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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

Late Effects	Risk Factors	Prevention and Screening Recommendations
Pulmonary complications:Chronic interstitial fibrosisIdiopathic pulmonary syndromeInfections (Bacterial > Fungal > Viral)	BCNU pulmonary toxicity:Cumulative doseHistory of lung diseaseAgeFemale genderDiagnosis of Hodgkin lymphomaChemotherapy‐resistant disease pretransplant General risk‐factors:Exposure to agents like bleomycin pretransplantPrimary diagnosis of AMLLow FVC pretransplantPoor KPS pretransplant	Clinical pulmonary assessment and smoking cessation advice at 6 month, 1 year, and then annuallyPulmonary function testing and chest radiography for new signs/symptoms [consider at 1 year for all high‐risk patients]
Cardiovascular complications:Congestive heart failureIschemic heart diseaseArrhythmiaValvular heart disease	Risk factors for CHF:Cumulative pretransplant anthracycline exposure ≥250 mg/m2HypertensionFemale sexDiagnosis of lymphomaAge at transplant Risk factors for CAD and cerebrovascular disease:≥2 traditional CV risk factors posttransplant, including obesity, hypertension, hyperlipidemia, and diabetesCyclophosphamide conditioningChest irradiation [specifically for CAD]Total body irradiation	Routine clinical assessment of CV risk factors at 1 year and at least yearly thereafterEarly detection and management of modifiable risk‐factors [hyperlipidemia, diabetes, hypertension, obesity, and smoking]Echocardiogram in symptomatic patientsTargeted screening of high‐risk patients with echocardiogram and/or electrocardiogram at periodic intervalsBehavioral modification and lifestyle interventions [increased fruit and vegetable intake, physical activity]Neurohormonal therapies [BB/ACEi/ARBs] for other compelling indications like CHF, DM type 2, proteinuria etc.
Secondary Malignancies:Secondary hematologic malignancySecondary solid tumors	Risk factors for t‐MN:Pretransplant radiation therapy≥4 chemotherapy regimens prior to transplant>5 days of apheresis to harvest adequate stem cellsMale sexCHIP Risk factors for solid tumors:Advanced ageExposure to radiation posttransplantAddition of rituximab to high‐dose therapyMelanoma risk: Male sex, age>45 years, and posttransplant relapse	Annual history and physical examination, including oral cavity, genitourinary, and skin examination at least until 10 years after transplantAnnual breast examination, mammograms, and MRIs beginning eight years after chest radiation or age 25Annual colonoscopy performed every 5 years beginning 10 years after radiation or age 35, whichever occurs lastFollow screening guidelines by USPSTF for breast, prostate, lung, and colon cancerAvoid high‐risk behavior e.g. smoking
Endocrine and Metabolic complications: Thyroid dysfunction Bone disease:Avascular necrosisOsteoporosis	TBINeck/thoracic radiotherapyElevated pretransplant TSH levelDiabetes mellitusLung diseaseCorticosteroid useHypogonadismDecreased physical activityRadiation	Thyroid function testing yearly posttransplant or when clinically indicatedDEXA scan at 1 year after transplant, then as clinically indicatedIncreased physical activity, healthy lifestyle, weight loss, smoking cessationCalcium and vitamin D supplementation in deficient patients
Kidney complications: Chronic kidney disease	Advanced ageHypertension	Measurement of serum creatinine, blood urea nitrogen, and urine protein at 6 months, 1 year, and then as clinically indicatedAggressive monitoring and management of hypertensionRenal imaging and/or biopsy as clinically indicated
Infectious Complications: Bacterial [Most common: pneumonia and sepsis]ViralFungal	Not well‐defined	Posttransplant immunizations per guidelinesProphylaxis for HZV until 6 months post‐transplant
Gonadal Dysfunction: Males: HypogonadismErectile dysfunctionLoss of libido Females:Ovarian suppressionLow libido	Exposure to pelvic or abdominal radiotherapyPrimary diagnosis of Hodgkin diseaseLow testosterone level → loss of libidoAdvanced ageTBIBusulfan	General recommendations: Monitor FSH, LH, and testosterone level for menClinical assessment for progression through puberty and prompt endocrinology referral if there is a delay Males:Discuss semen banking or cryopreservation of testicular tissue Females:Discuss cryopreservation of embryos, unfertilized egg, or ovarian tissue [use of GnRH agonists controversial]
HRQoL and Psychosocial Effects: AnxietyDepressionDistressDecreased HRQoL [multiple domains affected]	Primary MM diagnosis≥3 non‐malignant late effectsHigh‐risk diseaseOlder agePretransplant depression and energy level	Clinical assessment during transplant recovery period, at 6‐month, 1 year, and then annually

