scholarly journals Endothelial Activation and Stress Index (EASIX) Measured Pre-Transplant Identifies a Subgroup with High Transplant Related Mortality in Patients with Thalassemia Undergoing Stem Cell Transplantation Using Thiotepa-Treosulfan-Fludarabine Conditioning

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1781-1781
Author(s):  
Uday Prakash Kulkarni ◽  
Aswin Anand Pai ◽  
Kavitha M Lakshmi ◽  
Sushil Selvarajan ◽  
Sharon Lionel ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Clinical Outcomes ◽  
Peripheral Blood Stem Cell ◽  
Conditioning Regimen ◽  
Thalassemia Major ◽  
Endothelial Activation ◽  
Stress Index ◽  
Class Iii ◽  
Related Mortality

Abstract Allogeneic stem cell transplantation (SCT) is a curative treatment for beta-thalassemia major. The Pesaro risk stratification classifies patients with thalassemia into three groups (class I, II, and III) to predict the transplant-related mortality (TRM) and graft rejection after myeloablative conditioning with busulfan and cyclophosphamide. However, in developing countries, where inadequate chelation therapy prior to transplant is common, most patients would fall under the class III category. There is heterogeneity in the clinical outcomes in this group. Hence, our center introduced a further refinement in this risk stratification, identifying a subset of "class III high risk" as those with age greater than or equal to 7 years and liver size > 5cm (Mathews V et al. BBMT 2007). Subsequently, we showed that the use of a conditioning regimen containing thiotepa, treosulfan, and fludarabine (TTF) along with a peripheral blood stem cell graft led to improved outcomes in this subset with a reduction in early TRM from 46% (with busulfan-cyclophosphamide) to 13% (Mathews V et al. PLoS One 2013). There is still a need to identify predictors of poor clinical outcomes to optimize further the clinical outcomes of these class III high-risk thalassemia patients. Endothelial activation and stress index (EASIX) is a simple biomarker calculated using lactate dehydrogenase, creatinine, and platelet counts. EASIX has been shown to be predictive of overall survival in various settings like GVHD following reduced-intensity transplants for malignancies in adults, veno-occlusive disease, and nonrelapse mortality following SCT (Luft T et al. Lancet Haem 2017; Jiang S et al. Haematologica 2021; Luft T et al. BMT 2020). Here, we evaluated the role of EASIX (measured before conditioning therapy) as a biomarker in predicting early TRM in patients with thalassemia major who have undergone SCT with a uniform conditioning regimen using TTF at our center. During the study period from January 2012 to December 2019, 281 patients with thalassemia major underwent SCT with a uniform TTF protocol at our center. The median age was nine years (range 1 to 25 years). One hundred and nine (38.8%) were females. As per Pesaro classification (with Vellore modification), three (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. The stem cell donors were matched sibling (n=218, 77.6%), matched related non-sibling (n=23, 8.2%), or matched unrelated donors (n=40, 14.2%). The stem cell donor was HLA matched in all cases except 21 (7.5%), wherein there was a mismatch at one locus. Five (1.8%) had a bone marrow graft, while others had peripheral blood stem cell grafts. Thirty-eight (13.5%) patients had transplant-related mortality by day 100 (TRM100). The median follow-up of the cohort was 31 months (range 0 to 103 months). EASIX score pre-transplant was available for 184 (65.5%) patients. There was no difference in the rate of TRM100 in patients where EASIX was available compared to those where EASIX was not available (14.7% versus 11.3%, p 0.47). Also, there was no difference in overall mortality rate in patients where EASIX was available compared to those where EASIX was not available (21.2% versus 17.5%, p 0.53). Among patients with TRM100 vis-à-vis those who did not, the median EASIX score was significantly higher (1.09 versus 0.75, p 0.008). We then plotted a receiver operating characteristics (ROC) curve for predicting TRM100 using the EASIX score. The area under the curve was 0.661 (Figure 1a). A cut-off of 0.85 for the EASIX score had a 70.4% sensitivity and 62% specificity for predicting TRM100. The TRM100 for patients with EASIX above 0.85 was significantly higher than those with EASIX less than 0.85 (24.4% versus 7.5%, p 0.003). On multivariable logistic regression analysis, the factors independently predicting TRM100 were pre-transplant EASIX score, pre-transplant ferritin, unrelated donor source, and chimerism at day 60 (Figure 1b). In patients with thalassemia major undergoing SCT using a uniform TTF conditioning, EASIX score measured pre-transplant can identify patients at greater risk for Day100 TRM. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1017-1017
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Kavitha M Lakshmi ◽  
Aby Abraham ◽  
Rayaz Ahmed ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Clinical Outcomes ◽  
Peripheral Blood ◽  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Class Iii ◽  
Cell Source

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.

Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4308-4308
Author(s):  
Jean El-cheikh ◽  
Luca Castagna ◽  
Sabine Furst ◽  
Catherine Faucher ◽  
Benjamin Esterni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Allogenic Stem Cell Transplantation ◽  
Related Mortality

Abstract Abstract 4308 Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality. We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor; 41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease. With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation. The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5]. 2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC). Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies. Disclosures: No relevant conflicts of interest to declare.

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.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2996-2996
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Kavitha M. Lakshmi ◽  
Auro Viswabandya ◽  
Mammen Chandy ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Stem Cell ◽  
High Risk ◽  
Liver Fibrosis ◽  
Stem Cell Transplantation ◽  
Risk Group ◽  
Thalassemia Major ◽  
High Risk Group ◽  
Class Iii ◽  
Liver Size

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.

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