Читать книгу Blood and Marrow Transplantation Long Term Management - Группа авторов - Страница 123

Iron overload occurs frequently after HCT [19,20], usually as a result of red blood cell (RBC) transfusions before and after HCT, ineffective erythropoiesis with intestinal hyperabsorption and, in some patients, underlying hereditary hemochromatosis (HH). Certain children are more at risk for iron overload and its consequences due to years of ineffective erythropoiesis before HCT (thalassemia, sickle cell disease) or, numerous RBC transfusions for marrow failure (Fanconi anemia [FA], Diamond‐Blackfan anemia [DBA], aplastic anemia) or relapsed hematologic malignancies. Once normal hematopoiesis is restored post‐HCT without need for RBC transfusions, body iron stores decline over several years [21]. However, accumulated iron may be high enough that intervention is recommended to prevent liver and cardiac failure.

Liver and marrow iron content correlates poorly with a number of transfused RBC units. This, plus the fact that elevated serum ferritin (also an acute phase reactant) can be seen with GVHD, recurrent malignancy or infection, makes it challenging to determine who needs simple observation versus aggressive intervention for iron overload. The most accepted way to quantify hepatic, cardiac (and pancreatic) iron overload is by T2*MRI which provides a measurement of liver iron content (LIC) in mg/g dry weight liver [22,23]. However, for patients without significant RBC transfusion history (or HH), T2*MRI is an unnecessary expense; elevated serum ferritin with normal transferrin saturation can be treated by avoidance of iron‐containing multivitamin ± simple phlebotomy, until serum ferritin has normalized. T2*MRI testing is best utilized for survivors with a lifetime history of ≥20 RBC units (often >50), thalassemia, SCD, DBA, HH (carrier frequency for homozygous High Fe [HFE] gene mutation is 0.3–0.5% among individuals of Northern and Western European ancestry), a need for iron chelation before HCT, or chronic hepatitis C were iron overload may accelerate cirrhosis. Patients with thalassemia, SCD, DBA, HH require aggressive evaluation and management beginning ideally 6 months post‐HCT.

Table 8.1 LTFU recommendations for survivors

Organ System or Late Effect	Recommendations:	Qualifiers and other comments:
Engraftment	Annual CBC, MCV ± reticulocytes	More frequently, if persistent or progressive abnormalities that may be due to medications, infection, GVHD, relapse
Flow cytometry‐sorted lineage specific donor chimerisms	Minimum of annual in NMDs where long‐term graft stability is unclear (especially after NMT or RIC)SCD: check myeloid chimerism q3–6 months for 2 years, then yearly with HbS levelThalassemia: if microcytic anemia recurs check chimerism as for SCDUsually unnecessary in malignant diseases unless as a baseline before DLIUsually check chimerism in granulocytes and T cells, plus B and NK cells as applicable in NMD or PIDMixed chimerism undesirable for DBA and WAS (risk AML, MDS)
Iron overload	Ferritin, transferrin saturation (TS)	Check at day 80–100, 1 year, then annually until normalBe mindful of ferritin as an acute phase reactantConsider HFE gene testing if a family member has been diagnosed with HH or TS >45% in a patient of Northern or Western European ethnicityFA, DC, DBA, hemoglobinopathies require more aggressive management beginning at 6 months
	T2*MRI	Gold standard to quantify tissue iron‐burden, annual for DBA until resolved
cGVHD	Screen monthly while on IST, then q3 month x 2 years after IST stops	Screening includes GVHD‐focused history and physical [122] directed at skin, mouth, eyes, GI tract, genitalia, lungs (PFT frequency – see below), LFTs and P‐ROM
Infection and immunity	IgG, IgA, IgM	If history of chronic conjunctivitis, sinopulmonary infections, other recurrent, unusual, or severe infectionsNormalization of IgA, IgM plus increasing trough IgG levels before next IgG‐replacement dose due tracks with humoral recovery – especially in PIDs where replacement is routine
Peripheral blood T‐ and B‐lymphocyte counts	Some centers use arbitrary cut‐offs (CD4 >200 per microliter, CD19 >20 per microliter) for early vaccination beginning at Day 180 [38]
Routine vaccinations	DTaP, IPV, Hib, PCV13, PPSV23, MCV4, Hepatitis A and B, seasonal influenza, MMR, and risk‐based GpB meningococcus and HPV9 [38]. HPV vaccination from age 9–11 years up to age 26 (consider up to age 45 through shared clinical decision‐making in some cases) [123, 124]