Abbreviations: BCNU: Carmustine. CHF: Congestive Heart Failure. CAD: Coronary Artery Disease. CV: Cardiovascular. t‐MN: Therapy‐related myeloid neoplasms. CHIP: Clonal Hematopoiesis of Indeterminate Potential. MRI: Magnetic Resonance Imaging. USPSTF: United States Preventative Services Task Force. TBI: Total body irradiation. DEXA: Dual energy X‐ray absorptiometry. HZV: Herpes Zoster Virus. GnRH: Gonadotrophin Release Hormone. AML: Acute Myeloid Leukemia. FVC: Forced Vital Capacity. KPS: Karnofsky Performance Score. BB: Beta blockers. ACEi: Angiotensin Converting Enzyme inhibitors. ARBs: Angiotensin Receptor Blockers. DM: Diabetes mellitus.

Pulmonary toxicity in the form of chronic interstitial fibrosis has been described with both busulfan and carmustine (BCNU), which are both common chemotherapeutic agents used as a part of conditioning prior to autologous stem cell infusion. Furthermore, certain chemotherapeutic agents used prior to AHSCT, like bleomycin for HL [9], can increase the risk of subsequent pulmonary fibrosis. A single‐institution study of 78 patients undergoing AHSCT for NHL with Busulfan and Cyclophosphamide (Bu/Cy) demonstrated pulmonary fibrosis in two patients (2.6%) at four‐ and 14‐months post‐transplant [10]. Notably, lung biopsy in the latter showed diffuse alveolar hemorrhage in proliferative phase which was consistent with late busulfan‐induced lung injury. Late pulmonary fibrosis after exposure to BCNU is well documented in childhood brain tumor survivors [11,12]. In a study of eight children with previous exposure to BCNU, six had radiographic changes consistent with upper zone fibrosis [11]. Four out of six children were symptomatic with shortness of breath, cough, or both. Furthermore, light and electron microscopy showed interstitial fibrosis and elastosis with damage to epithelial and endothelial cells in all six patients with radiographic abnormality. Unfortunately, all patients died within two years of first respiratory symptoms despite treatment with corticosteroids [11]. IPS represents a heterogeneous group of lung disorders characterized by lung injury without evidence of infection and include interstitial pneumonitis or diffuse alveolar hemorrhage (DAH) or both. BCNU has also been reported to be associated with IPS. Risk‐factors for development of BCNU‐induced pulmonary toxicity include cumulative dose, history of lung disease, duration of exposure, age and platelet count nadir after treatment [13]. Unlike chronic interstitial fibrosis, IPS typically happens early after transplant, with the time‐to‐onset in the context of allogeneic HSCT being 58 days (range, 9–112 days) [14]. A large study of approximately 5000 lymphoma patients receiving auto‐transplant demonstrated a 1‐year IPS incidence ranging from 3 to 6% depending on the conditioning regimen [15]. Notably, the incidence was lower at 3% with BEAM (BCNU (≈300 mg/m²), Etoposide, Cytarabine, and Melphalan) and CBV^low (Cyclophosphamide, BCNU (≈300 mg/m²), and Etoposide), but higher at 6% with CBV^high (BCNU (≈450 mg/m2)). Factors significantly associated with a higher incidence of IPS were higher BCNU dose, use of total body irradiation (TBI), diagnosis of HL, female gender, chemotherapy‐resistant disease pretransplant, and age>55 years. Furthermore, patients developing IPS had a higher transplant‐related mortality, shorter progression‐free survival (PFS), and overall survival (OS). Another study of 94 consecutive patients receiving auto‐transplant with BCNU‐based conditioning regimen showed a higher 1‐year incidence of IPS at 28%, the majority of whom had the episode within 6 months [16]. Notably, a dose‐response relationship was observed with the incidence of IPS increasing from 15% with BCNU dose to less than 475 mg/m² to 47% with doses greater than 525 mg/m². The risk of IPS in long‐term survivors is low, with an incidence of <1% in 2‐year auto‐transplant survivors of HL and DLBCL [6].

Given the incidence of lung toxicity after autologous transplant, clinical lung examinations are recommended at 6‐months, 1‐year and then yearly after transplant [17]. Patients at a high risk of late pulmonary complications, like those with prior exposure to bleomycin or history of lung disease, should also undergo pulmonary function testing at 1 year, and subsequently as clinically indicated [18]. All patients should receive posttransplant immunizations, especially pneumococcal and influenza to reduce the risk of respiratory tract infections [19].