title: A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee).
abstract: BACKGROUND
  Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine.
  
  
  METHODS
  A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2)/d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse.
  
  
  RESULTS
  Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2)), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2)), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2). There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation.
  
  
  CONCLUSIONS
  Clofarabine MTD was 32 mg/m(2)/d in this combination which appeared feasible and effective in this population.
authors.affiliation: Pediatric Hematology, CHRU Lille, Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nelken
authors.affiliation: Department of Genetics, Robert-Debré Hospital, Paris, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Cave
authors.affiliation: Pediatric Haematology and Oncology Unit, Hopital Trousseau, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.affiliation: Pediatric Hematology Department, Hopital de La Timone, Marseille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Galambrun
authors.affiliation: Department of Pediatric Onco-Hematology, CHU-Hopital Purpan, Toulouse, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Plat
authors.affiliation: Pediatric Hematology Oncology, CHU de Nancy, Vandoeuvre, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Hematology Department, CHU de Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Pediatric Oncology Unit, University Hospital, Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vérité
authors.affiliation: Pediatric Hematology, Hopital Robert Debre AP-HP, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Brethon
authors.affiliation: Department of Pediatric Hematology/Oncology, CHU-Hopital Sud, Rennes, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Gandemer
authors.affiliation: Institute of Pediatric Hematology and Oncology, University Hospital, Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Department of Pediatric Hematology, Robert Debré Hospital, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Pediatric Hematology Unit, CHU Jean Minjoz Hospital, Besançon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rohrlich
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D001215:Asparaginase / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003907:Dexamethasone / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008942:Mitoxantrone / Q000627:therapeutic use; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016879:Salvage Therapy / Q000379:methods; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D005047:Etoposide; D000077866:Clofarabine; D003907:Dexamethasone; D008942:Mitoxantrone; D001215:Asparaginase
keywords: acute lymphoblastic leukemia; child; clofarabine; phase I; resistant disease