Pediatr Blood Cancer 2012;59:828–833 Results of AIEOP LNH-97 Protocol for the Treatment of Anaplastic Large Cell Lymphoma of Childhood Marta Pillon, MD, 1 Fabiana Gregucci, MD, 1 Alessandra Lombardi, MD, 2 Nicola Santoro, MD, 3 Matilde Piglione, MD, 4 Alessandra Sala, MD, 5 Emanuele S.G. D’Amore, MD, 6 Raffaela De Santis, MD, 7 Fiorina Casale, MD, 8 Marco Zecca, MD, 9 Lara Mussolin, PhD, 1 Angelo Rosolen, MD 1 * On behalf of the NHL-Committee of the Italian Association of Pediatric Hematology and Oncology (AIEOP) INTRODUCTION Anaplastic large cell lymphoma (ALCL) represents approxi- mately 15% of all pediatric non-Hodgkin lymphomas (NHL) [1]. First described by Stein et al. [2], ALCL is characterized by proliferation of anaplastic cells of T or null phenotype with CD30 antigen expression. ALCL exhibits a broad morphological spectrum, including common, lymphohistiocytic, and small cell variants [3]. The t(2;5)(p23;q35) translocation, resulting in the fusion of the nucleophosmin gene (NPM) at 5q35 and the tyrosine kinase gene ALK at 2p23, is identified in more than 90% of pediatric ALCL [4]. Expression of the fusion transcript NPM- ALK can be detected by reverse transcriptase polymerase chain reaction (RT-PCR) and represents a tumor-specific marker that can be exploited to evaluate minimal disseminated disease (MDD) in the bone marrow (BM). MDD at diagnosis is frequently detected in pediatric ALCL and can identify patients at risk of relapse [5]. The most common clinical features of ALCL in the pediatric population include systemic symptoms, especially high fever, generalized lymph-adenopathy and involvement of extra- nodal sites such as skin, bone, soft tissue, lung, and liver [6–13]. The central nervous system (CNS) is rarely involved [14]. In the literature, few cases of primary CNS ALCL have been described, but in those cases the tumor-associated mortality seemed to be lower in patients with ALK-positive ALCL and young age [15]. The secondary spread of primary nodal or systemic ALCL to the CNS is a rare event [7–12,16–18]. Optimal treatment for ALCL is not yet ultimately defined. Most European pediatric oncology groups have used short-pulse chemotherapy regimens, including high-dose methotrexate (MTX), cyclophosphamide, vincristine, doxorubicin, and cortico- steroids with a total duration of 4–6 months [7–9,16–18]. In the early nineties, like in North America, our group treated patients with ALCL with prolonged, repeated-pulse chemotherapy, based on a modified LSA-L2 protocol [10–12]. The results of the randomized clinical trial ALCL99 showed that a NHL-B-like therapy, based on six cycles of chemotherapy for 5 days each with MTX 3 g/m 2 in 4-hour infusion, showed the same efficacy when MTX was given at 1 g/m 2 in 24-hour infusion [19]. This study also showed that intrathecal prophylaxis is not necessary to prevent disease recurrence to the CNS. Adding vinblastine to the same therapy backbone significantly delayed the occurrence of relapse but did not reduce the risk of failure [20]. The event-free survival (EFS) rate ranges from 60% to 75% for most of the studies and recurrence is observed in up to 35% of patients [7–12,16–19]. Patients who suffer a relapse can be successfully treated with second line therapy, ranging from weekly vinblastine Background. Anaplastic large cell lymphoma (ALCL) represents approximately 15% of all pediatric non-Hodgkin lymphomas (NHL). It has distinct clinical features, including frequent involve- ment of extranodal sites and rare localization to the central nervous system (CNS). Despite varying treatment approaches the outcome of patients with ALCL has not significantly improved during the last two decades. Procedure. From October 1997 to beginning of 2000, newly diagnosed ALCL patients were enrolled into AIEOP LNH-97 protocol for ALCL. Thereafter and until 2007, only CNS positive patients were included. AIEOP LNH-97 was based on the BFM-95 schema for ALCL and included six high-dose chemotherapy courses. CNS prophylaxis was obtained with one intrathecal injection of chemotherapy in each course, whereas treatment of CNS involvement included three intrathecal injections without irradiation. Results. Thirty-two patients were eligible for the study. Lymph-node disease was the most frequent localization (69% of the cases), followed by mediastinal (25%), CNS (22%), bone marrow (16%), and skin (13%) involvement. Probabilities of overall survival (OS) and of event-free survival (EFS) at 5 years for the whole population were 87% (SE 6%) and 68% (SE 8%), respectively. Conclusions. This study confirmed that short pulse chemotherapy is an efficacious treatment option for first line therapy of pediatric ALCL, and that dose intensity may have some relevance for out- come, but not in all of the patients. Refinement and optimization of therapy strategies for ALCL may originate from a combination of clinical and biological prospective studies, as those in the pipeline of current international collaboration. Pediatr Blood Cancer 2012; 59:828–833. ß 2012 Wiley Periodicals, Inc. Key words: ALCL; child; clinical trials; non-Hodgkin lymphoma; outcome Additional Supporting Information may be found in the online version of this article. 1 Pediatric Onco-Hematology Unit, University Hospital of Padova, Padova, Italy; 2 Division of Onco-Hematology Children’s Hospital Bambino Gesu `-IRCCS, Roma, Italy; 3 Pediatric Onco-Hematology Unit, University Hospital of Bari, Bari, Italy; 4 Division of Pediatric Onco-Hematology, Regina Margherita Children’s Hospital, Torino, Italy; 5 Department of Pediatrics, San Gerardo Hospital, University of Milano Bicocca, Monza, Italy; 6 Department of Pathology, San Bortolo Hospital, Vicenza, Italy; 7 Unit of Pediatrics, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; 8 Pediatric Oncology Service, Second University of Napoli, Napoli, Italy; 9 Pediatric Hematology and Oncology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Grant sponsor: Fondazione Citta ` della Speranza; Grant sponsor: AIL (Associazione Italiana contro le Leucemie). Conflict of interest: Nothing to declare. *Correspondence to: Angelo Rosolen, MD, Pediatric Onco-Hematol- ogy Unit, University Hospital of Padova, Via Giustiniani 3, 35128 Padova, Italy. E-mail: angelo.rosolen@unipd.it Received 27 October 2011; Accepted 9 February 2012 ß 2012 Wiley Periodicals, Inc. DOI 10.1002/pbc.24125 Published online 2 March 2012 in Wiley Online Library (wileyonlinelibrary.com).