1 Introduction

Iron overload/toxicity is an unavoidable consequence in several diseases characterized by anemia and red blood cell transfusion requirement.

It is now clear that iron-related damage is due not only to iron level “per se” but to the presence in the serum of non-transferrin forms of iron (non-transferrin-bound iron [NTBI]). A component of NTBI, called labile plasma iron (LPI), is a potent redox-active agent capable of permeating into cells in an uncontrolled way, thus inducing cellular iron overload and impacts the delicate equilibrium of labile cellular iron (LCI). The breakage of LCI balance catalyzes the formation of reactive oxygen species (ROS), which leads to cytotoxic cell injury (DNA damage, lipid peroxidation, protein modification, and mitochondrial damage). Of course iron overload is a source of NTBI/LPI production.

Other factors significantly impact on iron toxicity: the quantity of the abovementioned toxic iron-related species, individual’s antioxidant genetics, environmental factors, and, most importantly, duration of exposure (Coates 2014).

Several cellular pathways are sensitive to the detrimental action of ROS in a non-dose-dependent manner. Different human tissues have a different capacity to respond to iron-mediated toxicity, indicating that the toxicity thresholds are disease-specific and patient-dependent (Pilo et al. 2022).

Notably, NTBI and LPI appear in the serum only when transferrin saturation exceeds 70% (de Swart et al. 2016) and are cheatable forms of iron.

NTBI and LPI measurement is today available in selected laboratories for research purposes only. Transferrin saturation is at the moment a valid surrogate indicating, when exceeding 70%, the presence of NTBI /LPI in patient serum. Table 46.1 reports today available methods to evaluate iron toxicity and iron load.

Table 46.1 Currently available methods to evaluate risk of iron toxicity and quantify iron overload
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The mechanisms that impact on the outcome of the transplant, and clinical implications, are different in the different temporal phases of HCT—before, during, and after (Angelucci and Pilo 2016)—and will be here discussed separately:

  • Before transplant: any time before the starting of the conditioning regimen.

  • During transplant: from the start of conditioning regimen up to a sustained engraftment is achieved.

  • After transplant: after sustained engraftment has been achieved.

2 Iron Overload Before HCT (Before the Start of Conditioning)

In thalassemia it has been very well demonstrated that HCT outcome is significantly impacted by a story of irregular chelation, presence of liver fibrosis, and hepatomegaly (Angelucci 2010a). Now we can recognize that all the three risk factors are related not only to the accumulated iron “per se” but to the intensity and duration of tissue exposition to the abovementioned iron toxic-related species (Angelucci et al. 2017).

Iron-mediated toxicity causes tissue damage that accumulates over the years and adds to the transplant-related toxicity, thus resulting in a cumulative additive effect. In this situation organs and tissues are less resistant to transplant-related morbidity. For example, in thalassemia there is no difference in the incidence of graft versus host (GvHD) in the different risk classes, but there is a dramatic difference in survival of grade III–IV GvHD in higher risk patients (Gaziev et al. 1997). In a GITMO study (MDS and acute leukemias) transfusional burden impacted in patients who had received a myeloablative conditioning and not in those who had received a reduced intensity conditioning (Alessandrino et al. 2010).

Therefore, any effort should be made to prevent tissue/organ damage by regularly suppressing NTBI/LPI in the years before transplant. This target can be achieved with early, regular, and consistent iron chelation. Thus, in any patient receiving transfusion therapy who may have an HCT in the future, the decision of starting chelation is critical and should be undertaken as soon as possible. Moreover, iron chelation must be taken regularly in the long term. Table 46.2 shows the iron chelators available on the market today. The indications depend on the registration which is different in different countries. Because of reported cases of agranulocytosis, deferiprone is usually not used in hemopoietic stem cell disorders.

Table 46.2 Available iron chelators. Indications and dosages depend on the registration and formulation which are different in different countries
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Limited data are available on the rationale for intensive pre-HCT chelation therapy unless sufficient time is available to correct iron overload and warrant tissue lesion repair likely only in young patients.

3 Iron Overload During HCT (from the Start of Conditioning up to Sustained Engraftment)

During conditioning regimen, a huge amount of NTBI and LPI enter the circulation due to massive erythroid marrow lysis (Dürken et al. 1997). Moreover, until the erythroid recovery begins, no iron can be released by serum transferrin to the erythroid system. Once erythroid recovery initiates, transferrin iron is greedily captured by the recovering erythroid system and unbound transferrin—a natural iron chelator—able to receive iron from the reticular endothelial system appears in the serum. NTBI and LPI disappear from the circulation by this natural mechanism in 3–4 weeks unless iron overload is present (Duca et al. 2018).

Transplant animal studies demonstrated that iron toxicity could impair the hematopoietic niche by damaging hematopoietic stem cells’ self-renewal potential, proliferation, and differentiation and the marrow microenvironment (Pilo and Angelucci 2018). These data suggest that iron can impact the HSC engraftment, the hemopoietic recovery, and possibly transplant outcome.

Inclusion of chelation therapy during the transplant phase to suppress NTBI/LPI should be considered an experimental treatment; however, in case of slow, delayed, or incomplete marrow recovery and high transferrin saturation, iron chelation can be considered.

4 Iron Overload After HCT (After Sustained Engraftment Has Been Achieved)

After successful transplantation, patients are usually free from transfusion support but affected by the already acquired iron overload that cannot be eliminated without active intervention. In this condition the already acquired iron overload continues to disrupt the delicate LCI equilibrium and promotes ROS generation. It has been prospectively demonstrated in transplanted thalassemia patients that elevated transferrin saturation persists indefinitely without treatment (Angelucci et al. 1998) and liver disease progresses even in the absence of other comorbidities (Angelucci et al. 2002). Of course, the deleterious effect can be worsened by the presence of comorbidities even with a low level of iron accumulation (Angelucci et al. 2002).

Therefore, even because of the results of epidemiologic studies in thalassemia (Coates et al. 2016), in rare transfusion-dependent anemias (Puliyel et al. 2015), and in the normal population (Ellervik et al. 2011) in the posttransplant setting, the target iron level should be a normal iron level. Normal transferrin saturation excluding the presence of toxic iron-reactive species should be the target level of posttransplant iron removal (Table 46.1).

Because of the acquired effective erythropoiesis, phlebotomy (Angelucci et al. 1997a; Inati et al. 2017) can be an alternative to chelation. The standard chelation program consists of blood sampling of 6 mL/kg every 14 days (Angelucci et al. 1997a). Table 46.3 reports the pros and cons for selecting phlebotomy or iron chelation for post-HCT iron removal.

Table 46.3 Factors to be considered in selecting the appropriate post-HCT iron removal strategy
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Key Points

  • Iron toxicity depends on several factors in addition to iron overload. The most important is the duration of exposition to free iron species: NTBI and LPI inducing oxidative stress and tissue damage.

  • Prevention of tissue damage by regularly and consistently suppressing tissue reactive iron species in the years before HCT is the key factor to improve transplant outcome.

  • Iron toxicity can impair the bone marrow microenvironment, the quantity and quality of bone marrow mesenchymal stem cells, the ratio of immature HSC, and the clonogenic capacity of hemopoietic stem and progenitor cells, thus likely impacting hemopoietic recovery and possibly transplant outcome.

  • After successful HCT, one should aim to achieve normal iron levels (i.e., normal transferrin saturation).