Serum viral PCR testing	As clinically indicated and may include serum PCR for CMV, EBV, HHV6, hepatitis B, C, HIV (HIV, HCV if exposed to blood products prior to universal testing)
Pitted RBC score and liver‐spleen scan (periodic)	SCD: ECO prophylaxis until splenic regeneration proven by liver‐spleen scan, pitted RBC score <1.5% and PCV13 and PPSV23 vaccinations completeThalassemia: If splenectomized need ECO prophylaxis life‐long [15]
Ocular	Annual full eye examination	Ask about vision, dry or gritty eyes, diplopia, halosFull eye exam focuses on cataracts (TBI, steroids, infection), retinal exam essential for late CMV staging or other infectionsFA: screen for vision, cataracts. DC: screen for vision, lacrimal duct stenosis, retinal pathology, and cataracts
Hearing	Annual audiology or per audiologist recommendations	If platinum exposure or had >30 Gy cranial radiation: testing advised through age 10 y or 5 y post‐HCT whichever occurs laterIf underlying HCT indication is FA or DC
Oral	Dental examinations and cleanings every 6 months. Educate on routine dental hygiene.	Ask about xerostomia, chewing difficulties, swallowing and speaking.Antimicrobial endocarditis prophylaxis per AHA guidelines
Baseline panorex	Special pediatric risks in the developing mandible, especially below age 6 years, include hypodontia, microdontia, enamel hypoplasia and root malformation
SMN screening Avoid oral tobacco	Minimum annual (see SMN below for more details)Increased risk for oral cancers if received TBI, had oral GVHD, or underlying FA or DC
	HPV vaccination	See under “Infection and Immunity” above
Pulmonary	Full PFTs at 3, 6 months, for 5 years annually or until adult (whichever is later)	Spirometry alone is usually feasible age >6 yearsPFTs at cGVHD diagnosis then every 3 months for 1 year, then at least annually while on ISTHigh‐resolution chest CT with inspiration and expiration to confirm air‐trapping and BOS (consider non‐parametric response mapping for age <6 years if unable to do PFTs)DC: lifelong lung symptom screening and annual PFTs because high‐risk for pulmonary fibrosis and pulmonary arteriovenous malformation (see also Cardiovascular)
Cardiovascular or metabolic	Blood pressure each visit, fasting blood glucose (or HbA1c) fasting cholesterol (LDL, HDL) and triglycerides, annually while on IST, then at least every 5 years	Early treatment of CVS risk factors like diabetes hypertension, dyslipidemiaIf patient had cranial TBI then screen neurocognitivelyCardiovascular risk assessment tools: https://ccss.stjude.org/cvcalc
Risk‐based ECG with echocardiogram Thalassemia, SCD: 1‐year check TRJV to rule out pulmonary hypertension and measure pulmonary arterial pressure if TRJV >3 m/s to confirm pulmonary hypertension	Use COG risk assessment tool to determine frequency: http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdfReferral to cardiology for abnormal or declining cardiac function. FA and DBA may also have congenital cardiac anomalies and cardiac iron‐overload (may need T2*MRI)Patients with pulmonary hypertension should be referred to a pulmonologist
Body composition by DEXA	Can also be done by anthropometry (arm‐muscle‐area, arm‐fat‐area)
GI or hepatic	ALT, bilirubin (direct and indirect), alkaline phosphatase, albumin PT/INR, albumin to assess liver synthesis as needed Liver biopsy (selective)	DC: surveillance for liver fibrosis and GI bleeding, ulceration, telangiectasias, varices as clinically indicatedThalassemia or SCD: Consider liver biopsy at 2 years if bridging fibrosis present before HCTConsider liver biopsy at 2 years for patients who had hepatitis B or HCV before HCTRefer patients who have HCV or HBV infection to gastroenterologist or infectious disease specialist for consideration of antiviral therapy
Liver ultrasound	If high‐risk for hepatocellular carcinoma (HBV, HCV, obesity, diabetes, low platelets)
Renal or genitourinary	Blood pressure Serum creatinine, BUN	FA, DC, DBA: follow‐up congenital genitourinary anomalies with a urologist and renal abnormalities and renal function with a nephrologistDC: exam for urethral stenosis
Urine microalbumin: creatinine ratio	If >30 mg/gm and <300 mg/gm, repeat with at least two tests in 3–6 monthsIf >300 mg/gm repeat every 3–6 monthsIf >300 mg/gm on one occasion or if >30 mg on 3 occasions within 6 months and has hypertension, consider treatment with an ACEI or ARB
Renal biopsy	If suspect TMA or unexplained kidney disease.
