Blood and Marrow Transplantation Long Term Management. Группа авторов

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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].

Cardiovascular Complications

      Late cardiovascular complications after AHSCT include cardiomyopathy, valvular dysfunction, arrhythmia, ischemic heart disease, and subsequent congestive heart failure (CHF)⁷. In a retrospective cohort study of 1244 AHSCT recipients, the cumulative incidence of CHF was 4.8% at 5 years, 6.8% at 10 years, and 9.1% at 15 years [20]. Significant risk factors for the development of CHF were female sex, diagnosis of lymphoma, and age at transplant. Furthermore, AHSCT survivors had a 4.5‐fold excess risk of developing CHF compared to a demographically matched healthy population, with the absolute increase in risk being greatest in patients less than 35 years of age [20]. Notably, the risk of CHF was substantially higher

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