Abrupt Increases in Ferritin Levels May Indicate a Malignant Process and Not Changes in Iron Overload in Thalassemic Patients

Introduction: Current therapeutic schemas with proper red blood cell transfusions and appropriate chelation therapy has led to a dramatic improvement in quality of life and survival in transfusion-dependent thalassemia (TDT) patients (pts). Alterations in iron metabolism and ferritin levels are considered amongst the main metabolic hallmarks and indexes of cancer. Aim: The aim of our study was to investigate whether changes in ferritin levels are indicative for cancer in TDT patients. Patients and Methods: A retrospective cohort study was conducted and included all TDT pts followed in our unit during 1/13-12/23. For TDT pts who developed cancer, data on the type of cancer, age at cancer diagnosis, survival status, and iron overload indexes as assessed by serum ferritin, liver and heart T2* MRI were recorded and analyzed. The mean (SD) ferritin levels were assessed for the following time intervals prior to the diagnosis of cancer:0-6months, 12-24 months and 1-5years. Statistical analysis was performed with RStudio v.3.6.2. Results: Twenty-one pts from a total of 376 TDT (median age 44 years; range:1-66, in 12/2023) followed in our unit, were diagnosed with cancer during the study period. For this population, the overall incidence for cancer was 5.6%, while the median age at diagnosis was 45years, with both values being significant worse compared to 0.5% and 66years, respectively, for the reference Greek population. Eight distinct types of cancer were diagnosed, with hepatocellular carcinoma being the most frequent (10 pts) followed by renal cell carcinoma (3 pts), non-Hodgkin lymphoma and colorectal cancer (2 pts each), thyroid carcinoma, pancreatic cancer, non-small cell lung cancer and cholangiocarcinoma (1 pt each). All pts were regularly transfused, with no statistically significant differences regarding consumption the year prior to cancer diagnosis, and all were under chelation treatment at a stable schema at least for one year prior to cancer diagnosis. Chelation therapy included deferasirox (DFX) (8pts), deferoxamine (DFO) or deferiprone (DFP) (3 pts each), DFP and DFO (5 pts), DFO and DFX or DFP and DFX (1 pt each).The results showed that ferritin levels, while they were no different between 1 year and 5 years prior to cancer diagnosis (p=0.13), rise sharply during 0-6 months prior to cancer diagnosis, with a mean increase of 933±1728(129% of baseline). Serum ferritin levels 0-6 months prior to cancer diagnosis (median 2116 ng/ml) differed significantly to levels 12-24 months (median 1180 ng/ml) (p=0.00014) and 1-5years (median 1404 ng/ml) (p=0.0098) prior to cancer diagnosis. At the same period, other indicators of iron overload, notably LIC and cardiac T2*, have remained stable(p>0.05) (mean change:0.39±4.09mg Fe/g.d.w. and 0.76±6.48msec, respectively). Of note is that a patient presented a notable increase in ferritin levels 0-6 months prior to cancer diagnosis, which resolved when remission was achieved, with a similar increase in ferritin levels occurring 4 years later upon relapse. Conclusions: TDT patients are at high risk for developing cancer, as shown by an increased incidence and occurrence at younger ages compared to general population. An abrupt and sustained increase of serum ferritin levels 0-6 months prior to cancer diagnosis, not reflecting changes in iron overload, was observed in our cohort. Thus, our data support that ferritin levels is a sensitive marker for malignancy even in thalassemic patients with iron overload. Unexplained changes in serum ferritin levels in this group of patients should prompt for timely evaluation for an underlying malignancy.