Musculoskeletal	Serum CPK, aldolase, CRP, ESR	If investigating cGVHD‐associated myositis/myopathy, or following myopathy/myositis while on tapered IST
Spine X‐ray	FA: screen for scoliosis
Bone health	DEXA to evaluate BMD at 1 year then annually if abnormal	DBA: can have significantly poor bone health (iron overload, endo, steroids)DC: commonly have osteoporosis
Vitamin D level annual while on IST or in growing child	Optimize calcium + vitamin D intake
MRI to rule out or stage AVN	Refer to Orthopedics if MRI confirms AVN findings
Skin	Examine for GVHD and subsequent neoplasms	See also “cGVHD” and “Subsequent Neoplasm” sections in this table for details
Endocrine	Plot height, weight, growth velocity, BMI on growth charts at least annually Bone age (left wrist) peri‐pubertally and before final adult height Evaluate suspected nutritional deficiency, obesity or sarcopenic obesity*	Evaluate for GH deficiency if reduced height velocity >1‐year post‐HCT. Refer to endocrinology if suspect GH deficiency especially if pre‐pubertalFA: full endocrine evaluation including GH levels (potentially with stimulation testing), IGF1, IGFBP3, Tanner staging and bone ageThalassemia: hypogonadism is common due to iron‐overload and busulfan or treosulfan‐based conditioning
Free T4, TSH annually	Full‐dose TBI, and to lesser extent high‐dose targeted BU particularly at risk for thyroid dysfunctionIf high TSH and normal Free T4, repeat in 2 monthsThyroid hormone replacement if high‐TSH/low T4 or persistently very high or progressively elevated TSH. Use lowest dose to achieve a mid‐normal range TSH
Annual Tanner stage From age 11 years, serum FSH, LH, estradiol (girls), free serum testosterone (boys) annually	Full dose TBI, high‐dose targeted busulfan, at higher risk for delayed puberty as well as patients with FA, DBA, DC and those with severe‐iron‐overloadRefer to endocrinologist, gynecologist, or urologist with abnormal pubertal timing or gonadal dysfunctionTreat ovarian failure with hormone replacement therapy
Infertility	Consider anti‐Mullerian hormone (AMH) to assess ovarian reserve if >25 years of age	Thalassemia: young pre‐pubertal less at risk (gonadal dormancy and shorter iron‐overload exposure)Referral to reproductive endocrinology, gynecology, urology as neededConsider semen analysis if age‐appropriate older male seeks fertility potential
Neurocognitive	Developmental milestone screen Educational or vocational progress Consider formal neuropsychological testing at 1 year or later	Neuropsychological test results may help develop a suitable individualized educational plan (IEP)Very high‐risk: >12 Gy TBI ± cranial radiation < age 4 y, FA, DC, DBA with craniofacial abnormalities and large ribosomal protein gene deletions, ALD, Hurler syndrome, SCD, and some forms of SCID
SCD: Brain MRA/MRI at 1‐year if pre‐HCT moya moya or stroke	Repeat every 2 years as clinically indicated
Ask about neuropathy symptoms	Gabapentin, pregabalin therapy might be indicated
Psychological, quality of life	Screen at least annually for pain, fatigue, sleep disturbance, anxiety, depression, social reintegration, non‐adherence to health recommendations and medications, and high‐risk behaviors	If positive depression screen, ask about suicidal ideationFA, DC, DBA: genetic counseling for patient and family, assistance with family planningCounseling about living with chronic conditions
Subsequent neoplasms	Baseline (general population screening guidelines): Full physical by healthcare provider yearly Urinalysis for hematuria Protect against sunlight and avoid excessive UV or radiation exposures	Special high‐risk diagnosis screening:DC: ENT with nasolaryngoscopy yearlyDBA: screening for luminal GI cancers, osteosarcoma [124]FA due to mutations in FANCD1/BRCA2 or FANCN/PALB2 need genotype specific cancer screening because of increased risks of medulloblastoma, Wilms tumor and other cancersLi Fraumeni (TP53 screening): complete physical examination every 3–4 months with blood pressure, anthropometry, evaluation for precocious puberty, and full neurologic examination. Imaging includes abdominal and pelvic ultrasound (± serum testosterone, DHEA and androstenedione) every 3–4 months, annual whole‐body MRI including brain (initially with contrast and thereafter without contrast if previous MRI normal and no new abnormality) [114]Liver US every 6 months if HBV+ or cirrhosis
Thyroid palpation annual	Rare thyroid tumors post‐TBI can often be cured with surgery
Full skin examination at least annual for BCC, SCC, melanoma.	If received full dose TBI or in FA, DC, skin screening by dermatologist every 6–12 months (increased risk SCC of head, neck, anogenital)
Oral examination annual	FA, DC: oral, skin, ENT examinations every 6 months.
