Iron overload screening, treatment modalities, and therapies in pediatric post-HSCT patients

The long-term clinical impact of transfusional iron overload and toxicity is not known in pediatric cancer survivors and patients who undergo hematopoietic stem cell transplantation (HSCT) for nonmalignant and malignant disorders. Recently, a variety of surveillance modalities that can be used to monitor iron overload during and after treatment in pediatric cancer and blood and marrow transplantation (BMT) survivors, were presented by Lalefar NR  during the 2021 Conference of the American Society of Pediatric Hematology/Oncology (ASPHO).¹

According to the recommendations made by the Children’s Oncology Group (COG) in their 2018 guideline, the following methods can be used for screening and testing iron overload:

• Ferritin screening and evaluation of iron content using T2*-based magnetic resonance imaging (MRI)
• A liver biopsy if there is excessive iron content
• Potential phlebotomy or chelation therapy for treating iron overload

Who should be monitored and how?

Post-therapy iron overload occurs due to an acute rise in free iron and decrease in iron utilization after chemo-induced erythroid hyperplasia in the bone marrow. Therefore, each patient should be assessed individually post-therapy. A total transfused volume of >100 ml/kilo, or approximately 10 transfusions, is associated with an increase in iron burden in children.

The COG 2018 guidelines for iron overload in pediatric oncology and BMT survivors, recommends the evaluation of packed red blood cell (pRBC) transfusion exposure post end-of-therapy hematopoietic recovery.

• Ferritin is used as a surrogate marker of total body iron stores. Evaluation of other serum markers (Table 1) in fasting is also recommended for iron overload evaluation.

Table 1. Serum markers to identify iron overload*

*Adapted from Lalefar NR, et al.1
Serum markers	Iron overload
Serum iron	↑
Serum ferritin	↑ (>1,000 µg/L)
Transferrin iron saturation, %	↑ (>50%)
Transferrin	↓
Total iron binding capacity	↓
Hemoglobin	Normal

• Ferritin monitoring has the advantage of being repeatable, noninvasive, widely available, and inexpensive.
• However, ferritin has the disadvantage of having a nonlinear relationship with iron overload and can be confounded by inflammation because it is an acute-phase reactant.

Methods for iron-overload monitoring

Several clinical methods are used to detect presence of excessive iron in various tissues (Table 2).

Table 2. Modalities to measure iron overload^†

BMT, blood and marrow transplantation; GvHD, graft-versus-host disease; MRI, magnetic resonance imaging. †Adapted from Lalefar NR, et al.1
Modality	T2* MRI	Cardiac T2* MRI	FerriScan®	SQUID	Liver biopsy
Principle	An indirect instrumental estimation of tissue iron concentration. Detects the extent of magnetic disruption due to iron deposition. In iron overloaded tissues, this disruption results in a magnetic gradient echo referred to as T2*.	Detects myocardial iron accumulation	Same as T2* MRI	Measures the interference of an exteriorly applied small, but highly constant, magnetic field by the paramagnetic liver storage iron of the patient.	Direct quantitative measure of liver iron concentration (LIC).
Normal iron concentration	80−480 µg/g wet liver weight OR 0.48−2.8 mg/g liver dry weight	T2* >20 ms, no cardiac iron detected. T2*= 10−20 ms, moderate cardiac iron.	—	—	—
Abnormal values/iron overload/threshold	>7 mg/g of liver dry weight	T2* <10 ms, severe cardiac deposition of iron	>1,000 ng/ml	—	—
Advantages	Noninvasive, and repeatable. Allows to measure iron deposition in the heart, liver, and pituitary gland. Validated in heart, and can provide functional information as well.	—	Clinically validated in the liver. No breath-holding required.	Direct instrumental measure of hepatic iron concentration. Good correlation with liver biopsy. Noninvasive.	Good at excluding other liver dysfunction such as fibrosis, cirrhosis, viral hepatitis, fatty liver, and cases of BMT patients for GvHD.
Disadvantages	Expensive, low accessibility, and may require anesthesia in some cases.	Expert handling. Standardization.	Same as T2*MRI. Not applicable for cardiac assessment.	Limited availability. Expensive.	Invasive, susceptible to sampling errors, and not feasible for patients with thrombocytopenia or coagulopathy.

