Introduction to a review series on immunotherapies for nonmalignant hematologic diseases

Immunotherapeutics have transformed the treatment of malignant diseases and also afford major opportunities for treating diseases beyond cancer. In particular, the immune system is critical to the etiology of many human diseases caused by underlying autoimmunity, and therefore, novel and targeted immune-based therapies are increasingly being explored in this setting. In addition, the allogeneic hematopoietic cell transplantation (HCT) platform, considered a fundamental immune-based therapy, has successfully broadened its applicability and is now considered a curative treatment not only for patients with blood cancers but also for patients with nonmalignant disorders. As therapies such as immune checkpoint inhibitors (ICIs) have become standard of care for cancer, there is increasing awareness regarding the adverse immune impact to the hematopoietic system. This series provides an overarching review of these areas of increasing interest that use immune therapies (including transplantation) for treating nonmalignant diseases as well as understanding and treating the adverse effects of ICIs.

• ▪

  Eleni Gavriilaki, Régis Peffault de Latour, and Antonio Maria Risitano, “Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond”

• ▪

  Zachariah DeFilipp, Mehrdad Hefazi, Yi-Bin Chen, and Bruce R. Blazar, “Emerging approaches to improve allogeneic hematopoietic cell transplantation outcomes for nonmalignant diseases”

• ▪

  Michael H. Kroll, Cristhiam Rojas-Hernandez, and Cassian Yee, “Hematologic complications of immune checkpoint inhibitors”

In the first article, Gavriilaki and colleagues describe the recent therapeutic advances in targeting complement for treating hematologic diseases, including paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), as well as other hematologic disorders currently under investigation for complement inhibition and other complement-related disorders. They also discuss the therapeutic strategies that have evolved beginning with eculizumab (an anti-C5 humanized monoclonal antibody), which was introduced in 2007 and has now become standard of care for hemolytic PNH.

The second article, by DeFilipp and colleagues, focuses on the increasing use of allogeneic HCT as a curative strategy for congenital or acquired nonmalignant diseases (NMDs) of the hematopoietic system, including primary immune deficiency, hemoglobinopathies, and bone marrow failure syndromes. The authors discuss the broadening applicability of this approach with respect to the choice of donor grafts, an expanded donor pool including “half HLA-matched” (haploidentical) donors, and varying intensities of the conditioning regimens, depending on the underlying nonmalignant disease being treated. The authors discuss how the priority for HCT in the nonmalignant setting is to effect a cure without unacceptable toxicities such as graft-versus-host disease. They also provide a comprehensive overview of this field and specifically describe how novel treatments can support and enhance HCT as a curative and safe approach for patients with NMDs.

The third article in this series discusses the hematologic issues that develop after therapy with ICIs. Kroll and colleagues first acknowledge that ICIs have transformed cancer care since the approval by the US Food and Drug Administration of 7 such agents for the treatment of 16 malignant diseases, including Hodgkin lymphoma and primary mediastinal B-cell lymphoma. The primary mechanism of action of ICIs is to overcome tumor immune evasion by blocking the inhibitory signals generated by tumor ligand engagement of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) receptors expressed by cytotoxic T cells. However, with increasing knowledge and experience in treating patients with these agents, it is clear that ICIs elicit a more diverse immune response. Moreover, such complexities in the immune effects have led to immune-mediated hematologic complications including cytopenias, bone marrow failure, hemophagocytic lymphohistiocytosis, and venous thromboembolism. This review article provides insights into the mechanisms leading to such hematologic complications and offers a clinical approach for diagnosis, adverse event management, and strategies for re-treatment to optimize anticancer effects while mitigating toxicity.

We hope that this review series, which presents comprehensive overviews by leaders in the field, will prove useful for laboratory-based and clinical-based researchers and clinicians alike.

Conflict-of-interest disclosure: C.M.B. has stock or ownership/board membership with stock options in Mana Therapeutics, Cabaletta Bio, Catamaran Bio, Neximmune, and Repertoire Immune Medicines.