Addressing Diagnostic Challenges in HSCT-TMA and Exploring Emerging Biomarkers

Supplements And Featured Publications, 2020 EBMT Meeting Reporter, Volume 1, Issue 1

Biomarkers predictive of risk in hematopoietic stem cell transplantation–associated thrombotic microangiopathy have undergone a recent evolution, with several new markers under exploration and many efforts focused on making current markers more precise and accurate to strengthen diagnostic criteria.

Biomarkers predictive of risk in hematopoietic stem cell transplantation (HSCT)–associated thrombotic microangiopathy (TMA) have undergone a recent evolution, with several new markers under exploration and many efforts focused on making current markers more precise and accurate to strengthen diagnostic criteria, Sonata Jodele, MD, said during the 2020 European Society for Blood and Marrow Transplantation Meeting.1

“We're striving to propose and compose biomarker panels that will help to identify patients who are at risk,” explained Jodele, who is a faculty member in the Division of Bone Marrow Transplantation and Immune Deficiency at the University of Cincinnati Department of Pediatrics. “[We would also like to] use the panels in prospective studies [that will help to develop] therapeutic strategies in the future.”

It is known that TMA can significantly impact the outcomes of those who undergo stem cell transplants. Several studies have demonstrated that transplant-associated mortality is increased in patients with TMA. Although TMA incidence can vary by institution and it is dependent on the awareness of the disease diagnostic and treatment approaches.

Previously, the diagnosis of this condition largely depended on hematologic biomarkers such as lactate dehydrogenase (LDH), schistocytosis, anemia, thrombocytopenia, and serum haptoglobin. “TMA diagnostic criteria are undergoing a revolution,” noted Jodele.

Because of prospective studies that were conducted mainly within pediatric populations, investigators have been able to update the criteria to be more precise. These changes include more specific measurements of renal function, proteinuria, hypertension, and terminal complement activation markers like elevated plasma concentration of sC5b-9.2

“Now we know that complement activation is one of the significant pathways of injuries in TMA that can be addressed and treated,” said Jodele.

Risk Stratification for TA-TMA in Children and Young Adults

One prospective study, which focused on pediatric patients and sought to validate several risk factors, included 100 pediatric patients who had received HSCT to determine the incidence of moderate and severe TMA and factors linked with poor outcomes. All patients had TMA and they were classified based on risk features, said Jodele. High-risk features included proteinuria and terminal complement activation, as measured by sC5b-9.3

“The group of patients who had TMA features and also had both high-risk markers—proteinuria and sC5b-9 elevation—had really poor outcomes after transplant,” said Jodele. “Now, we’re calling this disease risk group to be ‘high risk’ and we’re offering therapeutic strategies with complement-blocking agents.”

Patients who did not have those high-risk markers all survived without any therapeutic interventions, noted Jodele. Patients with at least 1 of those markers comprise the ‘moderate risk’ group and they must be examined on a case-by-case basis, added Jodele.

In another study, a total of 307 pediatric patients who underwent transplant were evaluated for TA-TMA using Cho et al criteria established in 2010 and Jodele et al criteria established in 2014 for the disease. Thirty-six percent of patients met the Jodele TA-TMA criteria following transplant, which was linked with a significantly worse overall survival (OS) and increased treatment-related mortality.4

Moreover, features linked with increased mortality included the need for more than 2 antihypertensive medications, acute kidney injury, and LDH more than 2 times the upper limit of normal.

Survival Based on sC5b-9 and Proteinuria

Another prospective study examined a total of 614 pediatric patients undergoing HSCT across 13 centers. Results showed that 19% of patients who had undergone an allogenic transplant had incidence of TMA, along with 10% of those who underwent autologous transplant (P = .004). “This study also nicely demonstrated that transplant outcomes are also affected by TMA,” said Jodele. A total of 516 patients who did not have TMA had more favorable OS outcomes than the 98 patients who had TMA.5

“Patients who had proteinuria and activated complement also have inferior survival following transplant,” added Jodele, who said that these data confirm single-institution observations.

Worse Outcomes Linked With Elevated sC5n-9

Looking even further into sC5n-9 as a disease marker, another study touched on how the presence of this marker correlates with mortality outcomes in patients with moderate- and high-risk TA-TMA. In patients with moderate-risk TA-TMA who had not received previous treatment (n = 48), elevated sC5b-9 was found to be linked with a higher mortality risk than nephrotic range proteinuria; the 1-year post-HSCT non-relapse mortality was 38% versus 15%.6

Additionally, in patients with high-risk TA-TMA who had previously received treatment with eculizumab (Soliris; n = 64), those who had higher levels of sC5b-9 at the time of their diagnosis with the disease were found to be less likely to respond to treatment with eculizumab. moreover, these patients required a higher number of doses of complement-blocking agents to control the disease (P = .0004).

“In atypical hemolytic uremic syndrome (aHUS), usually a complement activation is more restricted to organ of injury, such as kidney, and is generally more condensed and consoled,” Jodele explained. “In the transplant population, you have a very significant systemic activation of complement presenting as transplant TMA; that’s why most of these patients have activated sC5b-9 in the blood while patients with aHUS do not.”

Features of Organ Injury to Assist in Diagnosis of TA-TMA

Features associated with organ injury can also be used to assist in the diagnosis of TA-TMA. “By looking at kidney biopsies, autopsies, and biomarkers, we established that markers like hypertension and proteinuria are very useful in identifying patients with TA-TMA,” said Jodele.