Treatment

Frequently used treatments for iron overload are as follows:

• Phlebotomy
• Iron chelators

• deferasirox
• deferoxamine

 Phlebotomy

• Phlebotomy is used when Hb >11 g/dl and 5 ml/kg of blood is replaced with an equal volume of saline/oral fluid
• Ferritin and iron should be measured every 3 months to check if the values are trending normal and patients are not becoming iron deficient
• Liver iron concentration (LIC) is measured every 6−12 months

• It is safe and cost-effective
• However, frequent clinical visits are required depending on the patient; patients should come in for phlebotomy every 2 to 4 weeks

Iron chelators − deferasirox

• It is a tridentate iron chelator with good bioavailability, long half-life, and suitable for once/day
• Initial dose is 3.5 mg/kg/day, which can be increased up to 7 mg/kg/day over 3−6 months depending on iron studies
• Dose-related toxicities: Skin rash, nausea, diarrhea
• Other toxicities:
  • Transaminitis
  • Renal toxicities because of the risk of proximal renal tubule dysfunction; therefore, it is important to measure metabolic panel and phosphorus to prevent metabolic acidosis and hypophosphatemia
  • Contraindicated when the platelet count is <50 k, because of high risk of gastrointestinal (GI) hemorrhage that can be seen with these patients

Iron chelation − deferoxamine

• Hexadentate iron chelator binds one-to-one specifically with a ferric iron
• It is administered by infusion with an ambulatory pump, either subcutaneously or intravenously
• Treatment begins at a lower dose (20 mg/kg) for 8 hours/3 nights/week
• Toxicity comes with higher doses (>30 mg/kg)
• Toxicities that can be seen are the following: high-frequency sensorineural hearing loss, retinal, metaphyseal/spinal, or growth retardation
• Depending on the severity, lowering of dose, or stopping the treatment is recommended

Phlebotomy vs oral chelation

Both methods can result in the reduction of iron burden in patients. However, it was observed that LIC reductions were greater with deferasirox than with phlebotomy for patients with a baseline serum ferritin of 1,000 ng/ml or higher (−8.1 ± 1.5 vs −3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and nontransferrin-bound iron also decreased significantly.²

Surveillance and treatment algorithm

The treatment regimen will depend on the condition of the patient after BMT. Figure 1 summarizes the suggested treatment algorithm for posttransplant pediatric patients with iron overload.

ALT, alanine aminotransferase; LIC, liver iron concentration; MRI, magnetic resonance imaging; pRBCs, packed red blood cells.
*Adapted from Lalefar et al.^1
†Hb should be normal post-chemotherapy. Blood and marrow transplantation (BMT) patients should wait >100 days.
^‡Liver dry weight.
^§Post-pubertal adolescent/young adults, chronic GvHD, hepatitis C, history of liver fibrosis.

Implication of practice guidelines

According to a survey involving 55 participating centers carried out by the Pediatric Blood and Marrow Transplant Consortium (PBMTC) transplant centers in North America, 48% of the centers had practice guidelines for assessment and management of iron load, where ferritin was used as a surveillance modality in 100%, FerriScan^® in 90.2%, liver biopsy in 56.1%, and SQUID in 12.2%.

It was observed that oral chelation was the most popular modality, with an 87.5% score, followed by phlebotomy (82.5%), intravenous chelation (67.5%), a combination of chelation and phlebotomy (52.5%), and RBC pheresis (17.5%).

Conclusion

Iron overload is common in pediatric patients after HSCT and is associated with hepatic, cardiac, and endocrine dysfunction. Therefore, monitoring the serum iron and ferritin levels using the recommended modalities and tailored treatment as per condition of the patient, are necessary.