New targeted therapy options are needed for patients who develop autoimmune hemolytic anemia (AIHA) following a stem cell transplant, a review study says.
AIHA is characterized by the production of autoantibodies that attack and destroy red blood cells. It includes two variants, cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA), depending on whether autoantibodies bind more easily to red blood cells at lower or higher temperatures, respectively.
Both disorders are caused by a dysregulation in the complement system — a set of more than 20 blood proteins that are part of the body’s immune defenses — that, when overactive, can lead to a series of potentially life-threatening complications, including severe anemia.
The disease may also be classified as primary or secondary, depending on whether it is associated with an underlying medical condition or not.
“In recent years, there is accumulating evidence about AIHA arising after allogeneic hematopoietic stem cell transplantation (allo-HSCT, a procedure in which a patient receives stem cells from a genetically similar donor), with a reported incidence between 4% and 6%,” the researchers wrote.
In these cases, it may be harder for physicians to make an accurate diagnosis because other complications commonly seen after stem cell transplant — such as graft failure, infection and graft-versus-host disease (GVHD) — may mask the disease.
Of note, GVHD is a a potential life-threatening condition that occurs in transplant patients when the recipient’s immune system recognizes the donor’s cells as a threat.
This review study focused on summarizing the major risk factors associated with the onset of AIHA after a stem cell transplant, as well as therapy options available to treat the disease after the procedure.
The first studies reporting the occurrence of AIHA after a stem cell transplant were published between a decade and 15 years ago. These reports were also the first to describe a series of factors that might be involved in the onset of the disease after transplantation.
Receiving a transplant from an unrelated donor and developing chronic extensive GVHD were the first two risk factors reported to increase the odds a patient had of developing AIHA.
Since then, recent studies have identified other risk factors, including being younger than 15 years old at the time of the procedure, having an infection caused by cytomegalovirus (CMV), and being treated with alemtuzumab in conditioning regimens.
“Treatment of AIHA after HSCT is challenging and mostly supported by case reports/series and some large retrospective analysis. Although most cases usually present with severe or very severe anemia requiring transfusion and prompt intervention, a wait and see approach has also been used for selected non-life-threatening cases with spontaneous recovery in 80% of them,” the researchers said.
Conventional first-line therapy options have included steroids and intravenous immunoglobulin (IVIG), while second-line treatments have included rituximab, plasma exchange, splenectomy (surgery to remove the spleen) and cyclophosphamide.
However, the proportion of post-HSCT AIHA patients responding to these treatments is much lower compared to the percentage of patients with primary AIHA, suggesting that post-HSCT AIHA is more severe and harder to tackle with medications.
New therapy options, including sirolimus, bortezomib, abatacept, daratumumab and several complement inhibitors (e.g., eculizumab and APL-2), are now emerging as promising tools to address this specific form of AIHA.
“Post-allo-HSCT AIHA is definitely more severe and refractory than primary forms. Moreover, it arises in a complex and frail clinical context, marked by deep immunosuppression and possible multi-organ failure. All these factors lead to an increased mortality, which is hardly attributable to AIHA itself, GVHD, or infectious complications,” the researchers wrote.
“[S]teroids and rituximab, which are now consolidated therapies for primary AIHAs, show an unacceptable rate of failure in post-transplant forms, emphasizing the need for new-targeted therapies. A new class of inhibitors would probably add powerful tools to the therapeutic arsenal of post-HSCT AIHA, i.e., the several agents acting on the complement system,” they added.