Conditioning regimens are an important issue determining the outcome of hematopoietic stem cell transplantation (HSCT). Altering the administration order of Busulphan (Bu) and Cyclophosphamide (Cy) during conditioning from conventional method of administering Bu followed by Cy had resulted in an improved toxicity profile in few animal and subsequent human studies. However the data substantiating this approach is limited.

We retrospectively analyzed all consecutive patients receiving allogeneic stem cell transplant (Allo SCT) with myeloablative conditioning from 2009 to 2013. A total of 40 patient received Allo SCT of which 18 patient received Bu-Cy and 22 patients received Cy-Bu conditioning regimen. The Bu–Cy conditioning regimen consisted of i.v. Bu 0.8 mg/kg administered every 6 h (16 doses) on days −7 to −4, followed by i.v. Cy 60 mg/kg on days −3 and −2. Patients with the Cy–Bu regimen received i.v. Cy 60 mg/kg on days −7 and −6; followed by i.v. Bu 0.8 mg/kg administered every 6 hr (16 doses) on days −5 to −2. GVHD prophylaxis was given with Cyclosporine A and methotrexate. Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) was used for assessment of toxicity. The diagnosis of sinusoidal obstruction syndrome (SOS) was based on modified Seattle criteria.

Pre-transplant characteristics were comparable in the two cohorts (Table 1a and 1b). Time to platelet engraftment was earlier in the Cy-Bu cohort (21 days vs. 16 days; P=0.008) (Table 2).Treatment related side effects were similar in both the groups except hepatotoxicity which was higher in Bu-Cy as compared to Cy-Bu group (10 (55.16%) vs. 3 (13.64%); p=0.03). There was no significant difference in treatment related mortality (TRM) at day 100; however there was trend towards higher TRM at day 30 in Bu-Cy group (3 vs. none; p=0.083).There was no difference in aGVHD incidence, grade or stage of organ involved between the 2 groups.

As in previous studies hepatotoxicity in the present analysis was found to be less in patients who received Cy-Bu as the conditioning regimen and there was earlier platelet engraftment in this group. These findings suggest Cy-Bu has better toxicity profile than conventional Bu-Cy regimen. However further prospective studies are required to confirm these findings.

Table 1a.

Baseline Characteristics

Patient Characteristics
Bu-Cy (n=18)Cy-Bu (n=22)P value
Sex Male 15 16 0.424 
Age (in yrs) Median
(Range) 
17
(1-50) 
16
(1-48) 
 
≤18 13  
≥18  
Underlying Disease AML 14 12 0.415 
ALL  
CML  
MDS  
Primary Myelofibrosis  
Pre-transplant Remission Status CR 11 11 0.482 
Performance status (ECOG) 0.314 
16  
HSCT Comorbidity Index 14 15 0.341 
 
 
 
Patient Characteristics
Bu-Cy (n=18)Cy-Bu (n=22)P value
Sex Male 15 16 0.424 
Age (in yrs) Median
(Range) 
17
(1-50) 
16
(1-48) 
 
≤18 13  
≥18  
Underlying Disease AML 14 12 0.415 
ALL  
CML  
MDS  
Primary Myelofibrosis  
Pre-transplant Remission Status CR 11 11 0.482 
Performance status (ECOG) 0.314 
16  
HSCT Comorbidity Index 14 15 0.341 
 
 
 

Table1b.

