Arthritis Drug Acute GVHD in Unrelated Allo Stem Cell Transplants
Acute Graft versus Host Disease (AGvHD) is quite common following unrelated donor stem cell transplants. Severe instances of AGvHD (grade 3-4) are a major cause of death, especially after HLA-mismatched donors. [HLA stands for Human Leukocyte Antigens, proteins on the surface of cells that regulate the immune system]. It stands to reason then, that a mismatch of these proteins between the stem cell donor and the stem cell recipient are bound to create some difficulties for the recipient. Matching is usually graded on a scale of 1-8, though sometimes also on scales of 1-10 or 1-12. The higher the matching number, the better the match between donor and recipient.
There are no approved agents to prevent AGvHD and that provides ample reason to look for novel therapeutics.
The most recent issue of the Journal of Clinical Oncology provides a very interesting article that summarizes the effect of adding the injectable arthritis drug Orencia (abatacept), indicated for the treatment of rheumatoid arthritis to a combination of two drugs currently used to, hopefully, prevent the onset of AGvHD (one of those drugs is methotrexate, [MTX] the other is a calcineurin inhibitor [CNI] such as, e.g., tacrolimus).
Researchers completed two Phase II studies in adults and children with hematologic malignancies:
- A randomized, double-blind, placebo-controlled group of 142 patients (8/8-HLA-matched from unrelated donors), split over two arms, the first dosed with CNI/MTX plus abatacept, the second arm dosed with CNI/MTX plus placebo. These patients were followed, post-transplant for a median period of 716 days.
- A single-arm cohort of 43 patients (7/8-HLA-mismatched from unrelated donors) comparing CNI/MTX plus abatacept versus CNI/MTX controls. These patients were followed, post-transplant for a median period of 708 days.
The results are exciting and can be summarized as follows :
- In 8/8s [i.e., the ‘perfectly matched patients], grade 3-4 AGVHD was 6.8% (with abatacept) versus 14.8% (placebo). Severe AGvHD survival at +180 days was 93.2% for the group treated with CNI/MTX plus abatacept versus 82% for the group dosed with CNI/MTX plus placebo.ïIn the smaller 7/8 (unmatched) cohort, grade 3-4 AGVHD was 2.3% (for CNI/MTX plus abatacept), which compared favorably with a nonrandomized matched cohort treated with just CNI/MTX reporting 30.2 % severe AGvHD. For this group severe AGvHD survival at +180 days was 97.7% v 58.7%.
The authors conclude:
“Adding abatacept to [unrelated donor stem cell transplants] was safe, reduced AGVHD, and improved severe AGvHD survival at +180 days. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched stem cell transplants.” [Emphasis added]
It will most likely take 1-2 years before we will see this mix of products in clinical practice for allo-stem cell transplants, as the manufacturer of Orencia (Bristol Myers Squibb) will need to secure FDA approval for future use. Either way, this outcome is a major step forward in the treatment of patients who receive transplant from an unmatched, unrelated donor.