Trial Information

A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)

PRIMARY OBJECTIVES:

I. To compare - in a randomized fashion - the day 100 treatment related mortality (TRM)
incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine
phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to
hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia
(JMML), in order to determine the preferred regimen for future trials.

II. To compare - in a randomized fashion - the 18-month event-free survival (EFS) following
two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for
children with JMML, in order to determine the preferred regimen for future trials.

SECONDARY OBJECTIVES:

I. To determine the 18-month relapse incidence (RI) following two different myeloablative
conditioning regimens busulfan-fludarabine phosphate(BU-FLU vs. BU-CY-MEL) prior to HCT for
children with JMML.

II. To determine the graft failure rates following two different myeloablative conditioning
regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

TERTIARY OBJECTIVES:

I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the
two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL).

II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host
disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs.
BU-CY-MEL) in children with JMML.

III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future
patients.

IV. To determine the feasibility of assessing post-transplant disease burden by donor
chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear
and sorted cell subsets.

V. To validate gene expression and methylation classifiers predictive of relapse in patients
with JMML.

VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML
who are treated on this transplant protocol.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) once daily (QD), twice
daily (BID), or four times a day (QID) over 2-3 hours on days -8 to -5, cyclophosphamide IV
QD over 60 minutes on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.

TRANSPLANT: Patients undergo allogeneic HCT on day 0.

Patients receive tacrolimus IV then orally (PO) on days -1 to 98 (related donor) or 180
(unrelated donor) and mycophenolate mofetil IV over 2 hours TID then PO on days 1-30
(related donor) or 45 (unrelated donor).

ARM II:

CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV
over 1 hour on days -5 to -2.

TRANSPLANT: Patients undergo allogeneic HCT as in arm I.

Patients receive tacrolimus IV then PO on days -1 to 98 (related donor) or 180 (unrelated
donor) and mycophenolate mofetil IV over 2 hours TID then PO on days 1-30 (related donor) or
45 (unrelated donor).

After completion of study treatment, patients are followed up for 5 years.