New Approach to Treating GvHD After Stem Cell Transplant

While hematopoietic stem cell transplantation (HSCT) may offer a cure for patients with blood cancers, the chances of that are dashed if the patient develops graft-vs-host disease (GvHD). This happens in some 70% of cases.

GvHD is a major cause of morbidity and mortality in patients who undergo HSCT, and there are few effective treatment strategies. A new approach that uses decidua stromal cells (DSCs) from placentas of healthy mothers shows promise.

The finding comes from a pilot study of 38 patients who experienced severe acute GvHD after HSCT and showed an improvement in GvHD and survival when they received placenta-derived DSCs prepared with a modified protocol using human serum albumin as a suspension fluid.

The researchers, led by Olle Ringdén, MD, PhD, from the Karolinska Institute, Stockholm, Sweden, acknowledge that the results come from a small number of patients and require validation. But they add, "If confirmed in a larger prospective trial in future, this will be a breakthrough treatment of severe acute GvHD."

"If an effective therapy for severe acute GvHD is indeed found and validated, it will increase the usefulness of HSCT, with a possible broadening of indications," they comment.

The report was published March 13 in Stem Cells Translational Medicine. Editor-in-chief of the journal, Anthony Atala, MD, who is director of Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina, said, "These results are certainly promising…and are especially exciting because there has been no effective therapy for severe acute graft-versus-host disease."

The Journey to Find a Cure for Severe Acute GvHD

Ringdén and his colleagues have been on a decade-long journey to find novel ways of treating GvHD, which occurs when the donor's immune cells attack patient's normal cells. It is typically treated with steroids, but many patients have steroid resistance.

The team first explored the use of bone marrow–derived mesenchymal stromal cells as a treatment for GvHD, but long-term overall survival with these cells was no better than that in controls. Looking for alternate sources of stromal cells and knowing that the placenta protected the growing fetus from the mother's immune system, Ringdén and his colleagues settled on placenta-derived stromal cells.

Since 2011, Ringdén and his colleagues have been using DSCs to treat severe acute GvHD after HSCT. This report was a retrospective analysis of the safety and efficacy of DSCs in this setting. The team analyzed results from 38 consecutive patients who received DSCs for treating grade 2/3 GvHD.

Most patients received the transplant for malignant disease (only seven patients had nonmalignant disease). Before HSCT, patients received myeloablative or reduced-intensity conditioning.

After undergoing HSCT, all patients received GvHD prophylaxis, with the majority receiving a combination of cyclosporine and methotrexate.

All 38 patients included in this report had grade 2/3 acute gastrointestinal GvHD, as determined from the Seattle criteria and histologically confirmed from biopsy specimens taken during colonoscopy or gastroscopy. They also received first-line treatment for acute GvHD with oral or intravenous corticosteroids.

DSCs were prepared from human placentas of healthy mothers during elective caesarean-delivery births.

In their initial protocol, which was undertaken in the first 17 patients (group 1), frozen DSCs were thawed in 10% AB plasma; patients with severe acute GvHD received a single intravenous infusion of 2 × 10⁶ cells/mL per infusion.

The subsequent group of 21 patients (group 2) received DSCs thawed in 5% human serum albumin in two divided doses of 1 × 10⁶ cells/mL given 1 week apart.

Additional doses of DSCs were administered based on GvHD response.

Study Results

Response to treatment was evaluated 4 weeks after the intervention.

Complete response (CR) was defined as the disappearance of all symptoms of acute GvHD and was seen in 5 of 17 patients in group 1 and 11 of 21 patients in group 2.

Partial response (PR) was defined as an improvement by at least one organ-specific grade and was seen in 5 of 17 patients in group 1 and 10 of 21 patients in group 2.

No response was equivalent to no improvement; this occurred in 7 of 7 patients in group 1 and was not seen in any patients in group 2.

Ringdén and colleagues noted that albumin-thawed cells had a higher viability and that patients in group 1 received significantly fewer doses, more cells per dose, and stromal cells from a lower passage number.

One-year survival was 76% for patients in group 2, significantly higher than the 47% seen in group 1 (P = .013). The mortality rate from GvHD was significantly higher in group 1 than group 2: 41% vs 5%, respectively (P = .016).

The risk for relapse and chronic GvHD was similar across the two groups. Cumulative incidence of chronic GvHD at 1.5 years was 36% for group 1 and 31% for group 2.

Ringdén and colleagues also analyzed survival for patients with steroid-refractory GvHD, which is associated with poor clinical outcomes. Of the 38 patients in their analysis, 24 were steroid resistant: 13 of 17 patients in group 1 and 11 of 21 in group 2.

In patients with steroid-refractory disease, overall response (CR + PR) at 4 weeks after DSC intervention was 100% for group 2 and 46% for group 1. In comparison, the rate was 25% for historic controls from their institution.

For patients with steroid-refractory GvHD, 1-year overall survival was 73% for group 2, 31% for group 1, and 3% for the historical controls. GvHD-related mortality was

0% for group 2 and 54% for group 1 vs 81% for the control group.

The researchers say that treatment with DSC is safe. The serious adverse effects seen in these patients, including infections, relapses, and death, were common complications of acute GvHD, they comment.

"Because the patients treated with DSCs have survived longer than expected, they have had more time to experience adverse events after HSCT complicated by acute GvHD and heavy immunosuppressive treatment," Ringdén and colleagues note.

Many more long-term survivors of acute GvHD will be required to determine whether any particular causes of death and severe adverse events are associated with stromal cell therapy, they add.

One author received honoraria from Abbott and Gilead for presentations at meetings sponsored by the companies. Ringdén and the other authors have disclosed no relevant financial relationships.

Stem Cells Transl Med. Published online March 13, 2018. Full text

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