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.
Common posttransplant screening and prevention guidelines
One way to consider late effects is to evaluate them sequentially as either problem‐based, systems‐based, or organ‐specific domains from head to toe (Table 8.1).
Engraftment
Engraftment definitions based on early neutrophil and platelet recovery are insufficient to address late graft failure and rejection because nonmyeloablative and reduced intensity conditioning often results in mixed donor chimerism in one or more leukocyte lineages. This is rarely an issue for children with heavily pretreated malignancies, though falling chimerism is followed closely by some centers with the goal of preemptive intervention for impending relapse. Beyond this rationale, chimerism monitoring during LTFU is of questionable value for malignant diseases unless confirmation of residual donor hematopoiesis is necessary before donor lymphocyte infusion.
By contrast, mixed chimerism is essential in LTFU for NMDs, albeit dynamic patterns of lineage‐specific chimerism over months or years of follow‐up, and their meaning, remain to be firmly established for individual NMDs. What level of lineage‐specific chimerism is critical for durable correction of the underlying disease phenotype is also unclear for the full portfolio of NMDs [15,18]. Prospective LTFU studies are first needed to determine if complete donor chimerism is maintained in individual NMDs during extended LTFU. When mixed‐chimerism is present initially, or emerges over time, does the underlying disease phenotype, and/or autoimmunity, eventually return? For this reason, at least in primary immunodeficiency disease, the Primary Immunodeficiency Disease Transplant Consortium recommends lifelong, systematic and comprehensive assessment of lineage‐specific chimerism, plus numeric and functional immune reconstitution data, even if the patient is well and without signs of infection, to allow early detection and trajectory of possible declines in chimerism and immune function and so that intervention can occur before clinical complications of recurrent SCID emerge [17]. Testing begins no later than 3 months after HCT.
Iron overload
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
|