Combination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplant in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia

• Response rate (CR or PR) [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  The response rates in the up-front window with respect to whether or not patients had vas activating mutations will also be estimated by proportions.
  
  
• Duration of response [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  Will be estimated by Kaplan-Meier method.
  
  
• Progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Will be estimated by Kaplan-Meier method.
  
  
• Evaluation of prognostic importance of genetic marker [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  Logrank test and Cox proportional hazards model will be applied.
  
  
• Grade 3 or greater toxicities assessed using CTC version 2.0 [ Time Frame: Up to 6 years ] [ Designated as safety issue: Yes ]
  

• Survival of patients receiving the window vs. not [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  
• Response status on end of course reports (pre vs.post) [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  Signed-rank comparison of components of therapy will be done.
  
  

PRIMARY OBJECTIVES:

I. Determine the response rate of children with newly diagnosed juvenile myelomonocytic leukemia treated with R115777, isotretinoin, cytarabine, and fludarabine followed by allogeneic bone marrow or umbilical cord blood transplantation.

II. Determine the safety and toxicity of this regimen in these patients. III. Determine the tolerability of this regimen in these patients. IV. Determine the rate of 2-year event-free survival of patients treated with this regimen.

V. Determine whether prognostic subsets of these patients can be identified based on expression of clinical, genetic (NFI, monosomy 7, RAS gene), or hematopoietic characteristics.

OUTLINE: This is a multicenter study.

Patients may choose to receive upfront window induction therapy with oral R115777 twice daily on days 1-21. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients with progressive disease or stable disease with unacceptable hematopoietic recovery after 1 course proceed to induction chemotherapy. (R11577 portion of the study closed to accrual as of 08/2005)

All patients receive induction chemotherapy comprising oral isotretinoin once daily beginning on day 1 and fludarabine IV over 30 minutes and cytarabine IV over 4 hours on days 1-5. Treatment with fludarabine and cytarabine repeats every 28 days for 2 courses. Treatment with isotretinoin continues until allogeneic bone marrow or umbilical cord blood transplantation. Patients with progressive disease after 1 course proceed to transplantation.

After completion of isotretinoin, patients receive a preparative regimen comprising total body irradiation twice daily on days -7 to -4, cyclophosphamide IV over 2 hours on days -3 and -2, and anti-thymocyte globulin IV over 4-6 hours every 12 hours on days -3 to -1. Patients undergo allogeneic bone marrow or umbilical cord blood transplantation on day 0. Patients receive oral isotretinoin daily beginning on approximately day 60 and continuing for 1 year.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A maximum of 100 patients (18-46 receiving R115777 with induction chemotherapy [R11577 portion of the study closed to accrual as of 08/2005] and 27-54 receiving induction chemotherapy only) will be accrued for this study within 3.2 years.