How to manage iron toxicity in post-allogeneic hematopoietic stem cell transplantation?

KEYWORDS:

• Iron overload
• iron toxicity
• phlebotomy
• deferiprone
• deferoxamine
• deferasirox
• hematopoietic stem cell transplantation
• thalassemia
• leukemia
• myelodysplasia

1. Introduction

Hematopoietic stem cell transplantation (HCT) is a widely used form of treatment for many hematological malignancies and genetic disorders. The number of diseases and the number/age range of patients undergoing HCT are rapidly increasing [1,2].

The post-transplantation side effects affecting the long-term survival of about 0.5 million HCT patients are related to many complications including iron overload (IO) [1,2]. Iron overload is considered as an independent adverse prognostic factor in all diseases. The development of IO complications originates from the build-up of excess iron as a result of multiple red blood cell (RBC) transfusions, mostly pre-transplantation in many HCT patients including about 4000 with thalassemia and 1000 with sickle cell disease, as well as many more with myelodysplasia, leukemia, and other categories of patients [1–4].

Iron overload toxicity (IOT) affects the function of many organs and its intensity is proportional to the level of IO. In most cases, IOT in iron-loaded organs is reversible and restoration of normal function can be accomplished by the removal of excess iron. Phlebotomy is the standard form of treatment for IO in transfusion-independent post-allogeneic iron-loaded HCT patients. Chelation therapy is an alternative option for many cases of IO where phlebotomy cannot be used [3,4]. Most of the chelation protocols involve the administration of subcutaneous deferoxamine (DF), oral deferiprone (L1) and the DF/L1 combinations. The relatively new, oral deferasirox (DFRA) is also available for the treatment of IO including post-allogeneic iron-loaded HCT patients, but its effects are still under evaluation [5].

New developments in IOT monitoring and therapeutic approaches can lead to the complete elimination of IO in HCT and other categories of iron-loaded patients.

2. Iron toxicity

Iron is an essential metal ion involved in many biological processes including hemopoiesis. The transport, storage, and utilization of iron are strictly controlled by metabolic pathways involving proteins such as transferrin in plasma and intracellular ferritin. Hemosiderin is a breakdown product of ferritin, which is the major protein-iron form found in iron-loaded tissues [5,6].

Iron toxicity has been implicated in almost all diseases of tissue damage including IO in HCT because of the role/association of iron as the main biological catalyst in free radical pathology. The presence of excess iron mainly in the form of intracellular hemosiderin and labile iron can progressively cause molecular, cellular, and tissue damage and a vicious circle leading to oxidative stress toxicity (OST) damage in cells [6].

The OST damage can cause abnormalities in cell structure and function, including damage to organelles such as the disruption of lysosomes causing the release of proteolytic enzymes resulting in the malfunction of cellular processes and in particular cell apoptosis, autophagy, and necrosis. Cell death, ‘ferroptosis,’ due to IO has specific characteristics and is different from apoptosis or other cell death pathways [6].

Iron overload toxicity in post-allogeneic HCT and other iron-loaded patients can affect many organs including the heart, liver, spleen, and pancreas and cause cardiac complications including congestive cardiac failure, liver fibrosis and cirrhosis, diabetes, diminished growth, infertility, etc., [5,6].

Iron overload also promotes microbial infections, which is a cause of increased morbidity and mortality in iron-loaded patients and especially in immuno-compromised post-allogeneic HCT patients.

3. Monitoring of excess iron levels in iron overload diseases

Several diagnostic techniques are used for monitoring the level of excess iron, as well as the progress of iron depletion therapy in IO including post-allogeneic HCT patients.

The most common methods for monitoring IO are serum ferritin (SF), serum iron, transferrin iron saturation, and liver iron concentration (LIC). The physiological nontoxic levels of iron are usually characterized by the normal SF values (male 40–340 μg/l and female 14–150 μg/l), transferrin saturation (25–35%) and serum iron (10–40 μmol/l). Physiological LIC levels measured from liver biopsies are considered to be less than 1.6–2.0 mg iron per g liver dry weight (mg/g dw) and higher levels are associated with liver cirrhosis and fibrosis [7].

The relatively recent introduction of MRI T2* relaxation time techniques has been used for estimating the level of IO in the heart, liver, and other organs [7,8]. It was found that both LIC and SF do not appear to be related to IO of the heart, which is the main cause of increased mortality [7,8]. MRI T2* is also increasingly being used for the adjustment of the dose protocols during iron chelation therapy and phlebotomy rate.

The identification of the IO levels in each organ in post-allogeneic HCT patients increases the prospects of improved diagnosis and therapeutic approaches in the context of personalized medicine. Accordingly, different classifications apply in relation to IO and toxicity levels in each organ.

