Abatacept cuts severe graft-vs-host disease after stem cell transplant
Adding the immunotherapy abatacept to standard drug regimen used for preventing graft-versus-host disease (GvHD) significantly reduced, and almost eliminated, life-threatening severe acute GvHD in patients undergoing haematopoietic stem cell transplants.
Abatacept is a soluble fusion protein that has been approved by the FDA for renal transplant and rheumatoid arthritis. Abatacept has been shown to block T cell activation that can lead to debilitating joint inflammation in rheumatoid arthritis.
“Preventing GvHD and relapse after transplant requires a difficult balance of eliminating the bad, overactive effector T cells, without suppressing the good, regulatory T cells,” said lead author Dr Leslie Kean of Seattle Children's Ben Towne Center for Childhood Cancer Research in Seattle, Washington, US.
“Given the serious threat of GvHD … to see such striking results in patients at extremely high risk for GvHD is incredibly encouraging,” she added.
At 100 days after transplant, the cumulative incidence of grade III-IV acute GvHD was significantly lower in abatacept-treated patients who underwent mismatched unrelated donor stem cell transplants vs matched control patients receiving standard regimens of calcineurin inhibitor plus methotrexate only (CNI/MTX; 3 percent vs 32 percent; p=0.007). Similar reduction was also seen when compared with controls receiving CNI/MTX plus anti-thymocyte globulin (+ATG; 3 percent vs 22 percent). [ASH 2017, abstract 212]
Of note, the reduction in severe acute GvHD with abatacept was achieved without significant adverse impact on patient safety, hence improving transplant-related mortality at 12 months (12.5 percent vs 34 percent in CNI+MTX and 27 percent in +ATG; p=0.002 and 0.04, respectively).
Also, no increase in disease relapse was seen at 12 months in the abatacept arm vs controls (7.5 percent vs 15 percent and 11 percent; p=0.04 and 0.26, respectively).
According to Kean, analyses on viral reactivation and other infectious outcomes are still ongoing, “but uncontrolled infections were not a major problem.”
As a result, patients receiving abatacept had significant survival advantage over controls, in terms of disease-free survival (81 percent vs 50 percent and 63 percent; p=0.0003 and 0.016, respectively) and overall survival at 1 year post-transplant (85.4 percent vs 57 percent and 68 percent; p=0.0025 and 0.048, respectively). The results are consistent thus-far through 2 years.
The multicentre study comprised two cohorts, one single-arm stratum involving 43 patients who received mismatched unrelated donor transplant, and another double-blind stratum randomizing 140 patients who underwent HLA-matched unrelated donor transplant to receive abatacept in addition to CNI/MTX vs CNI/MTX alone. The current analysis included only data from the single-arm stratum, with matched controls from a national database.
“As a transplant physician, it’s beyond heart-breaking to witness a patient develop severe acute GvHD after having their leukaemia cured through bone marrow transplant,” said Kean. “To have a therapy at our disposal that safely targets just the T cells causing GvHD would represent a major step forward in stem cell transplantation. It not only offers new hope that we can prevent GvHD upfront, but that we can also significantly improve outcomes for patients requiring high-risk transplants.”