title: Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group.
abstract: BACKGROUND
  Juvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML.
  
  
  METHODS
  Eighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial.
  
  
  RESULTS
  Overall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib.
  
  
  CONCLUSIONS
  Administration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival.
authors.affiliation: Department of Pediatrics, Helen Diller Comprehensive Cancer Center, University of California San Francisco School of Medicine and Benioff Children's Hospital, San Francisco, California.
authors.forename: Elliot
authors.initials: E
authors.lastname: Stieglitz
authors.forename: Ashley F
authors.initials: AF
authors.lastname: Ward
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Y Lucy
authors.initials: YL
authors.lastname: Liu
authors.forename: Peter D
authors.initials: PD
authors.lastname: Emanuel
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Cheng
authors.forename: Nalini
authors.initials: N
authors.lastname: Jayaprakash
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Castleberry
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Bunin
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Todd M
authors.initials: TM
authors.lastname: Cooper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D015474:Isotretinoin / Q000008:administration & dosage; D054429:Leukemia, Myelomonocytic, Juvenile / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage*; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D004791:Enzyme Inhibitors; D015363:Quinolones; D003561:Cytarabine; D013186:Farnesyl-Diphosphate Farnesyltransferase; D015474:Isotretinoin; D014740:Vidarabine; C402769:tipifarnib; C024352:fludarabine
keywords: 13-cis retinoic acid; farnesyl transferase inhibitor; hematopoietic stem cell transplant; juvenile myelomonocytic leukemia; tipifarnib