Abatacept shows promise for steroid-refractory chronic graft-versus-host disease
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SALT LAKE CITY — Abatacept demonstrated efficacy among patients with steroid-refractory chronic graft-versus-host-disease, according to phase 2 study results.
Use of the agent led to durable reductions in prednisone dosing, findings presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR showed.
Rationale and methods
Abatacept (Orencia, Bristol Myers Squibb) — a recombinant fusion protein — is comprised of the extracellular domain of CTLA-4, linked to the modified Fc portion of human immunoglobulin G1 that binds to CD80 and CD86 on antigen-presenting cells, according to study background.
The agent is designed to attenuate CD28-mediated T-cell activation.
“Abatacept is being assessed for the treatment of steroid-refractory chronic GVHD — an indication for which it is not currently approved,” Anita G. Koshy, MD, clinical fellow in medicine at Beth Israel Deaconess Medical Center, said during her presentation. “Chronic GVHD remains a significant cause of morbidity and mortality following allogeneic HSCT, with a cumulative incidence of 50%. Transplant recipients with chronic GVHD have a decreased quality of life, indicating a substantial burden of this phenomenon despite curative intent with allogeneic HSCT.”
Systemic corticosteroids are often used as front-line therapy, but they are associated with inadequate response and significant toxicities. New, more effective therapies are needed, Koshy said.
Investigators sought to assess overall clinical response rate with abatacept for patients with steroid-refractory chronic GVHD.
The analysis included 39 patients (median age, 62 years; 54% women) who had undergone allogeneic HSCT a median 43 months before study entry.
More than half (n = 21) had severe chronic GVHD at baseline, whereas 18 had moderate chronic GVHD.
Baseline chronic GVHD assessment showed involvement in the following: skin (84%), joints (82%), eyes (72%), lung (56%), mouth (44%), liver (23%), gastrointestinal tract (15%) and genital tract (8%).
All study participants developed chronic GVHD defined by NIH consensus criteria and received at least 0.25 mg/kg prednisone daily for at least 4 weeks.
Patients received six doses of 10 mg/kg abatacept. Those who completed the six-dose regimen and continued to exhibit response could receive up to 12 more doses.
Study participants received a median eight doses (range, 2-18) of abatacept.
Overall response rate served as the primary endpoint.
Key findings
Results showed a 58% ORR. All patients who achieved response had partial responses.
Researchers reported the greatest improvement in the following organ sites: lung (36%), eyes (25%), skin (22%), mouth (22%) and joints (22%).
About one-third (33%) of patients experienced disease progression. Sites of involvement included mouth (14%), lung (8%), skin (6%), eyes (3%), liver (3%) and joints (6%).
At baseline, patients had been receiving a median daily dose of 20 mg of prednisone. Researchers reported a 27.5% reduction in prednisone dose from baseline to 1-month follow-up (P < .01) and a 50% reduction in prednisone at 4 months follow-up.
The most common adverse events observed in the study population included neutropenia, fatigue, headache and upper respiratory infection.
Four patients experienced a combined nine events of neutropenia (grade 2, n = 5; grade 3, n = 2; grade 4, n = 2).
One patient died of herpes simplex virus hepatitis within 30 days of receiving the sixth dose of abatacept.
Looking ahead
“There are ongoing immune correlative studies to help us better understand the mechanism by which abatacept may work in the treatment of chronic GVHD,” Koshy said. “Thus far, T-cell polarization assessments have shown no differences in IL-10 expression or interferon-gamma expression by CD4-positive T cells before and after treatment in clinical responders. However, cytokine profiling of patient plasma and single RNA sequencing are underway to better understand changes to the immune microenvironment caused by abatacept.”
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Koshy AG, et al. Abstract 32. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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