Improved Clinical Outcomes of High Risk β Thalassemia Major Patients Under Going a HLA Matched Related Allogeneic Stem Cell Transplant with the Use of a Treosulphan Based Conditioning Regimen and Peripheral Blood Stem Cell Grafts
Authors: Mathews Vikram , George Biju , Lakshmi Kavitha M , Abraham Aby , Ahmed Rayaz , Viswabandhya Auro , Srivastava Alok 
Published: October 2019

Abstract
Abstract 1017
Allogeneic stem cell transplant (SCT) remains the only curative option for patients with β thalassemia major (TM). However, the clinical outcome following SCT in patients with TM who belong to the Class III and the Class III high risk (HR) group remains poor. (Class III HR = age≥7 years and liver size≥5 cms: defined by us previously; BBMT 2007;13:889).
From October, 1991 to June, 2011, 332 HLA matched related transplants for TM were done at our center. In an attempt to improve the clinical outcomes we used a Fludarabine (Flu) with intensity reduced Bu/Cy conditioning regimen, for a short period in 2006 and from August, 2009 a treosulphan based conditioning regimen (thiotepa: 8 mg/kg on day-6, treosulphan: 14gm/m2 for 3 days from day −5 to −3 and fludarabine 40mg/m2 for 4 days from day -5 to -2). We undertook a retrospective analysis to compare the impact of these alterations on the clinical outcome, especially in the high risk groups.
A total of 178 (53.6%) Class III underwent SCT and 76 (42% of Class III) of these were Class III HR. Of the Class III patients, 135 received a conventional oral busulphan based conditioning regimen, 13 the Flu/Bu/Cy regimen and 30 the treosulphan based regimen (baseline characteristics of three groups summarized in Table 1). The treosulphan based regimen was associated with a significant reduction on the incidence of sinusoidal obstruction syndrome (SOS), TRM and rejections (table 1). The 2 year Kaplan-Meier estimate of EFS for these three groups was 59.6 ± 4.3, 23.1 ± 11.7 and 89.1 ± 6.0) respectively (P=0.000). Among those conditioned with a treosulphan based regimen DAH occurred in 4 and two of them (who also had features of SOS) succumbed to subsequent complications. With the treosulphan based regimen, initially bone marrow was the stem cell source (n=12) and this was associated with a delay in engraftment (median time to ANC>1000/mm3 was 19 days: range: 15–21), greater morbidity and a higher incidence of mixed chimerism on day 28 post transplant (50%) compared to PBSC (n=18, median time to ANC>1000/mm3= 15 days; range: 12–28, day 28 mixed chimerism in 12%). Use of PBSC was not associated with a significant increased risk of acute or chronic GVHD. It was noted that these favorable observations were retained in the Class III HR subset and the 2 year Kaplan-Meier estimate of EFS in this subset, with a treosulphan based conditioning regimen (n=19), was 89.5 ± 7.0% (Figure 1).
In conclusion a treosulphan based conditioning regimen with a peripheral blood stem cell graft is well tolerated in high risk patients with TM and significantly improves the clinical outcome.Table 1:Baseline characteristics and clinical outcomes of Class III patients conditioned with different conditioning regimens.Busulphan based N (%)/ Mean ± SD/ Median(Range)Fludarabine based N (%)/ Mean ± SD/ Median(Range)Treosulphan based N (%)/ Mean ± SD/ Median(Range)P-valueN1351330Age9 (2–24)11 (4–14)11 (4–21)0.102Sex: M85 (63)8 (61.5)19 (63.3)0.994Class III HR*53 (39.3)4 (30.8)19 (63.3)0.036Live size4 (2–11)4 (3–7)5 (2–10)0.066F>M#49 (36.3)5 (38.5)7 (23.3)0.379Splenectomy30 (22.2)1 (7.7)7 (23.3)0.455HbsAg5 (3.7)000.441HCV28 (20.7)1 (7.7)4 (13.3)0.371Stem cell source$———0.000    BM125 (92.6)13 (100)12 (40)    GBM9 (6.7)——    PBSC1 (0.7)—18 (60)CD34 dose6.4 (2.64–15.8)7.1 (2.80–12.7)11.4 (4.1–24.4)0.001ANC>0.5 × 109/Lt (days)16.88 ± 4.1419.12 ± 2.7516.03 ± 2.910.047Platelet>20 × 109/Lt (days)30 (10–137)32 (22–49)16.5 (9–44)0.000SOS@89 (65.9)4 (30.8)4 (13.8)0.000Treatment related mortality40 (31.7)5 (41.7)2 (6.7)0.012Rejections———0.034    Primary graft failure4 (2.9)6 (46.2)1 (3.3)    Secondary graft rejection12 (8.9)12 (15.4)0 (0)Ac GVHD55 (45.8)2 (20.0)11 (37.9)0.240Ch GVHD17 (18.1)03 (13)0.4122 yr KM estimate of EFS59.6 ± 4.323.1 ± 11.789.1 ± 6.00.0002 yr KM estimate of OS65.8 ± 4.253.8 ± 13.893.3 ± 4.60.028*HR high risk#F>M female donor to male recipient$Stem cell source. BM=bone marrow, GBM=G-CSF primed BM, PBSC=peripheral blood stem cells@SOS sinusoidal obstruction syndrome

Disclosures:
No relevant conflicts of interest to declare.