In 1983, Santos et al. reported on the use of busulfan (Bu) in combination with cyclophosphamide (Cy) at 200 mg/kg (BuCy4) as an alternative to total body irradiation (TBI) based myeloablative conditioning (MAC).r A number of prospective and retrospective trials have since compared Bu and TBI based regimens for acute and chronic myeloid leukaemia (AML, CML). Marked inter-individual variation in the pharmacokinetics of oral Bu has been well documented, and it has been demonstrated that high Bu levels are associated with increased risk of toxicity, and lower levels have been associated with increased risk of graft rejection and relapse, leading to the development of targeted Bu dosing based on levels. rr Subsequently, intravenous Bu has become available and demonstrates less individual variation and is also less hepatotoxic.rr
An alternative MAC regimen with fludarabine (Flu) substituted for Cy in combination with intravenous Bu has been developed in an attempt to reduce toxicity. There have been a number of randomised trials comparing IV BuFlu with BuCy with variable results.rrr Two meta-analyses - the meta-analysis by Ben-Barouch et al. reported a lower risk of non-relapse mortality (NRM) at 100 days as well as lower rate of infection with IV BuFlu compared to BuCy and the meta-analysis by Lei et al. reported increased risk of liver toxicity in BuCy arm.rr There was no difference in overall survival (OS), event-free survival (EFS), relapse or graft versus host disease (GVHD).
Few studies have evaluated the optimal MAC regimen for acute lymphoblastic leukaemia (ALL), however, most studies would suggest TBI-containing regimens offer better disease control than those incorporating Bu. Regarding TBI-mediated antileukaemic effect, a retrospective study by Nagler et al. showed that disease-free survival (DFS) in patients with acute myeloid leukaemia who received Bu/Cy was not statistically different from those who received Cy/TBI.r
Evidence Level (NHMRC) |
Study |
Study Design |
Disease |
Is the conditioning regimen* consistent with the protocol?
|
Comments |
I |
Socie et al.r |
Systemic review of 4 randomised trials |
CML, AML |
Similar, all received Cy 60 mg/kg
Bu/Cy: 16 mg/kg po
TBI (variable dependent on site)
|
Update of 4 randomised trials comparing Bu/Cy with Cy/TBI in patients with myeloid malignancy with mean follow up of 7 years.
Also assessed quality of life.
|
II |
Rambaldi et al.r |
Randomised phase III trial |
AML |
Yes. IV busulfan 0.8 mg/kg QID and cyclophosphamide 60 mg/kg (similar to current regimen) |
Randomised trial of IV Bu/Cy vs IV Bu/Flu |
III-2 |
Tutschka et al.r |
Prospective cohort study |
ALL, AML, CLL |
No. Busulfan po at 1 mg/kg (total 16 mg/kg) QID with cyclophosphamide 60 mg/kg IV |
This is the first report using busulfan in conjunction with the current dose of cyclophosphamide |
III-2 |
Andersson et al.r |
Cohort study |
CML |
Yes |
Regimen was modified from Tutschka et al. using busulfan IV
Measurement of Bu AUC and dose adjusted as required.
|
III-3 |
Copelan et al.r |
Retrospective study |
AML |
Cy/TBI vs po Bu/Cy (>9 mg/kg) vs IV Bu/Cy |
Comparison of po Bu/Cy versus IV Bu/Cy and Cy/TBI from CIBMTR |
*Chemotherapy ONLY; CLL = chronic lymphocytic leukaemia; AUC = area under the curve
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
Study |
Nos. of Patients |
Donor/Stem cell source |
NRM/TRM |
Relapse Rate |
OS (1 yr/2 yr) |
DFS |
Comments |
Socie et al.r |
484 |
Not reported |
No data provided on mortality specifically up to 2 yrs
3 secondary solid malignancies reported; 2 in Bu/Cy and 1 in Cy/TBI but no reported mortality
|
Not reported |
CML projected 10 yr survival: 65% Bu/Cy, 63% Cy/TBI (N.S)
AML projected 10 yr survival: 51% Bu/Cy, 63% Cy/TBI (N.S)
|
CML: 52% Bu/Cy and 46% Cy/TBI in 10 yrs (N.S)
AML: 47% Bu/Cy and 57% Cy/TBI (N.S)
|
No statistical significance of DFS between Bu/Cy and Cy/TBI
Data was demonstrated in Kaplan-Meier curve which showed no difference of survival
|
Rambaldi et al.r |
Total: 252 (lost 7 subjects post randomisation)
Bu/Cy: 121 subjects
Bu/Flu: 124 subjects
|
Related donors:
Bu/Cy 45%
Bu/Flu 46%
