Risk Factor Profile Determined for Development of Pediatric TA-TMA After HSCT

The development of high-grade acute graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT) poses the highest risk for transplant-associated thrombotic microangiopathy (TA-TMA) in pediatric patients, according to retrospective results presented at the 2019 European Society for Blood and Marrow Transplantation Annual Meeting.¹

Additional strong risk factors for TA-TMA include patient comorbidities at the time of transplant or undergoing more than 1 transplant.

The 2-year overall survival (OS) rate among TA-TMA cases was 52.0% compared with 83.0% in patients not developing TA-TMA (P = .0001).

“TA-TMA is a severe complication that can reduce survival after HSCT,” said lead study author Reem Elfeky MD, UCL Great Ormond Street Institute of Child Health in London, UK underscored the importance of identifying risk factors for this condition. “In this study, we found that patients developing TA-TMA had significantly poorer overall survival. Although some risk factors have been identified in adults, data in children remain scarce.”

Elfeky and colleagues reviewed clinical charts of 450 children who underwent 474 HSCTs between 2013 and 2016 at the Great Ormond Street Hospital (GOSH) and the Great North Children's Hospital (GNCH) to define a risk profile for the development of TA-TMA in children. TA-TMA was defined according to revised criteria.²

For the analysis, risk factors were categorized according to patient characteristics, the presence of an active comorbidity at day 0 of HSCT, transplant related factors, and posttransplant factors.

At a median of 5.6 months post-HSCT, the incidence of TA-TMA was 5.6%, with no difference between centers (P = .68).

Several variables were ruled out as risk factors on a multivariate analysis. No association was found between the development of TA-TMA and gender (P = .83), underlying disease of primary immune deficiency versus hematological disease (P = .40), the use of myeloablative versus reduced-intensity conditioning (P = .69), use of serotherapy or not (P = 1.00), the presence of veno-occlusive disease (VOD) or not (P = .31), and cytomegalovirus reactivation versus no reactivation (P = .15).

The use of total body irradiation (TBI) conditioning also did not associate with the subsequent development of TA-TMA; the 2-year cumulative incidence (CI) of TA-TMA with TBI was 5.6% versus 5.9% where TBI was not administered (P = .80).

Treatment with cyclosporine or tacrolimus for GVHD was associated with a lower risk of TA-TMA; the 2-year CI of TA-TMA was 4.5% when cyclosporine or tacrolimus were used versus 16.3% with mycophenolate mofetil (MMF) or no treatment (P = .001). Calcineurin inhibition use versus none was also not a risk factor for TA-TMA (odds ratio [OR] 3; P = .16).

An association was found between TA-TMA and donor type, with mismatched grafts posing a slightly higher risk for TA-TMA development; the 2-year CI of TA-TMA was 1.8% with a matched sibling donor or matched family donor (MSD/MFD) versus 6.1% with a matched unrelated donor (MUD), and 8.3% with a mismatched family or mismatched unrelated donor (MMFD/MMUD; P = .067).

The presence of an active comorbidity at transplant (OR, 5.2; P = .016), more than 1 transplant (OR, 5.1; P = .002), and grades 3/4 acute GVHD versus grades 0 to 2 GVHD (OR, 26.9; P <.0001), emerged as significant risk factors for TA-TMA.

The 2-year CI of TA-TAS was 12.9% in the presence of comorbidities versus 3.7% in the absence of comorbidity (P = .0001).

Univariate analysis depicted a strong rise in the risk of TA-TMA among patients with higher grades of acute GVHD. The 2-year CI of TA-TMA was 8.6% in grades 1 to 4 versus 1.6% in grade 0 GVHD (P = .002), 2-year CI was 12.3% in grades 2 to 4 versus 2.9% in grades 0 to I GVHD (P = .0001), and the 2-year CI was 25% versus 2.3% when grades 3/4 versus 0 to 2 were compared (P <.0001), respectively.

“TA-TMA might represent a form of vascular acute GVHD; therefore, continuing control of acute GVHD, including the use of calcineurin inhibitors, may be important to prevent worsening of TA-TMA associated with GVHD,” Elfeky remarked.

References

1. Elfeky R, Lucchini G, Lum SH, et al. New insights into risk factors for transplant-associated thrombotic microangiopathy (TA-TMA) in paediatric HSCT. Presented at: 2019 European Society for Blood and Marrow Transplantation Annual Meeting; March 24 to 27, 2019; Frankfurt, Germany. Abstract B287.
2. Jodele S, Khoury JC, Goebel J, et al. Clinical utility of diagnostic criteria for hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA): a prospective single center study. Biol Blood Marrow Transp. 2013;19(2):S249. doi: 10.1016/j.bbmt.2012.11.327.