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More than half a million HCT survivors are estimated by 2030 due to improvements in HLA‐typing and supportive care [1]. Unfortunately, among HCT‐recipients who survive at 2 years without recurrence of their original disease indication for transplant, there is a four‐ to nine‐fold increased mortality rate for 5‐year survivors relative to an age and sex‐matched general population [2–5].

This can be attributed to an increased cumulative incidence (CI) of chronic health conditions among HCT survivors; in one study 66% had at least one chronic health condition and the 10‐year CI for severe/life‐threatening conditions or death as result was 35% (95%CI, 32–39%). HCT survivors were 3.5 times as likely as siblings to develop a severe/life‐threatening condition, this was amplified further among those survivors with chronic graft‐versus‐host‐disease (cGVHD) [6].

All HCT late effects result from varying degree of interaction between underlying diagnosis, pre‐HCT exposures to chemotherapy and radiation, and post‐HCT complications including GVHD, immunodeficiency and medications (Figure 8.1). Risks for late effects are modified by other intrinsic and extrinsic factors like age, sex, genetics, underlying disease, social factors, comorbidities and lifestyle which can do so in a positive or negative manner.

The cGVHD burden cannot be overemphasized given its potential for protean manifestations over several years, especially with morbid forms that can include tissue sclerosis, joint contractures, bronchiolitis obliterans and failure thrive. Given that clinical immunologic tolerance may take years rather than months [7,8], toxicities arising from immunosuppressive therapies (IST) as well as medications used to treat side effects of IST can contribute to chronic health conditions per se, for example, hypertension, dyslipidemia, and chronic renal insufficiency to name a few.

Therefore, there is an increased focus on late complications that cause morbidity, mortality and quality‐of‐life impairments. Early detection and preventive efforts aim to recognize and mitigate patient‐, disease‐, or BMT‐related risk factors. A major barrier to these efforts is that long‐term follow‐up (LTFU) termination attenuates with extended follow‐up. A Japanese study of almost 18 000 survivors observed that 28% were lost to follow‐up by 10 years; 67% by 25 years [9]. Given that many HCT late effects have latency periods of 7–20 years, and children are generally expected to have longer life expectancy compared to their adult counterparts, this observation warrants a robust mitigation plan. Multivariate risk factors for LTFU termination include being aged 15–29 years, female, have standard risk malignancy or non‐malignant disease as the underlying reason for HCT, unrelated donor, and cGVHD. LTFU termination was mostly physician‐directed and based upon a patient being in good medical condition. Better physical condition might explain higher risk for LTFU termination among females; another study also suggested a greater concern for medical costs among females that might contribute to this observation [10]. Education of stakeholders must emphasize adherence to LTFU regardless of whether a young adult survivor appears well. Cooperation is needed between pediatric and adult systems to mitigate this known “lost in transition” phenomenon.

There are few large‐scale studies or randomized trials to guide LTFU recommendations. Consortia have published organ‐system categorized guidelines based on expert opinion or limited high‐quality evidence. They are HCT‐focused and relatively concise but for a given complication they lack granularity regarding pre‐HCT treatment exposures and/or age [11]. By contrast, Children’s Oncology Group (COG), provides more granular LTFU guidelines specifically for survivors of childhood, adolescent, and young adult cancers but not exclusive to HCT survivors [12]. COG consensus guidelines, developed by a panel of experts, are updated every 5 years and version 5.0 was released in October 2018. Unlike joint society guidelines, COG organizes LTFU by therapeutic exposures and their impact on various organ systems, which is pertinent to this heavily pretreated population. Sixteen sections address HCT‐specific late effects, including 9 GVHD‐focused sections. COG also developed an HCT Task force to provide organ system categorized HCT [13].

The International Guideline Harmonization Group (IGHG) is a collaboration of UK Children’s Cancer and Leukemia Group (CCLG), Dutch Childhood Oncology Group (DCOG), Scottish Intercollegiate Guidelines Network (SIGN) and COG that has so far published harmonized color‐ coded (green, yellow, orange, red) evidence‐based LTFU surveillance recommendations for breast cancer, cardiomyopathy, premature ovarian insufficiency, male gonadal toxicity, thyroid cancer and ototoxicity [14]. Recognizing that general oncology survivorship guidelines give insufficient focus for HCT survivors, especially regarding high‐dose conditioning, effects of GVHD and its management, and non‐malignant diseases (NMD), PBTCT convened a late effects consensus conference in 2016 to develop detailed HCT‐specific late effects guidelines for hemoglobinopathies, SCID and BMFS [15–17].

Figure 8.1 HCT late effects relate to exposures, genetics, age gender and lifestyle.