Immune-mediated cytopenias (IMCs) after HSCT for pediatric non-malignant disorders: epidemiology, risk factors, pathogenesis, and treatment

Abstract

Hematopoietic stem cell transplantation (HSCT) represents a curative option for pediatric patients affected by malignant and non-malignant disorders. Several complications may arise during the post-transplantation period, including immune-mediated disorders. Immune-mediated cytopenias (IMCs) account for up to 22% of pediatric HSCT complications, representing an important cause of morbidity and mortality post-HSCT. So far, their pathogenesis is not well-understood, and their management may be very challenging. Further, most patients are refractory to first-line treatment which is based on high-dose intravenous steroids, immunoglobulin, and the monoclonal anti-CD20 antibody - rituximab. No clear consensus has been reached for second- and third-line therapeutic options.

Conclusion: We reviewed the epidemiology, risk factors, pathogenesis, and treatment of IMCs, aiming to offer a deeper understanding of these complications as a guide to improving the management of these fragile patients and a cue for the design of tailored clinical trials.

What is known: • IMCs arising in the post-HSCT setting represent a rare but potentially life-threatening complication. Younger patients affected by non-malignant disorders are at the greatest risk of IMCs arising after HSCT. Corticosteroids, intravenous immunoglobulin, and rituximab represent the undiscussed first-line therapeutic approach.

What is new: • This review highlitghts how children present unique risk factors for post HSCT IMCs, which are the result of the complex relationship between the immaturity of their infantile immune system and all the perturbing agents and factors which characterize the post-HSCT setting. Future efforts are warranted to establish the best option for refractory patients, for whom a standard and validated approach is not currently available. Among new agents, ibrutinib or bortezomib and fostamatinib or low-dose IL-2 could represent a good therapeutic option for patients with graft-versus-host disease and hemolytic anemia or graft-versus-host disease and thrombocytopenia, respectively.

Keywords: Children; Immune-mediated cytopenias; Pediatric inherited disorders; Pediatric stem cell transplantation.

Fig. 1

Pathogenesis of IMCs post-HSCT. Different pathomechanisms have been proposed: an impaired central tolerance due to thymic damage arising from chemotherapy or immunosuppressant drugs employed in HSCT setting or related to the immaturity of the thymus in young children; the donor could transfer to the recipient autoreactive B and T cells; and the delicate immune balance between the reconstituting donor immune system and the depleted but still present recipient immune system could be shifted toward aberrant immune responses — by graft-versus-host disease and its related therapies or prophylaxis or by viral reactivations. All these factors could lead toward the expansion of autoreactive T and B cells and toward the shift to a T helper 2 response which could amplify itself the expansion of autoreactive B cell and their transformation into plasma cells producing antibodies that definitely recognize antigens present on red blood cells, platelets, or neutrophils

Fig. 2

Summary of available therapeutic options for IMCs arising post-HSCT