Patients with cardiac MRI T2* relaxation times of less than 8 ms are considered to be in the heavy hemosiderosis range and to be in danger of cardiac failure, moderate IO is 8–12 ms, mild IO is 12–20 ms and above 20 ms it corresponds to normal cardiac iron levels [9]. Regarding liver iron overload, MRI T2* relaxation times of less than 1.4 ms are estimated to contain more than 10 mg/g dw and considered to be in the severe hepatic hemosiderosis range, for moderate it corresponds to 1.4–2.7 ms and 5–10 mg/g dw, for mild it corresponds to 2.7–6.3 ms and 2–5 mg/g dw and for normal to more than 6.3 ms and less than 2 mg/g dw [7,8].

In cases of SF levels greater than 2500 μg/l, transferrin iron saturation above 100% and LIC greater than 7 mg/g dw suggest that there is a greater risk of IOT and irreversible tissue damage and also the need for the use of intensive iron depletion by phlebotomy and/or chelation therapy.

4. Ferrikinetics of iron overload in post-allogeneic HCT patients

Gastrointestinal iron absorption is about 1–1.4 mg/day in normal individuals, which is equivalent to that of iron excretion and other bodily iron losses. Iron excretion is higher by a few milligrams in iron-loaded patients than in normal individuals.

Almost all the excess iron in post-allogeneic HCT iron-loaded patients has been incorporated into the body from RBC transfusions, with a rate of about 1–3 units of packed RBC (1 unit, is about 200 ml = 200 mg of iron) around every 1–4 weeks, which on average causes a net iron intake and deposition in the body of about 15–25 mg/day.

In a 5–10 year follow up study involving 151 post-allogeneic HCT thalassemia patients, SF decreased from a mean of about 1000 μg/l pre-transplantation to normal levels within 5 years, in another iron-loaded group, from about 1900 to 1000 μg/l within 5 years and in a third group from about 3000 to 2000 μg/l, 7 years after transplantation. Comparable reductions to SF were also observed in LIC and unbound iron-binding capacity [10]. It was also observed that the long-term survival after HCT was more than 90% in the low iron-loaded group whereas in the heavily iron-loaded group was less than 50%.

It appears that the removal of excess iron without therapeutic intervention is slow and also that the normalization of the iron stores is associated with decreased morbidity and mortality in post-allogeneic HCT thalassemia patients. However, although IO, in general, is clearly considered as a major independent adverse prognostic factor, many other complications impact the long-term transplant outcome in post-allogeneic HCT patients.

5. Prevention of iron overload toxicity in post-allogeneic HCT patients

The prevention and complete removal of excess iron are the ultimate aims for the treatment of IO in post-allogeneic HCT patients.

There is a variety of approaches in the treatment of IO in post-allogeneic HCT, some of which have no specific targets or aim and no consideration of the risks/benefits to patients. Some of these approaches include the prevention of IOT.

The removal of excess iron implicated in tissue and organ damage can be accomplished in many cases of IO by using effective chelation therapy protocols prior to transplantation. This approach has not been a pre-requirement for many transplanting centers, despite the fact that it can offer complete treatment of IO and an overall better prognosis for the patients prior to, during and post-transplantation [11].

The International Committee on Chelation (ICOC) protocol using L1 (80–100 mg/kg/day) and subcutaneous DF (40–60 mg/kg/day, at least 3 days per week) was identified as the most tolerable, safe, and effective chelation protocol for achieving negative iron balance and normalization of the iron stores in transfused thalassemia patients [12]. The time period required for the normalization of iron stores varies and depends mainly on the initial IO of the patient and the overall dose of the chelating drugs. Complete elimination of IO in regularly transfused patients with SF of 700–4000 μg/l using the ICOC protocol was estimated to be about 6–30 months [12,13].

6. Phlebotomy in post-allogeneic HCT patients

The gold standard iron depletion treatment for IO transfusion-independent post-allogeneic HCT patients is phlebotomy [14]. There are many advantages in the use of phlebotomy in comparison to iron chelation, including better efficiency in iron removal, very low toxicity, and cost [14].

The rate of blood removal by phlebotomy usually depends on the IO of patients. For example in heavily iron-loaded idiopathic hemochromatosis patients 400–500 ml of blood, which is equivalent to 200–250 mg iron can be removed every week. In non-heavily iron-loaded patients, the same amount of blood can also be removed every 0.5 to 3 months. During phlebotomy treatments, the hemoglobin level is usually maintained above 11 g/dl.

Lower phlebotomy rates than idiopathic hemochromatosis are generally used in post-allogeneic HCT thalassemia patients. In a typical program of 6 ml/kg blood withdrawal every 2 weeks, complete normalization of the iron stores has been achieved within 1–3 years in most post-allogeneic HCT thalassemia patients involved in a study of 41 such patients with a mean age of 16 years. The reduction of SF was from about 2500 to 280 μg/l, transferrin saturation from 90% to 39% and LIC from 21 to 3 mg/g dw [7,14,15].

