Leukemia (2001) 15, 256–263 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu High-dose mitoxantrone + melphalan (MITO/L-PAM) as conditioning regimen supported by peripheral blood progenitor cell (PBPC) autograft in 113 lymphoma patients: high tolerability with reversible cardiotoxicity C Tarella1, F Zallio1, D Caracciolo1, A Cuttica1, P Corradini1,2, P Gavarotti1, M Ladetto1, V Podio3, A Sargiotto4, G Rossi5, AM Gianni6 and A Pileri1 1Dipartimento di Medicina e Oncologia Sperimentale, Divisione Universitaria di Ematologia; Serv. 3Univ. e 4Osped di Medicina Nucleare; 5Divisione Universitaria di Radioterapia-Azienda Ospedaliera S Giovanni Battista di Torino, Torino; and 6Unita` Trapianto Midollo, Ist Naz. Tumori, Milano, Italy Hematological and extrahematological toxicity of high-dose The ease deriving from the excellent tolerability of PBPC (hd) mitoxantrone (MITO) and melphalan (L-PAM) as condition- procedures probably slowed down the efforts aimed to look ing regimen prior to peripheral blood progenitor cell (PBPC) autograft was evaluated in 113 lymphoma patients (87 at dis- for innovative and possibly more effective conditioning regi- ease onset). Autograft was the final part of a hd-sequential mens. In fact, most autograft programs employed nowadays (HDS) chemotherapy program, including a debulkying phase are based on conditioning regimens designed several years (1–2 APO ± 2 DHAP courses) and then sequential adminis- ago, such as TBI + cyclophosphamide (CY), or regimens con- tration of hd-cyclophosphamide, methotrexate (or Ara-C) and taining nitrosurea or melphalan (L-PAM), such as BEAM, CBV etoposide, at 10 to 30 day intervals. Autograft phase included: or BEAC.17–21 Looking for a better conditioning regimen, one (1) hd-MITO, given at 60 mg/m2 on day −5; (2) hd-L-PAM, given at 180 mg/m2 on day −2; (3) PBPC autograft, with a median of should not only consider the antitumor activity of a given drug 11 × 106 CD341/kg, or 70 × 104 CFU-GM/kg, on day 0. A rapid combination, but should be concerned with its toxicity as hematological recovery was observed in most patients, with well. Today, hematological toxicity is not as severe as it used ANC .500/µL and Plt .20 000/µl values reached at a median to be, due to the availability of mobilized PBPC. Thus, efforts of 11 and 10 days since autograft, respectively. The good hem- should rather be addressed to reduce extra-hematological opoietic reconstitution allowed the delivery of consolidation toxicity of intensive programs. radiotherapy (RT) to bulky sites in 53 out of 57 candidate patients, within 1 to 3 months following autograft; five of these Lymphoma patients seem to benefit from anthracycline- patients required back-up PBPC re-infusion due to severe post- containing conditioning regimens. Unfortunately, their use at RT pancytopenia. Few severe infectious complications were high dosage has been hampered by the risk of cardiac tox- recorded. There was one single fatal event due to severe pancy- icity.22–24 Mitoxantrone (MITO), a molecule derived from topenia following whole abdomen RT. Cardiac toxicity was anthracenedione, has been proposed as an alternative. Several evaluated as left ventricular ejection fraction (LVEF), monitored studies have shown that this drug can be safely used alone or by cardiac radionuclide scan. LVEF prior to and after autograft in combination, at doses significantly higher than those com- was significantly reduced (median values: 55% vs 46%) in 58 25–30 evaluated patients; however, a significant increase to a median monly employed in conventional protocols. In spite of value of 50% was observed in 45 patients evaluated at 1 to 3 consistently reported good tolerability, there is presently a years since autograft. At a median follow-up of 3.6 years, 92 lack of studies conducted on wide and homogeneous groups patients are alive, with a 7-year overall survival projection and of patients and with an appropriately long follow-up. More- 6.7-year failure-free survival projection of 77% and 69%, over, few studies have been specifically addressed to analyze respectively. We conclude that a conditioning regimen with hd- MITO/L-PAM fits well within the HDS program. It implies good cardiac function prior and following high-dose MITO. tolerability and reversible cardiotoxicity and it may have con- In this study we investigated the tolerability of a combi- tributed to the good long-term outcome observed in this series nation of high-dose MITO and L-PAM in 113 lymphoma of patients. Leukemia (2001) 15, 256–263. patients. Autograft was the final part of a high-dose (hd) Keywords: mitoxantrone; conditioning regimen; autograft; cardi- sequential chemotherapy program.9,10,15 The study was aimed otoxicity; HDS; lymphoma to evaluate at short, medium and long term: (1) hematological toxicity; (2) extra-hematological toxicity and in particular car- diac function evolution; (3) life expectancy, of patients com- Introduction pleting