National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report

Abstract

Immune reconstitution following hematopoietic stem cell transplantation (HCT) beyond one year is not completely understood. Many transplant recipients who are free of graft versus host disease (GVHD) and not receiving any immunosuppression more than a year after transplant seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, two large registry studies over the last two decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multi-national registry of clinically significant infections (e.g., vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar driven and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis and definitions of infections would be of paramount importance to obtain clean, reliable data. Laboratory studies should specifically address the neogenesis, maturation and exhaustion of the adaptive immune system and in particular how these are influenced by persistent alloreactivity, inflammation and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefit as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.

Safety and immunogenicity of conjugate quadrivalent meningococcal vaccination after hematopoietic cell transplantation

“…Retrospective data suggest that the immune responses to the MCV4 vaccine are poor after HCT and that a 2-dose regimen may be required to achieve protective antibody titers 6 ; however, the immunogenicity of a single-or multiple-dose vaccine regimen has not been prospectively evaluated. Given the knowledge gaps regarding the safety and immunogenicity of MCV4 after HCT, 7 we conducted a vaccine response study among adult HCT recipients.…”

Long-Term Survivorship after Hematopoietic Cell Transplantation: Roadmap for Research and Care

“…Optimal immune reconstitution has been operationally defined as the restoration of functional pathogen-specific immunity and establishment of anticancer immunity without dysregulation by GVHD and/or HCT-associated autoimmunity [18]. Factors influencing immune reconstitution include age, underlying disease, immunosuppressive state, prior infections, conditioning regimen, donor type, degree of match, stem cell source, immunosuppression, anti-infective practice, GVHD, viral infections, and therapies to prevent relapse [59–63].…”

“…To address delayed infectious mortality, it is critical to understand the pathogens responsible, the risk factors, and immunologic correlates. A long-term, multicenter, prospective study with samples collected for immunologic testing has been identified as a critical priority [18]. Such a study will also allow, as an adjunct, the measurement of microbiota changes after HCT and the association of such changes with late infections and immunity.…”

“…The scope was limited to the most important challenges that would advance the science or change guidelines/clinical care/standard approach [13]. Six broad areas of emphasis were identified, as follows: health care delivery [14]; research methodology and study design [15]; subsequent neoplasms (SN) [16]; quality-of-life and psychosocial outcomes [17]; immune dysregulation [18]; and cardiac, vascular, and metabolic events [19]. Working groups involved international experts, representation of adult and pediatrics, subject matter experts, governmental agencies, advocacy groups, and transplantation societies.…”

Contemporary analysis of functional immune recovery to opportunistic and vaccine‐preventable infections after allogeneic haemopoietic stem cell transplantation

“…However, it is becoming evident that the timing of vaccination would be more appropriately based on each patient's capacity to respond to vaccine antigens. Evolving data suggest that such immune responses can be measured . However, a more detailed analysis is required prior to developing novel vaccine schedules to better guide effective vaccination post‐alloHSCT.…”