 involvement. The median number of prior chemotherapy Allogeneic BM 2 regimens was 2.5 (range 1–5) (Table 1). Syngeneic BM 1 Median follow-up (months) 50 (range 24–84) Treatment regimen VP 16 dose 30 mg/kg 8 A total dose of busulfan of 16 mg/kg was administered 45 mg/kg 12 − Prior radiotherapy orally in four divided doses daily for 4 days (days 8to Mediastinum 9 −5). Etoposide (30 mg/kg n = 8 or 45 mg/kg n = 12) was Abdomen 4 administered on day −4 either undiluted over 6 h or split Supra- and infradiaphragmal 4 and diluted over 1 h. There was no randomization in terms Involved field Ͼ30 Gy 6 of etoposide dose: 30 mg/kg was given to patients with Median prior chemotherapies 2.5 extended prior radiotherapy, eg to liver or mediastinum. Cyclophosphamide 60 mg/kg was given intravenously over 1 h for 2 days (days −3 and −2). Phenytoin was given to score.18 The maximum score for each organ system was prevent busulfan induced seizures until 2 days after stop- recorded. Skin toxicity was described as mild in cases of ping busulfan. Uroepithelial prophylaxis was achieved with erythema or as more severe in cases of desquamation. hyperhydration and mesna. Bone marrow or peripheral Attempts were made to exclude from this evaluation toxi- blood stem cells were infused 24–48 h after the last cyclo- cities due to GVHD. phosphamide administration (day 0). Results Stem cell source Patients received hematopoietic stem cells from autologous All patients were evaluable for toxicity and response. (n = 3), allogeneic (n = 2), syngeneic (n = 1) marrow or = from G-CSF-mobilized peripheral blood (n 14). The tech- Transplant-related toxicity nique for PBSC harvest following G-CSF application, cryo- preservation, CD34+ cell counting and progenitor cell assay One patient (5%) died of causes other than malignancy has been described elsewhere.17 All patients received G- before day 100 after transplant. She developed severe hep- CSF beginning on day +1 post transplant (10 ␮g/kg n = 16; atic toxicity, which fulfilled the Seattle criteria of veno- 5 ␮g/kg n = 4) until engraftment. occlusive disease (VOD) of the liver.19 Before transplan- tation she had received radiotherapy to the abdomen, which is one of the major risk factors in developing VOD. All Regimen-related toxicity patients developed mucositis, 90% of them grade II that Regimen-related toxicity affecting the renal, hepatic, car- required intravenous analgesics. Skin toxicity was mild in diac, pulmonary, the gastrointestinal, the CNS system and 60% of patients with localized erythema mainly of palmar mucous membranes were graded using the Bearman or plantar surfaces, only three (15%) experienced moderate High-dose Bu/Cy/etoposide for malignant lymphoma ¨ N Kroger et al 1173 toxicity with local desquamation. All cases of mucositis and skin toxicity resolved completely. Hepatic toxicity grade I 1.0 with maximum serum bilirubin of 3.9 mg/dl was seen in six (30%), renal toxicity grade 1 in two and mild diarrhea 0.8 (grade I) in three patients (15%). Patients treated with 45 mg/kg etoposide experienced a slightly higher degree of 0.6 50% toxicity than patients treated with 30 mg/kg (Table 2).
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