the whole program including autograft. The results indicate that MITO can be safely employed in conditioning In the last decade high-dose chemotherapy and autograft have regimens before PBPC autograft, with an acceptable hematol- significantly improved the outcome of lymphoma patients. ogical and extra-hematological toxicity; there was a certain This approach is presently the first choice for relapsed high cardiac toxicity but this was unexpectedly reversible, at least grade non-Hodgkin’s and Hodgkin’s lymphoma.1–4 Moreover, in part. Finally, the prolonged long-term survival indicates that in the last few years evidence has been produced pointing the combination MITO/L-PAM may contribute to the effective- towards a role for autograft as first-line treatment for both low ness of hd-sequential chemotherapy programs. and high grade poor prognosis non-Hodgkin’s lymphoma.5–12 The wide applicability of this procedure has been possible due to the advantages offered by peripheral blood progenitor cells Patients and methods (PBPC) in reducing hematological toxicity.13–16 Patients Correspondence: C Tarella, Cattedra di Ematologia, Via Genova 3, 10126 Torino, Italy; Fax: 0039–011–696.3737 A retrospective analysis on overall tolerability and cardiac tox- 2Present address: Unita` Trapianto, Ist Sc. S. Raffaele, Milano, Italy icity of the combination of hd-MITO + L-PAM was carried out Received 8 June 2000; accepted 13 October 2000 by collecting data from 113 lymphoma patients treated at the Reversible cardiotoxicity following HDS and autograft with high-dose mitoxantrone C Tarella et al 257 University Division of Hematology of Turin, Italy between ing prior to the hd-phase with four APO + two DHAP 1991 and 1998. All patients were part of study protocols (dexametasone/hd-Ara-C/cisplatin) courses. In the subsequent based on the use of the original or modified high-dose sequen- hd-phase, the CY/VP16 sequence was inverted, in order to tial (HDS) chemotherapy regimens. They received hd-MITO/L- schedule PBPC harvest at the end of the hd-scheme. In PAM followed by PBPC autograft as the conclusive phase of addition, a chemotherapy-free interval of 30 days was the program. The protocols, including the final PBPC auto- included prior to hd-CY in order to allow adequate marrow graft, were approved by the local Ethical Committee and all repopulation and optimal progenitor cell mobilization.31 In patients gave written informed consent to both chemotherapy the chemotherapy-free interval, a total of three hd-dexame- program and autograft. All enrolled patients had a biopsy- thasone courses (dexamethasone at 40 mg/day for 4 consecu- proven diagnosis of lymphoma. They received the HDS pro- tive days) were administered every 10 days. G-CSF (Filgrastim) gram either at disease onset, if they presented with advanced- was given at 5 µg/kg/ day following CY, VP16, Ara-C and stage and poor prognostic features, or at disease relapse. Eligi- autograft, until myelopoietic recovery or completion of har- bility criteria included normal heart, renal and liver functions vesting procedures. The HDS chemotherapy schedules, ie as well as negative tests for HIV, HBsAg and HCV. All patients original HDS, i-HDS and C-HDS, are detailed in Figure 1. All underwent routine staging procedure before starting the patients presenting with bulky disease received additional chemotherapy program; their main clinical features are shown radiotherapy (RT) to bulky sites 1 to 2 months after autograft. in Table 1. Twenty-six patients received the HDS program as salvage after disease recurrence. Their previous treatments consisted of MACOP-B (four patients), CHOP (seven patients), MINE (one HDS treatment schedules patient), chlorambucil (two patients) and ABVD or MAMA hybrid schemes (12 patients). Only six patients had also All patients received either the original (64 patients) HDS received involved field radiotherapy. chemotherapy regimen or one of the two ‘second-generation’ schedules, named i-HDS and C-HDS.9,10,15 The original HDS regimen included the sequential administration of: (1) hd-CY Collection and evaluation of hemopoietic progenitors given at 7 g/m2 i.v., with PBPC harvest at hemopoietic recov- ery; (2) methotrexate (8 g/m2) plus vincristine (2 mg i.v.) PBPC were mobilized and collected following hd-CY or, in a approximately at day 16; (3) hd-etoposide (VP16) at 2 g/m2, few patients, following hd-Ara-C or hd-VP16. A BM harvest approximately at day 23; (4) myeloablative treatment with PBPC autograft approximately between days 48 and 52. In 21 high-risk patients, hd-Ara-C replaced hd-methotrexate (C- HDS). To minimize hematological toxicity, a small amount of PBPC (1–2 × 106 CD34+ cells/kg) were re-infused following hd-Ara-C. In addition, a debulkying phase including three APO courses (A = doxorubicin 75 mg/m2;O= Vincristine 1.2 mg/m2, both drugs given at 15–21 day intervals; P = prednisone at 50 mg/m2/day for 15–21 days), was also added.