Complication of Stem-Cell Transplantation Appears Rooted in Genetic Variants, the Fingerprints That – Until Now – Have Long Eluded Researchers

by Tom O’Neill

 

In children who have undergone stem-cell transplantation, some forms of thrombotic microangiopathy (TMA) can progress from manageable to potentially fatal with elusive silence.

TMA does, however, leave one crucial clue: a genetic fingerprint of susceptibility.

That discovery is driving new strategies for early diagnosis and treatment at Cincinnati Children’s, led by Sonata Jodele, MD, Division of Bone Marrow Transplant and Immune Deficiency.

In a prospective study published online Nov. 24, 2015, in the journal Blood, Jodele’s team used gene-expression profiling to find the functional significance of gene variants found among 77 patients who underwent genetic testing. Of the group, 34 had TMA, and of those, 65 percent had genetic variants in at least one gene compared with only nine percent of patients without TMA.

Sonata Jodele, MD.

Dr. Sonata Jodele’s research into the functionality of gene variants has provided insight into why some children with stem cell transplants are more susceptible to thrombotic microangiopathy than others. She credits the strong sense of collaboration at Cincinnati Children’s and delights in sharing former patients’ photos with the lab researchers so integral to her work.

PROGRESS IN EARLY DETECTION

TMA is a fairly common complication of hematopoietic stem-cell transplantation. If left unchecked, symptoms can cascade from anemia and platelet consumption to thrombosis and, in some children, multiple organ failure and death.

Cincinnati Children’s is the only center in the U.S. that performs the full array of molecular and cellular diagnostic testing for TMA. Yet until recently, there was no data addressing individual susceptibility to TMA, nor any pre-transplant screening that could alter risk-assessment and transplant regimens.

“Our study reveals important differences in genetic susceptibility based on genotype,” Jodele says. “Now, we are looking at how these markers in the blood line up over time, the role of genetics and complement gene defects.”

The new study, which involved scientists from the divisions of Human Genetics and Biomedical Informatics, follows up on a July 24, 2014, study, also published in Blood. In that study, Jodele’s team established a new algorithm for early diagnosis, and showed the potential of eculizumab therapy, a humanized monoclonal antibody that functions as a terminal complement inhibitor.

Last year, Cincinnati Children’s awarded Jodele one of its 11 Innovation Fund awards to build upon her work in TMA.

PICTURES OF SUCCESS

Jodele’s office walls are a tapestry of another type of award: art and photos of the children whose lives she has helped save.

“It’s very rewarding,” Jodele says, “because we see kids who are suffering and dying. But then you see them go home and go back to school, it’s wonderful.”

One of those kids is Ava Pannozzo, 7, of upstate New York. She was treated in 2013-14 at Cincinnati Children’s for hemophagocytic lymphohistiocytosis (HLH), a disorder of the immune system. She developed severe TMA, was days or weeks from dying, and now is a first-grader taking ballet dance lessons.

Told of Jodele’s art and photo collection, her father, Chris, paused. “That’s tremendously humbling,” he says. “I think we should have a shrine to her.”