Mammogram annual begins at age 40 Gynecology evaluation with PAP beginning age 18–21 HPV vaccination (see “Infection and Immunity” above	Chest wall radiation, BRCA1/2, ATM gene mutations: annual mammogram (or MRI in some) starting age 25 or 8 years after radiation (whichever later but not age >40)Gynecology examinations might start sooner in girls with cGVHDFA: Annual gynecologic evaluation for PAP smear and HPV screening, starting in the early teenage years

Abbreviations: AHA, American Heart Association; ALD, adrenoleukodystrophy; AML, acute myelogenous leukemia; AVN, avascular bone necrosis; BCC, basal cell carcinoma; BMD, bone mineral density; BMI, body mass index; BOS, bronchiolitis obliterans syndrome; CBC, complete blood count; cGVHD, chronic graft versus host disease, CPK, creatine phosphokinase; CRP, C‐reactive protein; DBA, Diamond‐Blackfan Anemia; DC, dyskeratosis congenita; DLI, donor lymphocyte infusion; DTaP, diphtheria‐tetanus‐acellular pertussis; ECG, electrocardiogram; ECO, encapsulated organism; ESR, erythrocyte sedimentation rate; FA, Fanconi anemia; Free T4, free thyroxine; GH, growth hormone; GVHD, graft versus host disease; HDL, high density lipoprotein; HH, hereditary hemochromatosis; HFE, high ferrous gene; HPV9, 9‐valent human papilloma virus vaccine; IGF‐1, insulin‐like growth factor 1; IGFB3, insulin‐like growth factor binding protein 3; IPV, inactivated polio vaccine; IST, systemic immunosuppressive therapy; LDL, low density lipoprotein, LFT, liver function tests; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; NMD, non‐malignant disease; NMT, nonmyeloablative transplantation; PCV13, 13‐valent pneumococcal‐conjugated vaccine; PID, primary immunodeficiency disease; PFT, pulmonary function tests; PPSV23, 23‐valent pneumococcal‐polysaccharide vaccine; P‐ROM, photographic range of motion assessment; RIC, reduced intensity conditioning; SCC, squamous cell carcinoma; SCD, sickle cell disease; SCID, severe combined immunodeficiency disease; TSH, thyroid stimulating hormone; TRJV, tricuspid regurgitation jet velocity; WAS, Wiskott Aldrich Syndrome.

Extreme iron overload (LIC >15) is aggressively treated to mitigate risks for dysrhythmias and cardiac failure, portal fibrosis and cirrhosis, diabetes mellitus and other endocrinopathies. Iron overload also increases susceptibility to infections due to mucor, aspergillosis, Listeria monocytogenes, non‐cholera Vibrio species, and Yersinia enterocolitica, among others [20,24]. LIC >15 is usually treated by monthly phlebotomy ± an iron chelator. LIC 7–15 is treated with phlebotomy or, second choice with a single iron chelator. When LIC is 2–7, observation is acceptable unless the patient has HH, in which case, phlebotomy aiming for ferritin <100 ng/mL is the goal. Phlebotomy is a generally safe and cost‐effective approach but requires adequate venous access and normal hematopoiesis (hematocrit ≥35%), or hematopoiesis that can respond to weekly erythropoietin or every‐other‐week darbepoietin. A typical phlebotomy regimen is 3–5 mL/kg/month as tolerated until LIC<7 (non‐HH patient) or ferritin <500 ng/mL (<100 ng/mL if HH). If phlebotomy cannot be performed within 3–6 months of HCT and iron mobilization is indicated, iron‐chelator therapy can be used but caution is required due to added toxicities associated with the currently available chelators. Mobilization of iron in heavily overloaded patients improves cardiac function, normalizes serum alanine aminotransferase (ALT) levels, and results in improved liver histology [25,26].