A New Stratification Strategy That Identifies a Subset of Class III Patients among Children with β Thalassemia Major Undergoing a Matched Related Allogeneic Stem Cell Transplantation.
Authors: Mathews Vikram , George Biju , Lakshmi Kavitha M. , Viswabandya Auro , Chandy Mammen , Srivastava Alok 
Published: October 2019

Abstract
The current risk stratification of patients with β thalassemia major undergoing an allogeneic stem cell transplantation (SCT) is based on liver size (>2cm), presence of liver fibrosis and inadequate iron chelation (Lucarelli et al, NEJM 1990). Our clinical observation suggested that patients in Class III (presence of all three adverse features) were a heterogeneous group and included a large number of patients who would otherwise have a good prognosis. We therefore undertook a retrospective analysis to study the pre-transplant variables that have an impact on outcome. Between 1991 and 2005, 189 patients underwent 196 HLA matched related allogeneic SCT for a diagnosis of β thalassemia major at our center. Except for two cases, all patients were less than 18 years of age at the time of transplant. The majority (97.5%) of patients received myeloablative (BuCy) conditioning regimen. The median (±SD) age of this cohort was 7±4.1 years with 68% males. There were 11(5.6%), 81(41.1%) and 105(53.3%) in Lucarelli Class I, II and III respectively. The Kaplan-Meier 5 year event free survival (event defined as rejection, relapse or death) for Class II and III patients was 78.53±4.53 and 51.97±5.14, respectively. (Table 1) summarizes the impact of pre transplant variables on the EFS. Patient age and liver size as continuous variables were significantly associated with an adverse outcome. Using a receiver operating characteristic (ROC) curve plot analysis, cutoff values of 7 years and 5 cms respectively for age and liver size gave the highest likelihood ratios for an adverse effect on EFS (1.6 and 2.7 respectively). These cut off values significantly discriminated patients’ EFS on a univariate analysis.
Table 1: Unadjusted adverse effect of pre-transplant variables on EFS Pre-transplant variable RR (95% CI) P-value Age (≥ 7 years) 2.9 (1.6– 5.2) 0.000 Sex (F) 1.5 (0.9 – 2.6) 0.082 F>M transplant 0.9 (0.5 – 1.5) 0.715 Liver size (≥5 cm) 3.5 (2.1 – 5.9) 0.000 Chelation (inadequate) 2.9 (0.7 – 12.2) 0.130 Liver fibrosis (yes) 1.7 (0.8 – 3.3) 0.106 SGPT 1.0 (1 – 1.006) 0.080 Ferritin 1 (0.8 – 1.2) 0.056
On a forward stepwise multivariate analysis only age ≥7 years and liver size ≥ 5 cms retained their significance (RR 2.2 and 3.6, P-values 0.014 and 0.000 respectively). Using these two variables patients were categorized as high risk if they were ≥ 7 years and had a liver size ≥ 5 cms. There were 41 cases in this sub group (all were Class III). The 5 year EFS and OS in this high risk group (n=41) was 23.93±6.88 and 39.01±7.96 respectively, while in the remaining Class III patients (n=64) the 5 year EFS and OS was 73.23±5.56 and 81.22±4.89. Statistical analysis of these survival curves by a log rank test revealed that they were both statistically significant (P=0.000 for both EFS and OS). The majority of the events in the high risk group happened in the first 100 days [TRM=17(41.4%), rejection=3(7.3%) and death from GVHD=3(7.3%)].
Using age ≥ 7years and liver size ≥ 5 cms we were able to identify a significant subset of patients in class III (39%) who have a poor outcome with allogeneic SCT and could benefit from novel approaches while the others with clinical outcomes comparable to those in class II should probably be classified with them and managed accordingly.