A retrospective cohort study was done on data obtained from a tertiary center’s bone marrow transplantation unit registry. The medical files of adult patients with ALL who received a transplant during the period 2000 to 2016 were reviewed. Patients aged 19 years or above at the time of first allo-HSCT from an HLA-matched sibling donor using TBI/Cy or Bu/Cy as a MAC regimen were included, either in first complete remission (CR1), CR2, or beyond. All patients had adequate performance scale and negative serology for the hepatitis B virus and the human immune deficiency virus (HIV).
Patients aged 60 years or above and those who received syngeneic or haploidentical allo-HSCT were excluded.
Detailed history has been reviewed, including data about age, sex, time from diagnosis to transplantation, Philadelphia chromosome, and disease status at transplantation time, associated comorbidities, viral status, donor type, stem cell source, CD34 cell dose, graft versus host disease (GVHD) prophylaxis, and transfusion requirements. Allo-HSCT outcome was assessed with the following parameters: time to engraftment, acute and chronic GVHD, incidence and severity of infections, and conditioning regimen-related toxicities. Survival outcomes included OS, DFS, NRM, and relapse.
Conditioning regimens
Patients included in our study were divided into two groups based on their conditioning regimens:
Group 1 included ALL patients who received allo HSCT from 2000 to 2015 and received TBI/Cy. The TBI dose was 12 Gy fractionated over 5 days (from day –10 to day –6). Cy was administrated as 30 mg/day (from day –5 to day –2 of the stem cell infusion).
Group 2 included ALL patients who received allo HSCT from 2000 to 2016 and received Bu/Cy. The dose of oral busulfan was 16 mg/kg total dose over 4 days to be given as 4 mg/day orally. The Cy dosage over 4 days was 120 mg/kg IV to be given as 30 mg/day.
GVHD prophylaxis
All patients received prophylaxis for GVHD using methotrexate (MTX) and cyclosporine (CSA). MTX dose was 15 mg/m2 IV given on day +1 then changed to 10 mg/m2 on days +3, +6, and +11, as well as folinic acid rescue 15 mg/m2 IV TDS for just 24 h on the day after MTX injection. MTX was monitored by the degree of mucositis and bilirubin level with the appropriate drug titration. CSA was administered in two divided doses from day −1 at a dose of 3 mg/kg/day IV that was replaced by an oral form once tolerated. The dose was modified to reach a therapeutic plasma CSA level of 200–250 mg/ml. Renal functions and electrolytes were also monitored with drug titration accordingly.
Supportive care
Gastric protection by pantoprazole, antiemetics, using ondansetron were initiated at the start of the conditioning regimens and maximized as needed. All patients were given uromitexan guard against cyclophosphamide-induced hemorrhagic cystitis. Seizure prophylaxis by phenytoin was given before and during the administration of busulfan. Local mouth care and prophylaxis against bacterial, fungal, and viral infections were also given to all patients. Pneumocystis Jirovecii infection prophylaxis was done by trimethoprim-sulfamethoxazole (stopped in day −2 and re-initiated after engraftment). Preemptive treatment for cytomegalovirus (CMV) reactivation was given according to close molecular monitoring. Supportive irradiated blood products were administrated when needed; whole blood and granulocyte colony-stimulating growth factors (G-CSF) were received in some patients until neutrophil recovery.
Study endpoints and operational definitions
The primary endpoints were OS and DFS. OS was defined as time to death or last contact for survivors. DFS was identified as a time to treatment failure (relapse or death); for survivors, it was considered as the last contact in remission. The secondary endpoints were relapse and NRM. Relapse was considered as the recurrent appearance of hematological disease. We define NRM as a death in remission.
Engraftment was identified as the first of three consecutive days with an absolute count of neutrophils > 500/μL and platelets > 20,000/μL (unsupported) [6]. The diagnosis and grading of acute and chronic GVHD were based on the established criteria [7, 8]. VOD diagnosis was based on the Baltimore clinical criteria [9]. Mucositis was identified and graded according to the National Cancer Institute (NCI-CTC) criteria [10], and grade 1 was considered as mild, grade 2 as moderate, and grades 3 and 4 as severe mucositis. Renal complications in our study were defined when serum creatinine was ≥ 2mg/dl and/or requiring CSA cessation. CMV infection or reactivation was diagnosed when 2 consecutive titres of CMV DNA are above 500 copies/mL in the presence of GVHD or above 1000 copies/mL in the absence of GVHD.
Statistical analysis
The collected data were organized, tabulated, and statistically analyzed by SPSS version 24 (Statistical Package for Social Studies) created by IBM, Illinois, Chicago, USA. For numerical values, the range, mean, and standard deviations were calculated. The differences between mean values were tested using (t) test while the Mann-Whitney test (Z) was used for other variables where data were not normally distributed. For categorical variables, the number and percentage were calculated, and differences between subcategories were tested using the chi-square test. When chi-square was not appropriate, Fisher and Monte Carlo exact tests were used as appropriate. For risk estimation, odds ratio was calculated and its 95% confidence interval. For calculation of the hazard ratio and its 95% confidence interval for the independent effect of each predictor on a certain outcome to occur during the survival period of studied patients, Cox regression was performed. The level of significance was adopted at p < 0.05.