Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group

Pediatr Blood Cancer. 2015 Apr;62(4):629-36. doi: 10.1002/pbc.25342. Epub 2014 Dec 8.


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.

Procedure: 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.

Keywords: 13-cis retinoic acid; farnesyl transferase inhibitor; hematopoietic stem cell transplant; juvenile myelomonocytic leukemia; tipifarnib.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Child
  • Child, Preschool
  • Cytarabine / administration & dosage
  • Disease-Free Survival
  • Enzyme Inhibitors / administration & dosage
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
  • Female
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Infant
  • Isotretinoin / administration & dosage
  • Leukemia, Myelomonocytic, Juvenile / drug therapy*
  • Leukemia, Myelomonocytic, Juvenile / enzymology
  • Leukemia, Myelomonocytic, Juvenile / mortality
  • Leukemia, Myelomonocytic, Juvenile / pathology
  • Male
  • Middle Aged
  • Quinolones / administration & dosage*
  • Survival Rate
  • Vidarabine / administration & dosage
  • Vidarabine / analogs & derivatives


  • Enzyme Inhibitors
  • Quinolones
  • Cytarabine
  • Farnesyl-Diphosphate Farnesyltransferase
  • Isotretinoin
  • Vidarabine
  • tipifarnib
  • fludarabine