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.

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.

• Authors: Elliot Stieglitz, Ashley F Ward, Robert B Gerbing, Todd A Alonzo, Robert J Arceci, Y Lucy Liu, Peter D Emanuel, Brigitte C Widemann, Jennifer W Cheng, Nalini Jayaprakash, Frank M Balis, Robert P Castleberry, Nancy J Bunin, Mignon L Loh, Todd M Cooper
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 62 Issue 4 Pg. 629-36 (Apr 2015) ISSN: 1545-5017 [Electronic] United States
• PMID: 25704135 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

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

Topics

• 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, enzymology, mortality, pathology)
• Male
• Middle Aged
• Quinolones (administration & dosage)
• Survival Rate
• Vidarabine (administration & dosage, analogs & derivatives)