Trial Information

Randomized Study Comparing i.v. Busulfan ( Busilvex®) Plus Fludarabine (BuFlu) Versus Busilvex®Plus Cyclophosphamide (BuCy2) as Conditioning Regimens Prior AlloHSCT in Patients (Age >= 40 and =<65 Years) With AML in Complete Remission.

Hematopoietic stem-cell transplantation (HSCT) is a potentially curative treatment modality
for patients with Acute Myelogenous Leukemia (AML).

An effective conditioning regimen is based on the association of oral Busulfan 4 mg/kg daily
in 4 doses, each of 1 mg/kg, on each of 4 successive days (total dose, 16 mgkg), followed by
CY 60 mg/kg intravenously on each of 2 successive days (BuCy2). The antileukemic activity of
this latter program was tested and confirmed in most large randomized clinical trials
conducted in AML and CML patients in which the BU-CY regimen was associated with survival
and relapse probabilities that compare favourably with the CY-TBI regimen. The BuCy2 program
is considered a golden standard preparative regimen for allogeneic transplantation in AML
patients.

Nonetheless, for many years the treatment related toxicities of all these full myeloablative
conditioning regimens has substantially limited the overall applicability of the transplant
procedure to young patients with a good performance status (PS). The observation that
allogeneic stem cell transplants have a potentially curative graft-versus-leukemia (GVL)
effect in addition to the antileukemic action of myeloablative conditioning regimens was a
major stimulus for the development of reduced-intensity conditioning (RIC) regimens, aimed
primarily at securing engraftment to provide the GVL effect, while minimizing
regimen-related toxicity.

The observation that allogeneic stem cell transplants have a potentially curative
graft-versus-leukemia (GVL) effect in addition to the antileukemic action of myeloablative
conditioning regimens was a major stimulus for the development of reduced-intensity
conditioning (RIC) regimens, aimed primarily at securing engraftment to provide the GVL
effect, while minimizing regimen-related toxicity. As a consequence reduced-intensity
conditioning (RIC) regimens might give possibility to extend access to allogeneic
transplantation to patients who would not have previously been considered reasonable
candidates because of their age and for the presence of comorbidities. However, after a lot
of initial enthusiasm, it has become clear that a more intensive conditioning is associated
with a reduced risk for relapse after HSCT. Therefore, while it is clear that RIC
transplants have opened the way to using allogeneic SCT in patients several years older than
the upper age limit of 60, the superiority of the RIC approach cannot be assumed even in
this subgroup of patients. This is why, more recently, investigators are looking for
conditioning programs that while better tolerated still might retain a strong ability of
inducing a direct ablation of the leukemic hematopoiesis. This has led to the new concept of
reduced toxicity rather than reduced intensity conditioning programs. One of such a program
is based on the association of a myeloablative dose of intravenous Busulfan (0.8 mg/kg/d for
4 days), with Fludarabine (30 mg/m2/d for 4 days) which has been reported as highly
effective in patients with AML. In elderly patients with this disease, this program might
lead to an overall outcome at least as good as that following conventional myeloablative
programs such as those based on Cyclophosphamide combined to the same dose of IV Busulfan or
the TBI. In fact, when compared to these latter programs, the Busulfan Fludarabine regimen
was found associated with lower non relapse mortality although a higher relapse rate was
still documented, but not in all published experiences. In all, outcomes for standard
transplant regimens have generally improved and these newer myeloablative regimens of
Fludarabine with full-dose intravenous Busulfan achieve 1 year TRM below 10%. So, based on
these considerations, protocol GITMO-AML.R2 has been designed to compare intravenous
Busulfan plus Fludarabine (BuFlu) versus Busulfan (I.V. Bu; Busilvex®) plus Cyclophosphamide
(BuCy2) as conditioning regimens prior to allogeneic Hematopoietic Stem Cell Transplantation
(alloHSCT) in patients (aged between 40 and 65 years) with Acute Myeloid Leukemia (AML) in
Complete Remission (CR).

So, based on these considerations, protocol GITMO-AML.R2 has been designed to compare
intravenous Busulfan plus Fludarabine (BuFlu) versus Busulfan (I.V. Bu; Busilvex®) plus
Cyclophosphamide (BuCy2) as conditioning regimens prior to allogeneic Hematopoietic Stem
Cell Transplantation (alloHSCT) in patients (aged between 40 and 65 years) with Acute
Myeloid Leukemia (AML) in Complete Remission (CR).

The principal objective of this trial is the evaluation of one year transplant-related
mortality (TRM) of AML patients undergoing allogeneic hematopoietic stem cell
transplantation after a reduced toxicity conditioning regimen (I.V.BuFlu) as compared to the
conventional I.V. BuCy2 program.

To this purpose, in the IV BuCy2 arm, reference TRM was assumed to be 25% (range 16-50%)
while in the IV BuFlu arm and an estimated 12.5% TRM is assumed (range 0-30%). The study is
designed to demonstrate a relative risk reduction of 50%. For the event-driven two-sided
test, an alpha-level probability of 0.05 (type I error) and a power of 80% (type II
error=0.2) has been considered. The ratio between the numbers of patients included in each
arm is set equal to 1:1. The resulting required sample size is 240 (120 patients in each
arm). Sample size estimation is based on the intention-to-treat principle.

The accrual time is 2.5 years, and an additional follow-up of 2 years is planned after the
last patient entry in the study and before the final analysis.