Biopsies ARE Essential During Monitoring of Response to Mesenchymal Stromal CELL Therapy in Children with Gastrointestinal ACUTE GRAFT Versus HOST Disease

Acute graft-versus-host disease (aGvHD) of the gut based only on clinical symptoms may be difficult to distinguish from other causes. Assessing response to treatment may be hampered by persistent diarrhea resulting from damage to the gut in the absence of ongoing aGvHD. Histological examination of gut biopsies confirm the diagnosis but are invasive. We aimed to determine the importance of biopsies to evaluate the response to treatment with mesenchymal stromal cells (MSC) and assess the usefulness of biomarkers.

In this study, 18 patients received MSC for severe steroid refractory aGvHD of the gut (confirmed by a biopsy in 16 patients). In 89% (n=16) diarrhea persisted after the first MSC and a second (and in 3 cases a third) MSC infusion was considered. A second gut biopsy was taken from 9 patients before subsequent MSC infusion and in 6 of these biopsies (67%) no signs of aGvHD were seen. The 3 patients with biopsy confirmed active aGvHD showed a response after a subsequent MSC infusion. Nine out of 18 patients showed a complete (CR), 4 a partial response (PR) and 5 no response (NR) at 28 days after starting MSC therapy (1-3 infusions). Our data suggests that without biopsy evaluation after MSC infusion, the response to treatment may be underestimated and over treatment occurs. In contrast patients with a positive biopsy may benefit from additional MSC treatment.

However, a biopsy of children with aGvHD is not always feasible. Therefore, the value of previously reported biomarkers was assessed in our patient cohort (sIL2Ra, sCK18F, sTNFR1). Patient samples were longitudinally measured starting before SCT until 50 days after the last MSC infusion. At the start of aGvHD, serum concentrations of sIL-2Ra, sTNFR1 and soluble cytokeratin 18 fragment (sCK18F) were significantly elevated compared with samples before onset. The response at day 28 can be predicted using sIL-2Ra concentrations on day 7. Patients with CR/PR (n=13) have lower sIL-2Ra concentrations compared to non-responders (n=5) (p=0.015). The value of REG-3a in predicting the occurrence of gut aGvHD and monitoring the effect of treatment is currently being investigated.

In our opinion biomarkers can contribute to the diagnostic process, but biopsy remains the golden standard for the diagnosis and short term response to treatment of aGvHD. Sequential biopsies should be included in randomized controlled trials to validate the importance of biomarkers in monitoring response to experimental cellular therapy.