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

Abstract

▪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 1aBaseline CharacteristicsPatient Characteristics Bu-Cy (n=18)Cy-Bu (n=22)P valueSexMale15160.424Age (in yrs)Median (Range)17 (1-50)16 (1-48)≤18913≥1899Underlying DiseaseAML14120.415ALL34CML13MDS02Primary Myelofibrosis01Pre-transplant Remission StatusCR11110.482Performance status (ECOG)0430.3141916HSCT Comorbidity Index014150.341115222310Table1bBaseline CharacteristicsTransplant characteristicsBu-CyCy-BuP valueTime from diagnosis to TransplantMean (days) + SD548.16750.567HLA MatchingHLA identical (6/6)17210.884HLA mismatch (5/6)11DonorMatched Sibling17160.884UCB11Donor AgeMedian(Range)20 (0-47)16 (0-50)0.781Donor SexMale5140.034Female128Sex mismatch12130.458Female Donor in Male patient1170.064Harvest SourcePeripheral Blood (PB)15210.269Bone Marrow (BM)20Cord Blood (UCB)11CD 34 Count(x106 cells/kg)Mean+SD5.12+2.605.66+2.370.499CD 3 Count(x107 cells/kg)Mean25.517.50.200Table 2ResultsOutcomeBu-CyCy-BuPANC recovery14 (11-30)11 (8-32)0.119Platelet recovery21 (17-44)16 (11-27)0.008Platelets transfused6 (1-10)4 (1-15)0.166Days of GCSF18 (12-36)14 (9-37)0.126D100 Complete Donor Chimerism9 (90%)12(85.71%)1.000Transplant Response15/17 (88.24%)19/22 (86.36%)1.000 Days of Antimicrobial use13 (0-34)13 (0-36)0.83 Hepatotoxicity (grade3-4)10/18 (55.56%)3/22 (13.64%)0.030Nephrotoxicity (grade3-4)3/18 (16.67%)1/22 (4.55%)0.204Mucositis (grade3-4)6/18 (33.33%)6/22 (27.27%)0.677Any Grade 3-4 toxicity10/18 (55.56%)9/22 (40.91%)0.356D30 TRM3 (16.67%)00.083D100 TRM4 (22.22%)2 (10%)0.395Follow up28.67 months7.6 monthsAcute GVHD3/18 (16.67%)5/22 (22.73%)0.709 DisclosuresNo relevant conflicts of interest to declare.