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.

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

Fig 1

(A) Transplant-related mortality in patients who completed HSCT on-study and received (FTI) or did not receive (no FTI) tipifarnib. Three patients died from transplant-related causes: one patient who received 200 mg/m²/dose of tipifarnib and a matched unrelated stem cell source died at 13 days post-transplant due to sinusoidal obstructive syndrome, one who received 300 mg/m²/dose of tipifarnib and a matched unrelated stem cell source died at 35 days post-transplant due to infection, and one who did not receive tipifarnib and was transplanted using mismatched unrelated cord blood died at 158 days post-transplant due to infection. (B) Relapse risk after transplant in patients who completed HSCT on-study and received (FTI) or did not receive (no FTI) tipifarnib.

Fig 2

(A) Five-year overall survival of all eligible patients who received (FTI) or did not receive (no FTI) tipifarnib. (B) Five-year event-free survival of all eligible patients who received (FTI) or did not receive (no FTI) tipifarnib.