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Conventional conditioning regimen with intravenous (i.v.) Busulphan (Busilvex), 12.8 mg/kg followed by Cyclophosphamide, 120 mg/kg iv.

Reduced toxicity conditioning regimen with intravenous (i.v.)Busulphan (Busilvex), 12.8 mg/kg plus Fludarabine, 4 x 40 mg/m².

I.V. Bu (Busilvex), 12.8 mg/kg:

Day -9: 0.8 mg/kg/dose x 4 doses Day -8: 0.8 mg/kg/dose x 4 doses Day -7: 0.8 mg/kg/dose x 4 doses Day -6: 0.8 mg/kg/dose x 4 doses Day -5: Rest

Followed by:

Cyclophosphamide, 120 mg/kg iv:

Day -4: 60 mg/kg Day -3: 60 mg/kg

Busulphan plus Cyclophosphamide

I.V. Bu (Busilvex), 12.8 mg/kg:

Day -6: 0.8 mg/kg/dose x 4 doses Day -5: 0.8 mg/kg/dose x 4 doses Day -4: 0.8 mg/kg/dose x 4 doses Day -3: 0.8 mg/kg/dose x 4 doses plus:

Fludarabine, 4 x 40 mg/m² iv:

Day -6: 40 mg/m² Day -5: 40 mg/m² Day -4: 40 mg/m² Day -3: 40 mg/m²

Busulphan plus Fludarabine

Alessandro AR Rambaldi, Professor

The purpose of this prospective phase III, open-label, randomized multicenter study is to evaluate whether Acute Myeloid Leukemia (AML) elderly patients in Complete Remission (CR) undergoing allogeneic hematopoietic stem cell transplantation after a reduce toxicity conditioning regimen (I.V. BuFlu) as compared to the conventional I.V.

BuCy2 program will experience:

1. A lower transplant-related mortality (TRM) at 1 year after Hematopoietic Stem Cells Transplant (HSCT)
2. A similar anti-leukemic activity and a similar or better safety profile, in terms of:

   * Early and/or late graft rejection
   * Hematopoietic and immunologic recovery
   * Chimerism
   * Toxicity and incidence of Veno-occlusive Disease (VOD)
   * Acute (aGvHD) and chronic graft-versus-host disease (cGvHD)
   * Cumulative incidence of TRM at +100 days and 2 years after transplant
   * Cumulative incidence of relapse by 1 and 2 years after transplant
   * Event-free (EFS) and overall survival (OS) by 1 and 2 years after transplant

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 Chronic Myeloid Leukemia (CML) patients in which the BU-CY regimen was associated with survival and relapse probabilities that compare favourably with the CY-Total Body Irradiation (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.

Busulfan (BU) Plus Fludarabine Vs Intravenous BU Plus Cyclophosphamide as Conditioning Regimens Prior Allogeneic Hematopoetic Stem Cells Transplant (HSCT) in AML

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.

The primary endpoint is to determine the cumulative incidence of transplant related mortality (TRM) defined as non-relapse mortality. Assessment will be performed at 1 year after transplantation.

TRM will be defined as any death by causes other than relapse and/or progressive disease. Deaths after persistent post-transplant relapse will be categorized as due to the disease irrespective of the proximate cause.

Assessment in the two arms of the safety and efficacy profile defined as: early and/or late graft rejection, hematopoietic recovery, chimerism, toxicity and incidence of VOD, incidence and severity of acute (aGvHD) and chronic graft-versus-host disease (cGvHD), cumulative incidence of TRM, relapse, event-free (EFS) and overall survival (OS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Busulfan (BU) Plus Fludarabine Vs Intravenous BU Plus Cyclophosphamide as Conditioning Regimens Prior Allogeneic Hematopoetic Stem Cells Transplant (HSCT) in AML	NCT01191957	Acute Myeloid L...	Busulphan plus ... Busulphan plus ...	40 Years - 65 Years	Gruppo Italiano Trapianto di Midollo Osseo
Busulfan (BU) Plus Fludarabine Vs Intravenous BU Plus Cyclophosphamide as Conditioning Regimens Prior Allogeneic Hematopoetic Stem Cells Transplant (HSCT) in AML	NCT01191957	Acute Myeloid L...	Busulphan plus ... Busulphan plus ...	40 Years - 65 Years	Gruppo Italiano Trapianto di Midollo Osseo

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