title: Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study.
abstract: An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
authors.affiliation: Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris Registre des Histiocytoses Centre de Référence des Histiocytoses, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;
authors.forename: Jean
authors.identifier: http://orcid.org/0000-0002-4485-146X
authors.initials: J
authors.lastname: Donadieu
authors.affiliation: Hémato Oncologie Pédiatrique, Centre Hospitalier Universitaire (CHU) de Montpellier, Montpellier, France;
authors.forename: Frederic
authors.initials: F
authors.lastname: Bernard
authors.affiliation: Department of Pediatric Hematology Oncology, Erasmus MC-Sophia's Children's Hospital, Rotterdam, The Netherlands;
authors.forename: Max
authors.initials: M
authors.lastname: van Noesel
authors.affiliation: Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris Registre des Histiocytoses Centre de Référence des Histiocytoses, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;
authors.forename: Mohamed
authors.initials: M
authors.lastname: Barkaoui
authors.affiliation: Direction Recherche et Innovation, Centre Hospitalier Régional Universitaire (CHRU) Montpellier-Centre Administratif André Benech, Montpellier, France;
authors.forename: Odile
authors.initials: O
authors.lastname: Bardet
authors.affiliation: Pediatric Hematology Oncology, Ospedale microcetemico, Cagliari, Italy;
authors.forename: Rosella
authors.initials: R
authors.lastname: Mura
authors.affiliation: Pediatric Hematology Oncology, Azienda Sanitaria Provinciale, Ragusa, Italy;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Arico
authors.affiliation: Pediatric Hémato Oncology, CHU, Limoges, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Piguet
authors.affiliation: Pediatric Hémato Oncology, CHU, Rennes, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Gandemer
authors.affiliation: Pediatric Hémato Oncology, CHU, Grenoble, France;
authors.forename: Corinne
authors.initials: C
authors.lastname: Armari Alla
authors.affiliation: Pediatric Hematology Oncology, Universitets Hospital of Aarhus at Skejby, Aarhus, Denmark;
authors.forename: Niels
authors.initials: N
authors.lastname: Clausen
authors.affiliation: Hémato Oncologie Pédiatrique, Centre Hospitalier Universitaire (CHU) de Montpellier, Montpellier, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Jeziorski
authors.affiliation: Pediatric Hémato Oncology, Hopital Jean De Flandre, CHU, Lille, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Lambilliote
authors.affiliation: Pediatric Hematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada;
authors.forename: Sheila
authors.initials: S
authors.lastname: Weitzman
authors.affiliation: Department of Women's and Children's Health, Karolinska Institute, Karolinska Univeristy Hospital, Stockholm Sweden; and.
authors.forename: Jan Inge
authors.initials: JI
authors.lastname: Henter
authors.affiliation: Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Van Den Bos
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002675:Child, Preschool; D017338:Cladribine / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006646:Histiocytosis, Langerhans-Cell / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D007801:Langerhans Cells / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D012008:Recurrence; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D015996:Survival Rate; D014747:Vinblastine / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D003561:Cytarabine; D017338:Cladribine; D014747:Vinblastine