patients with AL amyloidosis receiving high‐dose melphalan conditioning prior to AHSCT, the decision to administer a melphalan dose <200 mg/m2, pretransplant left ventricular ejection fraction of <60%, and involvement of amyloid in three or more organs were significantly associated with cardiac dysfunction at 4 months posttransplant [21].
A case‐control study on 249 patients surviving 1+ year after transplant identified pre‐and posttransplant risk factors for coronary artery disease (CAD) and cerebrovascular disease22. Around 65% of patients in this study were AHSCT survivors. Two independent risk factors for development of late cardiovascular disease were identified: ≥2 traditional risk factors including obesity, hyperlipidemia, hypertension, and diabetes posttransplant (5‐fold increased risk) and conditioning with cyclophosphamide (2.5‐fold increase in risk). Furthermore, pretransplant chest irradiation was associated with an almost 10‐fold increased risk of CAD [22]. Notably, neck or cranial irradiation was not associated with an increased risk of cerebrovascular disease. The incidence of cardiovascular risk factors such as hyperlipidemia and diabetes are greater in transplant survivors compared to healthy controls [23]. Exposure to TBI can also lead to an increased incidence of hypertension and diabetes in transplant survivors, leading to downstream cardiovascular complications [24].
The risk of late deaths due to cardiac complications in AHSCT survivors is higher in females (SMR 4.4 compared to a demographically matched healthy population) [8]. Guidelines for monitoring patients for late cardiac and cardiovascular complications have been previously published [17,18]. Briefly, AHSCT survivors should undergo routine clinical assessment for cardiovascular risk factors at one year and at least yearly thereafter in a survivorship clinic to identify and intervene on modifiable risk‐factors such as hypertension, hyperlipidemia, smoking, obesity, and diabetes. In patients with a high risk of atherosclerotic cardiovascular disease (≥10% at 10 years), treatment of hypertension should be initiated at a threshold of 130/80 mmHg, with the treatment threshold for remaining patients being 140/90 mmHg [25]. A meta‐analysis of 17 randomized controlled trials testing neurohormonal therapies (β‐blockers, mineralocorticoid receptor antagonists, or angiotensin converting enzyme inhibitors/angiotensin receptor blockers) against placebo in adult patients receiving chemotherapy showed a statistically significant but clinically modest increase in left ventricular ejection fraction (LVEF) with neurohormonal therapies [26]. Notably, there was substantial heterogeneity between studies and the clinical significance of a modest LVEF increase is unclear. Hence, with limited evidence on the efficacy of neurohormonal therapies for prevention of chemotherapy‐induced cardiotoxicity, these drugs should be administered to AHSCT survivors only for other compelling indications (e.g. angiotensin converting enzyme inhibitors in diabetes and beta‐blockers in well compensated CHF). Longitudinal monitoring of global longitudinal strain, in addition to ejection fraction, can help identify early or subclinical cardiotoxicity from chemotherapy [27]. In patients with LDL‐C (Low Density Lipoprotein‐Cholesterol) more than 190 mg/dl (4.91 mmol/l) or at a high risk of atherosclerotic cardiovascular disease, high‐intensity statin therapy should be initiated [28]. The HbA1c goal for patients with diabetes mellitus should be individualized, based on age, and comorbidities and co‐management with an endocrinologist should be considered. Identification of novel risk factors for CAD like clonal hematopoiesis of indeterminate potential (CHIP) [29] can help identify high‐risk patients who would benefit from targeted screening and early intervention.