Unrelated donors:
Bu/Cy 55%
Bu/Flu 54%
Bone marrow:
Bu/Cy 33%
Bu/Flu 28%
PBSC:
Bu/Cy 64%
Bu/Flu 69%
|
1 yr NRM:
17% BuCy vs 8% Bu/Flu (P=0.026)
2 yr NRM:
18% Bu/Cy vs 9.5% Bu/Flu (P=0.047)
5 yr NRM:
19% Bu/Cy vs 11% Bu/Flu (P=0.05)
|
1 yr relapse:
22% Bu/Cy vs 24% Bu/Flu
2 yr relapse:
30% Bu/Cy vs 32% Bu/Flu
5 yr relapse:
38% Bu/Cy vs 38% Bu/Flu
|
1 yr OS:
72% Bu/Cy vs 77% Bu/Flu
2 yr OS:
64% Bu/Cy vs 62% Bu/Flu
5 yr OS:
54.8% Bu/Cy vs 55.2% Bu/Flu
|
1 yr DFS:
61% Bu/Cy vs 67% Bu/Flu
2 yr DFS:
52% Bu/Cy vs 59% Bu/Flu
5 yr DFS:
43% Bu/Cy vs 52% Bu/Flu
|
Although NRM was lower in Bu/Flu group at 1 and 2 yrs post transplant, there is no significant difference in DFS and OS is similar in both groups at 1, 2 and 5 yrs post transplant. |
Tutschka et al.r |
Total: 50
Group 1: 20 standard risk in 1st/2nd remission or CML in chronic phase
Group 2: 30 high risk acute leukaemia, relapsed leukaemia, CML in accelerate/blastic phase
|
HLA-identical sibling donor
Bone marrow all patients
|
10% at day 100 |
0 relapse in standard risk
20% clinical relapse in high risk group
|
65% 3 year survival |
100% standard risk, 65.5% high risk |
Reported all evaluable patients achieved complete remission |
Andersson et al.r |
36 |
HLA matched family donors
Bone marrow: 26
Peripheral blood stem cell: 10
|
0 at day 100
8 deaths from cGVHD
|
3 deaths from relapse |
Only reported as log hazard ratio vs AUC, no subject data available |
Not reported |
Study main discussion is related to toxicity |
Copelan et al.r |
1230 |
HLA matched sibling donors 53%
Matched URD 36%
Mismatched URD 11%
|
1 yr NRM: 21% TBI vs 14% po Bu vs 12% IV Bu
5 yr NRM: 31% TBI vs 18% po Bu vs 18% IV Bu
|
1 yr: 20% TBI vs 16% po Bu vs 23% IV Bu
5 yrs: 28% TBI vs 27% po Bu vs 25% IV Bu
|
1 yr: 65% TBI vs 76% po Bu vs 72% IV Bu (P<0.001)
5 yrs: 43% TBI vs 61% po Bu vs 58% IV Bu
|
DFS 5 yrs: 41% TBI vs 54% po Bu vs 57% IV Bu (P<0.001) |
Better DFS and OS and lower relapse after 1 yr in IV Bu arm compared to TBI |
TRM = treatment-related mortality; N.S = not significant; PBSC = peripheral blood stem cell; HLA = human leukocyte antigen; URD = unrelated donor; cGVHD = chronic graft versus host disease
Toxicity
A summary of the toxicities associated with this protocol are included in the table below:
Study |
Mucositis |
aGVHD
|
cGVHD
- total
- extensive
- limited
|
Rejection |
VOD/SOS |
Lung/IPS |
Infection |
Comment |
Socie et al.r |
N.S |
N.S |
AML: extensive cGVHD 20% Bu/Cy and 19% in Cy/TBI
CML: extensive cGVHD 37% Bu/Cy and 39% in Cy/TBI
|
N.S |
N.S |
Pulmonary disease: 6% AML
15% CML
|
N.S |
|
Rambaldi et al.r |
19% grade II mucositis in Bu/Cy and Bu/Flu group |
28.1% aGVHD in Bu/Cy
19.4% aGVHD in Bu/Flu
|
27.5% cGVHD in Bu/Cy
25.8% cGVHD in Bu/Flu
|
Bu/Cy: 2 patients
Bu/Flu: 1 patient
|
Bu/Cy: 2 patients
Bu/Flu: 2 patients
|
<1% overall reported lung toxicity in both arms |
Bu/Cy: 17%
Bu/Flu: 10%
|
Overall toxicity was similar in both Bu/Cy and Bu/Flu group
|
Tutschka et al.r |
No reported severe mucositis |
15 had aGVHD
grade 1: 11
grade 2: 1
grade 3: 2
grade 4: 1
3 deaths due to grade 3-4 aGVHD
|
25 had cGVHD; 5 limited, 19 (42%) extensive |
|
1 patient resolved |
6 developed IPS with 4 deaths |
62% had early infections (<Day+30)
13 with late infections (>Day+50)
|
|
Andersson et al.r |
17 (47%): 10 had grade 2 while 7 had grade 3 |
12 (33.3%) with aGVHD grade 2-3 |
8 deaths due to cGVHD |
Nil |
3 had grade 2 and 7 had grade 3 liver toxicity (no clinical VOD) |
None reported |
None reported |
Correlation between Bu plasma AUC and regimen related SAEs; no grade 4 toxicity reported |
Copelan et al.r |
Not reported |
Grades 2 - 4
51% Cy/TBI vs 39% po Bu vs 40% IV Bu (p<0.001)
Grades 3 - 4
25% TBI vs 14% po Bu vs 17% IV Bu (p<0.001)
|
At 1 yr: 44% Cy/TBI vs 42% po Bu vs 49% IV Bu (N.S)
At 5 yrs: 52% Cy/TBI vs 48% po Bu vs 55% IV Bu (N.S)
|
Not reported |
9% po Bu, 7% IV Bu, 6% TBI (N.S) |
10% TBI, 5% po Bu, 3% IV Bu (p<0.001) |
Not reported |
|
aGVHD = acute graft versus host disease, VOD = veno-occlusive disease; SOS = sinusoidal obstruction syndrome; IPS = idiopathic pneumonia syndrome; SAE = serious adverse event