The normalization of the iron stores in post-allogeneic HCT patients is usually accompanied by a decrease in liver enzymes, absence of hemosiderin granules in liver biopsies and absence of iron deposits in the liver, heart, and other organs as detected by MRI T2* assessment [7,8,14,15].

7. Chelation therapy in post-allogeneic HCT patients

Many allogeneic HCT patients especially with myelodysplasia and leukemia are not transfusion-independent following transplantation and chelation therapy may be necessary for the removal of IO. The decisions on chelating drug dose protocols are usually based on a risk/benefit assessment including complications of the underlying disease, drug toxicity, and quality-adjusted life years [16,17].

There is no consensus in chelating drug protocols and different clinics and countries are using different chelating treatments. Most of these protocols involve the administration of DF, L1, and the DF/L1 combinations, which have been used for more than 20 years in the treatment of IO [5]. Several studies using DFRA suggest that it can also be used in post-allogeneic HCT patients despite that other investigators reported serious toxicities and discontinuation of chelation treatment [16–21]. The level of toxicity of chelation therapy by DFRA, L1, and DF in HCT patients is expected to be similar to that reported for other categories of iron-loaded patients [5].

Variable effects of DF, DFRA, and L1 are generally observed in iron-loaded patients. Each chelating drug has a different mode of action, efficacy, toxicity, and cost, which overall affects the morbidity and mortality of post-allogeneic HCT and other iron-loaded patients [5,16–21].

The general recommended doses of the chelating drugs in iron-loaded patients are 40–60 mg/kg/day for DF, 75–100 mg/kg/day for L1 and 20–40 mg/kg/day for DFRA [5]. However, variations in IO and targeted therapies can result in the application of a range of therapeutic protocols from intensive chelation e.g. combinations of DF (40–60 mg/kg/day) and L1 (80–100 mg/kg/day) in heavily transfused iron-loaded patients to intermittent withdrawal of chelation in less heavily iron-loaded patients [12,13].

The lack of consensus and sometimes misconceptions on the use of chelation therapy such as the timing of initiation of chelation not only increases the risks of IOT damage in iron-loaded patients but also decreases the prospects of complete treatment of IO. In this context, chelation therapy should be initiated as soon as possible after a few RBC transfusions and when SF is approaching 500 μg/l. Deferiprone is recommended to be used at these SF levels since DF and DFRA appear to be toxic according to their drug label information. Complete iron removal can be easily and rapidly achieved in patients with low IO by comparison to patients with heavy IO [5,7,12,13].

8. Future therapeutic approaches to minimize iron overload toxicity

The treatment of IOT in post-allogeneic HCT patients is not satisfactory at present and there is an urgent need to develop new effective therapeutic strategies prior to, during and after transplantation.

The major therapeutic strategy and ultimate aim in all IO patient categories are the complete removal of excess iron and the normalization of the iron stores. Prevention strategies of IO in post-allogeneic HCT patients can be accomplished by effective chelation therapies such as the ICOC L1/DF combination or similar protocols prior to transplantation. Chelating drug monotherapies do not appear to be as effective as combination therapies [12,13].

Reevaluation of therapeutic strategies includes the timing of the initiation of iron removal following transplantation by either phlebotomy or chelation. There are different approaches and no consensus on related protocols [4,11,14,15,17]. Initiation of iron removal as soon as possible after transplantation could be more efficient for eliminating IO and IOT in the long term.

Reevaluation of the phlebotomy strategies including the introduction of intensification programs could also increase the rate of iron removal and reduce IOT [11,15].

A combination of phlebotomy and chelation therapy is another proposed option for the rapid removal of excess iron from heavily iron-loaded post-allogeneic HCT patients. The introduction of a modest chelation therapy program accompanied by close monitoring of iron diagnostic parameters could ensure the safety of this procedure.

The introduction of erythropoietic biologics such as luspatercept (Reblozyl) could be considered for the reduction of RBC transfusions and subsequently overall IO and IOT in allogeneic HCT patients [22–24]. However, serious concerns remain on the cost, efficacy, and safety of luspatercept and other biologics since in general the immunogenicity of these compounds has not yet been fully investigated.

The problem of hematological toxicity of IO, and of the possible usefulness of iron chelation in promoting post-transplant hematopoietic recovery, especially in the setting of myeloid and related malignancies, should also be further investigated [25–27]. However, as previously shown in similar cases the development of such initiatives is generally based on commercial and not academic criteria [28].

It is envisaged that with the introduction of new approaches and therapeutic combination strategies prior to, during and after transplantation, IOT can be drastically reduced or eliminated resulting in further reduction in morbidity and mortality in iron-loaded allogeneic HCT patients.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

This work was supported by research funds of the Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus. I thank Dr Christina N. Kontoghiorghe for reviewing the manuscript and also for the useful comments.

Additional information

Funding

This paper was not funded.