Quantification by Superconducting Quantum Interference Device (SQUID) of Iron Overload after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
Authors: Busca Alessandro , Falda Michele , Manzini Paola , D’antico Sergio , Locatelli Franco , Chiappella Annalisa , D’Ardia Stefano , Longo Filomena , Calabrese Roberto , Piga Antonio 
Published: April 2020

Abstract
Introduction. Iron overload (IO) is an adverse prognostic factor in patients who undergo allogeneic HSCT for thalassemia and appears to play a similar role in patients with other hematological disorders. Estimation of IO is primarily based on serum ferritin, however many confounding factors particularly in HSCT recipients may result in frequent ferritin overestimation. Aim of the study was to quantify IO by SQUID after HSCT and evaluate the impact on hepatic function and infections. Additionally, the feasibility of iron-depletion has been investigated.
Methods. Between December 2005 and December 2007, 102 consecutive pts who were admitted at our outpatient department have been analyzed. Patients received HSCT from a matched sibling (n=66), a partially matched relative (n=4) or a matched unrelated donor (n=32). Primary diagnosis included acute leukemia/MDS in 61% of cases. Assessment of IO after HSCT included serum ferritin and in those with hyperferritinemia (&gt; 1000 ng/ml), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate (LIC 1000–2000 microg/gww) or severe (LIC &gt;2000 microg/gww) IO.
Results. Patients who were in complete remission underwent ferritin assessment at a median time of 578 days from transplantation. Fifty-seven had a ferritin level below the threshold of 1000 ng/ml; in this cohort the median time from HSCT to ferritin assessment was 1006 days, significantly different from the median time of 183 days of the 45 patients who had a ferritin level &gt; 1000 ng/ml. LIC evaluated by SQUID was available for 42/45 patients with elevated ferritin values. Overall, 29 patients had moderate to severe IO: median LIC values were 1493 microg/gww (range 1030–3253 microg/gww). Thirteen patients had normal LIC values (LIC&lt;400 microg/gww) despite high serum ferritin levels. Multivariate analysis showed a significant correlation between ferritin levels &gt; 1000 ng/ml and the occurrence of liver dysfunction defined by the presence of at least one abnormal liver function test (LFT) on two or more occasions (OR 6.8; 95%CI 2.2–20.6); the correlation hold the statistical significance even including into the multivariate model the different time of ferritin assessment. In addition, the rate of proven/probable invasive fungal disease was significantly higher among patients with hyperferritinemia as compared to patients with normal ferritin levels (13% vs 0%; p=.006). Nineteen of the 23 patients considered eligible to iron depletion, underwent regular phlebotomy: 9 patients completed the program after a median time of 10 months (range 3–13 months), reaching the target of ferritin &lt; 500 ng/ml; for 6 patients the program is still ongoing, while 4 patients discontinued the phlebotomy protocol (relapse n=2; hypotension, n=1; progressive anemia, n=1). In 8/9 patients who were revaluated by SQUID at the end of iron depletion program there was a significant decrease of LIC (median 1368 microg/gww to 606 microg/gww; p=.005) that parallels changes of serum ferritin; one patient did not show e remarkable reduction of LIC despite serum ferritin normalization.. Three of the 4 patients ineligible to phlebotomy were successfully treated with deferasirox and 1 patient was treated with deferoxamine.
Conclusion. The measurement of LIC obtained by SQUID documented the presence of moderate/severe IO in 69% of the patients with high ferritin levels. Our preliminary data showed that in HSCT recipients, high ferritin level is an independent risk factor for the occurrence of abnormal LFTs and IO may be considered a potential risk factor for fungal infections. A phlebotomy program resulted feasible in 65% of the patients who might benefit from a procedure of iron depletion