title: Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.
abstract: The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.
authors.affiliation: Department of Pediatric Hematology-Oncology, Children's Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL 60614-3394, USA. nhijiya@childrensmemorial.org
authors.forename: Nobuko
authors.initials: N
authors.lastname: Hijiya
authors.forename: Blythe
authors.initials: B
authors.lastname: Thomson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Isakoff
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Peter G
authors.initials: PG
authors.lastname: Steinherz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: Richard
authors.initials: R
authors.lastname: Kadota
authors.forename: Todd
authors.initials: T
authors.lastname: Cooper
authors.forename: Violet
authors.initials: V
authors.lastname: Shen
authors.forename: Gary
authors.initials: G
authors.lastname: Dahl
authors.forename: Jaideep V
authors.initials: JV
authors.lastname: Thottassery
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Kelly
authors.initials: K
authors.lastname: Maloney
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Paul
authors.forename: Elly
authors.initials: E
authors.lastname: Barry
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Paul S
authors.initials: PS
authors.lastname: Gaynon
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D033703:Nucleoside Transport Proteins / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D012333:RNA, Messenger / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D001087:Arabinonucleosides; D033703:Nucleoside Transport Proteins; D012333:RNA, Messenger; D005047:Etoposide; D000077866:Clofarabine; D003520:Cyclophosphamide