National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Abstract

Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists in order to reduce the burden of SN in the rapidly growing population of HCT survivors.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Patient-Centered Outcomes Working Group Report

“…Although there is sufficient evidence to conclude that active cGVHD predicts poorer outcomes, it is not yet convincing whether those with resolved cGVHD also have poorer outcomes. Moreover, like many late effects such as subsequent neoplasm or lower bone mineral density (169), more investigation is needed to determine whether cGVHD itself or its treatment is the cause of poor outcomes. Additionally, longitudinal cohort studies will clarify which patient-centered outcomes are persisting long-term complications that begin during HCT and continue into the years of survivorship or are late effects that have onset in the years after HCT, or as seen with PTSD, whether some outcomes may have either onset pattern.…”

Intrahepatic cholangiocarcinoma as a rare secondary malignancy after allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia: A case report

“…Older age at diagnosis may partly explain why ICC has not previously been reported as a secondary malignancy after HCT. In addition, the latency period for solid malignancies following HCT is typically long (≥10 years), with an increasing incidence with longer time after transplant . In this exceptional case, our patient developed ICC at age 26, just 3 years following HCT.…”

“…With the increasing rate of HCTs performed annually, as well as improved survival following HCT, secondary cancers have become a significant cause of non‐relapse mortality among HCT recipients . Although highly dependent on tumor histology, SMN has been demonstrated to account for up to 5%‐10% of late deaths in patients who survive more than 2‐5 years post‐transplantation .…”

“…In fact, patients with childhood ALL who survive at least 25 years from diagnosis have a five‐fold increased risk of SMN compared with the general population . Patients who undergo allogeneic HCT, which is an important component of treatment for those with high‐risk or relapsed disease, are at increased risk for SMN …”

Ovarian Sertoli–Leydig tumor after bone marrow transplant for sickle cell disease

“…Patients undergoing HSCT for any reason have a twofold higher risk of secondary malignancy compared to the general population. The risk of secondary malignancy may differ based on the primary disease, pretransplant conditioning regimen, and the presence of GVHD . Secondary malignancies are usually categorized into B‐ or T‐cell malignancies, or solid tumors.…”