Secondary Malignancies
Development of therapy‐related hematologic and solid tumors is an important late complication after AHSCT and is the second leading cause of death in survivors [8]. In a large study on patients surviving ≥2 years after AHSCT, one‐fourth of late deaths were caused by secondary malignancies, with the most common entity being therapy‐related myeloid neoplasms (t‐MN) including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) [8]. Literature on incidence and risk factors for development of t‐MN after AHSCT has been mostly described in the context of primary lymphoma diagnosis [30–32]. A single‐institution study of approximately 500 patients undergoing AHSCT for lymphoma demonstrated a 7% actuarial incidence of t‐MN at 10 years [31]. Risk factors for t‐MN include pretransplant exposure to radiation therapy, four or more chemotherapy regimens prior to transplant, and apheresis duration of more than 5 days to collect enough stem cells. Another Italian study on more than 1000 transplant survivors with HL, NHL, and T‐cell lymphoma showed the cumulative 5‐ and 10‐year incidence of t‐MN to be 3.09 and 4.52% respectively [30]. Risk‐factors for t‐MN in this study were male sex and the use of second harvest peripheral blood stem cells. Stem cell mobilization with etoposide in lymphoma AHSCT recipients confers a 12‐fold increase in risk of t‐MN with 11q23/21q22 abnormalities [32]. Furthermore, the latency between exposure to etoposide and development of t‐MN is lower (2–3 years) compared to that after exposure to alkylating agents (≈5 years). Pretransplant CHIP is a novel risk factor for subsequent t‐MNs and is present in 30% of lymphoma patients prior to AHSCT [33]. In a cohort of 401 NHL patients undergoing AHSCT between 2003 and 2010, the 10‐year cumulative incidence of t‐MN in patients with and without CHIP was 14.1% and 4.3% respectively [33]. The median time to diagnosis of t‐MN was around 4 years from AHSCT. Patients with more than one CHIP mutation had a 17% risk of t‐MN compared to 4% in those with one mutation. Presence of CHIP was an independent predictor of t‐MN on multivariable analysis, along with exposure to a nucleoside analogue and lifetime dose of cyclophosphamide exceeding 10 g/m2. Furthermore, patients with CHIP had an inferior overall survival at 10‐years compared to those without (30% vs 61% respectively), attributable to increased death from t‐MN as well as cardiovascular disease [33].
Therapy‐related solid cancers account for approximately 10% of late deaths after AHSCT, with the most common fatal solid cancer being unspecified adenocarcinoma [8]. The 5 and 10‐year cumulative incidence of solid tumors after lymphoma AHSCT in the rituximab era is 2.54% and 6.79% respectively. Risk factors for development of solid tumors are advanced age, exposure to radiation posttransplant, and the addition of rituximab to high‐dose therapy [30]. Frequent solid cancers noted in this study were that of lung, gastrointestinal (GI) tract, skin, head and neck, breast, and urinary bladder. An Australian study on 7765 AHSCT survivors found an increased risk of melanoma (standardized incidence ratio [SIR: 2.6]), NHL (SIR: 3.3), and t‐MN (SIR: 20.6) compared to the general population at a median follow‐up of 2.5 years [34]. Notably male sex, age>45 years, and posttransplant relapse of primary malignancy predicted melanoma risk in this study.
Transplant survivors should be counseled regarding the risk of secondary malignancies and educated about the signs and symptoms. All patients should undergo yearly physical examination and laboratory testing as clinically indicated at least up until 10 years after transplant. United States Preventative Services Task Force (USPSTF) guidelines should be followed for screening for subsequent cancers, including mammography for breast cancer, low‐dose chest computed tomography (CT) for lung cancer in high‐risk patients, prostate‐specific antigen for prostate cancer, and colonoscopy for colorectal cancer [27]. In females with exposure to chest radiation, annual breast examination, annual mammograms, and MRI scans should be considered beginning eight years after radiation or age 25, whichever occurs last [18]. Similarly, in patients exposed to TBI, colonoscopy should be performed every 5 years beginning 10 years after radiation or from age 35 [18]. The risk of secondary malignancies can change dynamically after transplant depending on posttransplant therapies (e.g. lenalidomide maintenance in MM, which will be discussed in greater detail below). Hence, continued monitoring of these patients and communication between the transplant physician and the treating oncologist is crucial for optimal surveillance.
Endocrine and Metabolic Complications
Thyroid Dysfunction
New‐onset thyroid disease is one of the most common non‐malignant late effects after AHSCT, with a cumulative incidence of 14.2% [3]. The median time to diagnosis from transplant is approximately 1 year [3]. A Spanish study on 169 AHSCT survivors has identified thyroid dysfunction in 62 (37%) patients, with subclinical hypothyroidism,
