Blood and Marrow Transplantation Long Term Management. Группа авторов

CHAPTER 7 Late effects post‐autologous hematopoietic stem cell transplantation

       Rajshekhar Chakraborty1 and Betty K. Hamilton2

      ¹ Hematology/Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

      ² Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

Introduction

      The number of autologous hematopoietic stem cell transplants (AHSCT) has been increasing since the early 2000s, with approximately 14 000 AHSCTs performed in the United States (US) in 2015 according to data from the Center for International Blood and Marrow Transplant Research (CIBMTR) [1]. The increase in activity has been attributed to a rise in the number of AHSCTs performed for plasma cell disorders (PCDs) and lymphoproliferative neoplasms, as well as an increasingly liberal age threshold for AHSCT [1]. In adults, the most common indication for AHSCT is multiple myeloma (MM), followed by non‐Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). In children, the most common indication for AHSCT is solid tumors, followed by HL, and NHL. With increasing activity, the number of AHSCT survivors are projected to increase from 67 000 in 2009 to approximately 200,000 in 2025 [2]. As many AHSCT recipients are followed by local physicians after the first few months after transplant, late complications can be difficult to follow, and thus, transplant and cellular therapy physicians as well as non‐transplant hematologist/oncologists will have to increasingly monitor and manage late effects in this growing population. Ideally, patients should be followed in a dedicated survivorship clinic to monitor and provide guidance on the screening of late effects.

      Exposure to chemotherapy and/or radiation prior to transplant, in the conditioning regimen, as well as post‐transplant, collectively determine the nature, frequency, and severity of late effects in AHSCT survivors. Approximately 45% of AHSCT survivors have at least one non‐malignant late effect at 5 years, with 2.5% having three or more late effects³. The three most common organ systems impacted by non‐malignant late effects in AHSCT recipients are bone, thyroid, and lung [3]. The risk of death in long‐term AHSCT survivors approaches that of the general population at 10 years and the frequency of non‐relapse mortality exceeds that of relapse mortality after 10 years [4]. Common causes of late non‐relapse mortality include secondary malignancies, cardiovascular, and pulmonary diseases [4].

In this chapter, we will summarize system‐specific late effects in auto‐transplant survivors. We will describe the incidence, risk factors, pathobiology if known, prevention, and management of late effects. Common late effects, known risk factors and consensus screening or monitoring guidelines has been summarized in Table 7.1. Subsequently, we will focus on two of the most common indications for auto‐transplant, i.e. MM and lymphoma, and describe late effect considerations specific to those diseases.

Pulmonary Complications

      Pulmonary complications are observed in approximately one‐quarter of patients after AHSCT, with 50% being infectious, 37% non‐infectious, and 13% both infectious and non‐infectious [5]. The most common infections observed after AHSCT are bacterial, followed by fungal, and viral pneumonias [5]. While the majority of infectious complications occur within the first few months of transplant, opportunistic bacterial, viral, and fungal infections may still occur late, especially in patients on prolonged immunosuppression (e.g. MM patients on prolonged corticosteroids). Similarly, non‐infectious complications are also reported to occur most commonly early (within 3 months) post‐transplant [5], though, late complications do occur, with a reported incidence of pulmonary complications (interstitial pneumonitis, bronchiolitis obliterans, pulmonary hemorrhage) of 14%, ≥ 2 years post‐AHSCT [6].

Common non‐infectious complications include acute pulmonary edema, diffuse alveolar hemorrhage, peri‐engraftment respiratory distress syndrome, idiopathic pneumonia syndrome (IPS), and acute lung injury/acute respiratory distress syndrome [5,7]. Furthermore, the cumulative incidence of obstructive or restrictive lung disease after AHSCT is 8.2%, with the median time to diagnosis from transplant being 369 days [3]. The mortality risk following pulmonary complication is greatest in the first six months, with a 1‐year cumulative mortality of 30.5% [5]. Among two‐year survivors of AHSCT for acute leukemia or lymphoma, the risk of late death due to pulmonary dysfunction is approximately six‐fold compared with the general population [8]. Notably, male sex and HL survivors are at a higher risk of pulmonary complications leading to late death (Standardized Mortality Ratio [SMR] of 6.7 and 29.2 respectively) [3].

Table 7.1 Common Late Effects and Complications after Autologous Hematopoietic Cell Transplantation