Introduction
Standard treatment for children, adolescents, and young adult patients
(CAYA) patients with acute myeloid leukemia (AML) includes up to five
cycles of chemotherapy containing cytarabine and anthracyclines.
Improvements in supportive care, including oral and skin care regimens,
empiric broad spectrum antibiotics and prophylactic antifungals have had
a meaningful impact on the treatment related toxicity associated with
AML therapy1, 2. Despite this, more than 40% of
patients ultimately die of refractory or relapsed disease or treatment
related toxicity3. Patients with high-risk AML are
candidates for allogeneic hematopoietic cell transplantation (allo-HCT)
which similarly carries regimen related toxicities in addition to risk
for graft-versus-host disease (GvHD). Advancements in supportive care
have also led to improvement in survival for patients with myeloid
malignancies undergoing allo-HCT4.
The choice of conditioning regimen plays a major role in a patient’s
likelihood of achieving a graft-versus-host-free-relapse-free survival
(GRFS), however there is no consensus on the optimal conditioning
regimen. Historically, the most common preparative regimen used for
patients with AML was total body irradiation (TBI) with cyclophosphamide
(CY) which was later largely replaced by busulfan (BU) and
CY5. BU-CY was associated with comparable disease
control without the long-term secondary effects of
irradiation6. BU-fludarabine (FLU) gained significant
traction to reduce the toxicity of high dose CY, however it led to
inferior progression-free-survival (PFS), when compared to BU-CY in
adults7. To improve the efficacy of pre-transplant
conditioning while keeping non-relapse mortality (NRM) low, three drug
regimens were introduced with an additional alkylator. These included
thiotepa (TT)-BU-FLU, BU-CY-melphalan (MEL) or BU-FLU-MEL. In an adult
study, TT-BU-FLU demonstrated superior survival as compared to BU-FLU
due to a reduced risk of relapse, with comparable
NRM8. BU-FLU-Mel was also associated with better
overall (OS) in adult patients without increase in non- NRM compared to
FLU-BU due to decreased relapse9. There is limited
pediatric data on the comparison of three drug regimens to the more
conventional BU-CY or TBI-CY. A multi-center study by the European Group
for Blood and Marrow Transplantation (EBMT) reported on AML patients
between ages 2-18 years. Patients receiving BU-CY-MEL showed a lower
incidence of relapse, higher OS and PFS with a comparable NRM when
compared to those conditioned with BU-CY or TBI-CY10.
We previously demonstrated that BU-FLU-MEL conditioning was safe and
effective in a limited series of six pediatric patients with high-risk
myeloid malignancies11. Herein, we expand our
experience utilizing this regimen effectively in CAYA with myeloid
malignancies undergoing matched or alternative donor allo-HCT.