Cyclophosphamide Followed By Busulphan in Place of Standard BuCy Regimen for Patients Undergoing Allogeneic Stem Cell Transplantation: A Preliminary Experience from a Single Centre in India
Authors: Bhethanabhotla Sainath , Sahoo Ranjit Kumar , Kumar Lalit , Sharma Atul , Bakhshi Sameer 
Published: October 2019

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 9 13 ≥18 9 9 Underlying Disease AML 14 12 0.415 ALL 3 4 CML 1 3 MDS 0 2 Primary Myelofibrosis 0 1 Pre-transplant Remission Status CR 11 11 0.482 Performance status (ECOG) 0 4 3 0.314 1 9 16 HSCT Comorbidity Index 0 14 15 0.341 1 1 5 2 2 2 3 1 0

Table1b. Baseline Characteristics Transplant characteristics Bu-Cy Cy-Bu P 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) 1 1 Donor Matched Sibling 17 16 0.884 UCB 1 1 Donor Age Median(Range) 20 (0-47) 16 (0-50) 0.781 Donor Sex Male 5 14 0.034 Female 12 8 Sex mismatch 12 13 0.458 Female Donor in Male patient 11 7 0.064 Harvest Source Peripheral Blood (PB) 15 21 0.269 Bone Marrow (BM) 2 0 Cord Blood (UCB) 1 1 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 Outcome Bu-Cy Cy-Bu P 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 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.