Baseline Characteristics

Transplant characteristicsBu-CyCy-BuP value
Time from diagnosis to Transplant Mean (days) + SD 548.1 675 0.567 
HLA Matching HLA identical (6/6) 17 21 0.884 
 HLA mismatch (5/6)  
Donor Matched Sibling 17 16 0.884 
 UCB  
Donor Age Median(Range) 20
(0-47) 
16
(0-50) 
0.781 
Donor Sex Male 14 0.034 
 Female 12  
 Sex mismatch 12 13 0.458 
 Female Donor in Male patient 11 0.064 
Harvest Source Peripheral Blood (PB) 15 21 0.269 
 Bone Marrow (BM)  
 Cord Blood (UCB)  
CD 34 Count(x106 cells/kg) Mean+SD 5.12+2.60 5.66+2.37 0.499 
CD 3 Count(x107 cells/kg) Mean 25.5 17.5 0.200 
Transplant characteristicsBu-CyCy-BuP value
Time from diagnosis to Transplant Mean (days) + SD 548.1 675 0.567 
HLA Matching HLA identical (6/6) 17 21 0.884 
 HLA mismatch (5/6)  
Donor Matched Sibling 17 16 0.884 
 UCB  
Donor Age Median(Range) 20
(0-47) 
16
(0-50) 
0.781 
Donor Sex Male 14 0.034 
 Female 12  
 Sex mismatch 12 13 0.458 
 Female Donor in Male patient 11 0.064 
Harvest Source Peripheral Blood (PB) 15 21 0.269 
 Bone Marrow (BM)  
 Cord Blood (UCB)  
CD 34 Count(x106 cells/kg) Mean+SD 5.12+2.60 5.66+2.37 0.499 
CD 3 Count(x107 cells/kg) Mean 25.5 17.5 0.200 

Table 2

Results

OutcomeBu-CyCy-BuP
ANC recovery 14
(11-30) 
11
(8-32) 
0.119 
Platelet recovery 21
(17-44) 
16
(11-27) 
0.008 
Platelets transfused 6
(1-10) 
4
(1-15) 
0.166 
Days of GCSF 18
(12-36) 
14
(9-37) 
0.126 
D100 Complete
Donor Chimerism 
9 (90%) 12(85.71%) 1.000 
Transplant Response 15/17
(88.24%) 
19/22
(86.36%) 
1.000
 
Days of Antimicrobial use 13
(0-34) 
13
(0-36) 
0.83
 
Hepatotoxicity
(grade3-4) 
10/18
(55.56%) 
3/22
(13.64%) 
0.030 
Nephrotoxicity
(grade3-4) 
3/18
(16.67%) 
1/22
(4.55%) 
0.204 
Mucositis
(grade3-4) 
6/18
(33.33%) 
6/22
(27.27%) 
0.677 
Any Grade 3-4 toxicity 10/18
(55.56%) 
9/22
(40.91%) 
0.356 
D30 TRM 3 (16.67%) 0.083 
D100 TRM 4 (22.22%) 2 (10%) 0.395 
Follow up 28.67 months 7.6 months  
Acute GVHD 3/18 (16.67%) 5/22 (22.73%) 0.709 
OutcomeBu-CyCy-BuP
ANC recovery 14
(11-30) 
11
(8-32) 
0.119 
Platelet recovery 21
(17-44) 
16
(11-27) 
0.008 
Platelets transfused 6
(1-10) 
4
(1-15) 
0.166 
Days of GCSF 18
(12-36) 
14
(9-37) 
0.126 
D100 Complete
Donor Chimerism 
9 (90%) 12(85.71%) 1.000 
Transplant Response 15/17
(88.24%) 
19/22
(86.36%) 
1.000
 
Days of Antimicrobial use 13
(0-34) 
13
(0-36) 
0.83
 
Hepatotoxicity
(grade3-4) 
10/18
(55.56%) 
3/22
(13.64%) 
0.030 
Nephrotoxicity
(grade3-4) 
3/18
(16.67%) 
1/22
(4.55%) 
0.204 
Mucositis
(grade3-4) 
6/18
(33.33%) 
6/22
(27.27%) 
0.677 
Any Grade 3-4 toxicity 10/18
(55.56%) 
9/22
(40.91%) 
0.356 
D30 TRM 3 (16.67%) 0.083 
D100 TRM 4 (22.22%) 2 (10%) 0.395 
Follow up 28.67 months 7.6 months  
Acute GVHD 3/18 (16.67%) 5/22 (22.73%) 0.709 

Disclosures

No relevant conflicts of interest to declare.

Author notes

*

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