Pediatric patients with more than 2 anti-hypertensive medications needed in allogenic stem cell transplant or any therapy in autologous transplant is suggestive of disease. Moreover, proteinuria in the nephrotic range, defined as a protein/creatine ratio of over 2 mg/kg, is also very strongly associated with TA-TMA.7 “Serum creatinine is not that great of a marker in TA-TMA in the pediatric population,” added Jodele.

TA-TMA can also present in other organ injuries, including intestinal TA-TMA (ischemic colitis, intestinal bleeding, and bowl strictures), pulmonary TA-TMA (acute hypoxemia, pulmonary hypertension, and heart failure), central nervous system TA-TMA (seizures, hypertension, bleeds), and skin TA-TMA (vasculitis, vessel thrombosis, purpura, complement deposits).8,9

“We're often asked, ‘How do you differentiate TMA from other endothelial injury disorders like veno-occlusive Disease (VOD)?,’” Jodele added. “You’ll likely be able to identify TMA versus graft-versus-host disease (GVHD) versus VOD quite easily.”

TA-TMA: Is There a Genetic Predisposition?

The question of whether a genetic predisposition exists for TA-TMA is one that is often raised in the field, according to Jodele, along with if screening should be used for this disease. Patients with TA-TMA have multiple heterozygous complement variants present, according to a transplant recipient and donor genetic screening sample. “It’s not 1 particular variant that makes a difference in diagnosis or disease severity; rather, it’s a clustering of these variants,” said Jodele.

In a study, which examined 17 genes, investigators showed that 3 or more variants in 1 patient was associated with very severe TA-TMA, increased transplant mortality, and multiorgan injury.10 “We're still studying this and so far, genetic screening is not being used in clinical practice for TA-TMA,” Jodele said.

The Three-Hit Theory for TA-TMA

Another possible theory to help predict the development of TMA in patients who are undergoing transplantation is broken up into 3 hits: The first hit has to do with underlying genetic predisposition and what happens to a patient prior to transplantation, said Jodele. The second hit in the development of the disease would be a conditioning process in endothelial injury. The third hit would be needed to activate complement system or other inflammatory pathways, like GVHD, viral infections, and other triggers that could kickstart the complement activation process.11,12

Establishing Predictive Biomarkers: Tumorigenicity 2 Suppression

Other research efforts are examining markers that could possibly identify at-risk patients up front before they undergo transplantation. Once such marker is tumorigenicity 2 suppression (ST2), according to Jodele. Both adult and pediatric studies have shown that elevated ST2 is associated with steroid-resistant GVHD or worse outcomes following transplantation.13-15

Based on these studies, investigators examined whether or not elevated ST2 could affect outcomes in TA-TMA. Similar to what was found in GVHD, investigators established a link between TMA and elevated ST2 levels and is believed to be a possible cause of excess mortality.

"We're getting to know the interplay between TA-TMA and GVHD and we can use ST2 as a marker, at least for predictive algorithms,” concluded Jodele.

References

  1. Jodele S. Diagnostic challenges in HSCT-TMA. Presented at: 2020 European Society for Blood and Marrow Transplantation Annual Meeting; August 30-September 2, 2020; Virtual. Session IS28-3.
  2. Pagliuca S, Michonneau D, Sicre de Fontbrune F, et al. Allogeneic reactivity–mediated endothelial cell complications after HSCT: a plea for consensual definitions. Blood Adv. 2019;3(15):2424-2435. doi:10.1182/bloodadvances.2019000143
  3. Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124(4):645-53 doi:10.1182/blood-2014-03-564997
  4. Schoettler M, Lehman LE, Margossian S, et al. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. 2020;4(11):2536-2547. doi:10.1182/bloodadvances.2019001242
  5. Dandoy C, et al. Unpublished data. Oral abstract presented at: Virtual 46th Annual EBMT Meeting; August 31-September 1. 2020. A-1137-0018-01323.
  6. Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. doi:10.1182/blood.2019004218
  7. Laskin BL, Goebel J, Davies SM, et al. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation–associated thrombotic microangiopathy. Blood. 2011;118:1452-1462. doi:10.1182/blood-2011-02-321315
  8. Jodele S, Laskin B, Dandoy CE, et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191-204 doi:10.1016/j.blre.2014.11.001
  9. Jodele S, Dandoy CE, Myers KC, et al. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016;54(2):181-90. doi:10.1016/j.transci.2016.04.007
  10. Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016;127(8):989-96. doi: 10.1182/blood-2015-08-663435.
  11. Dvorak C, Higham C, Shinano KA, et al. Transplant-associated thrombotic microangiopathy in pediatric hematopoietic cell transplant recipients: a practical approach to diagnosis and management. Front Pediatr. 2019;7:133. doi:10.3389/fped.2019.00133
  12. Jodele S. Complement in pathophysiology and treatment of transplant-associated thrombotic microangiopathies. Semin Hematol. 2018;55(3):159-166. doi:10.1053/j.seminhematol.2018.04.003.
  13. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369(6):529-39. doi:10.1056/NEJMoa1213299
  14. Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD Blood. 2018;131(25):2846-2855. doi:10.1182/blood-2018-01-822957.
  15. Rowan CM, Pike F, Cooke KR. Assessment of ST2 for risk of death following graft-versus-host disease in pediatric and adult age groups. Blood. 2020;135(17):1428-1437. doi:10.1182/blood.2019002334