Chronic Myeloid Leukemia following Exposure to Radioactive Iodine (I¹³¹): A Systematic Review Open Access

Therapy-related leukemia and secondary leukemia are the terms that describe the occurrence of leukemias following exposure to hematotoxins and radiation to emphasize the difference from leukemia that arises de novo [1]. Many leukemogenic agents have been described in the literature – for example, ionizing radiation. Radiation predisposes to damage to cellular components, macromolecules, and organelles, through energy transfer either directly or through interaction with water and reactive free radicals production; this injury results in somatic and oncogenic mutations when important genes are affected [2, 4]. The observation of atomic bomb survivors is an illustration of this relationship [5].

A number of medication classes have been associated with the pathogenesis of t-ML. Alkylating agents such as cyclophosphamide, melphalan, and nitrosoureas can induce intra- and interstrand DNA cross-linking and breaks, affecting DNA integrity [2, 6, 7]. Depending on the degree of DNA repair, strand breaks may initiate cellular lethal or sublethal mutations, increasing the odds of oncogene activation and tumor suppressor gene inactivation [3, 4, 6, 7]. Topoisomerase 2 inhibitors are also thought to have a dose-dependent association with the rise of these secondary leukemias [2, 4, 6]. Antimetabolites (e.g., fludarabine and azathioprine) and recombinant granulocyte-colony stimulating factors have been implicated as leukemogenic [4]. The risk of leukemogenesis is generally increased by extended exposure to the inducing agent(s).

Additionally, patient factors play a role in predisposition to t-ML. Significant examples include the presence of (a) rare inherited cancer predisposition syndromes such as neurofibromatosis type 1, Li-Fraumeni syndrome, Fanconi anemia, ataxia telangiectasia, Shwachman-Diamond syndrome, amegakaryocytic thrombocytopenia, congenital neutropenia, dyskeratosis congenita, and Blackfan-Diamond syndrome and (b) genetic polymorphisms in chemotherapy drug-metabolizing enzymes such as polymorphisms in the genes encoding the glutathione-S-transferases, NAD(P)H:quinone oxidoreductase, myeloperoxidase, n-acetyltransferase, cytochrome P450 1A1 and 3A4, methylenetetrahydrofolate reductase, and cystathionine beta-synthase [4, 7, 8]. In contrast to the inherited cancer predisposition syndromes, genetic polymorphisms in drug-metabolizing enzymes are extremely common; however, these polymorphisms are generally not associated dramatic increase in the risk for the development of leukemia when considered in isolation from other factors [8].

The presentation and diagnosis of t-ML are not different from de novo leukemias [4]. Furthermore, according to WHO, t-MNs have no specific biological features to differentiate them from de novo myeloid malignancies [4].

Therapy-related chronic myeloid leukemia (t-CML) has been reported. However, according to one article, excluding atomic bomb survivors and patients exposed to XR radiation, developing t-CML is less than the risk of developing therapy-related acute myeloid leukemia [9]. A possible explanation is that (a) chronic myeloid leukemia (CML) originates from a more premature progenitor cell, usually less susceptible to DNA damage, and (b) in radiotherapy, the current therapeutic doses are less likely to provoke BCR-ABL fusion as the primary intent is to result in cell death [9, 10].

Papillary and follicular thyroid carcinomas represent differentiated thyroid carcinoma. They arise for the thyroid follicular epithelial cells. Their etiology, presentation, diagnostic, and therapeutic details are beyond the scope of this review. These cancers are treated with surgery, usually total thyroidectomy, and radioactive iodine (RAI) therapy. This combination has resulted in improved long-term prognosis and a lower risk of recurrence.

RAI therapy is a type of nuclear medicine treatment involving ingestion of I¹³¹ intending to destroy and the remnants of thyroid tissue after surgery and to treat metastatic disease. It can be used in other thyroid conditions such as toxic nodular goiter and Graves’ disease. However, since its introduction, concerns have been raised about its possible carcinogenic effects. Previous reports suggested that the risk of leukemia is not increased or maybe mildly increased [11, 12]. For example, in a study of t-ML following RAI, data from multiple German centers between 1982 and 2011 showed that 18/39 developed therapy-related acute myeloid leukemia and 21/39 developed therapy-related myelodysplastic syndromes (8 refractory anemia with excess blasts I/II, 6 refractory anemia with multilineage dysplasia, 3 myelodysplastic syndromes with del(5q), 1 refractory anemia, 1 refractory anemia with ring sideroblasts, 1 chronic myelomonocytic leukemia II, 1 myelodysplastic/myeloproliferative neoplasm unclassifiable) [13]. No t-CML was described. Reports of t-CML following RAI are increasing, and thus, this review is dedicated to highlighting (a) the association of CML after RAI as possible although infrequent complication and (b) document all the reported cases of CML following RAI therapy.

All the reports from the 1960s to date related to CML following radioiodine treatment were searched on Google Scholar and PubMed. We used different search terms, including “CML,” “chronic myeloid leukemia,” “chronic myelogenous leukemia,” “radioiodine,” “I¹³¹,” “radioactive iodine, ”and “radiotherapy,” with Boolean function to search for the relevant articles.

We included all patients aged 18 years or above; a confirmed diagnosis of chronic myeloid leukemia; treatment with radioiodine therapy of any duration and dose. We included all the studies for review, including case reports, case series, and conference abstracts. Cases of CML following RAI ablation that did not report data that we could extract for use in our analysis were not included. Extracted data included (1) histology of thyroid cancer, (2) the dose of RAI, (3) time from administration of RAI to the diagnosis of chronic myeloid leukemia, (4) other treatments offered to patients besides RAI, and (5) other extracted information including age and gender.

We identified ten articles that have reported 14 cases of t-CML following radioiodine (I¹³¹) treatment. The results are represented in Figure 1 and Table 1.

There are some limitations concerning the reports that were reviewed. Ten articles were case reports describing 1 patient each [11, 14, 22]. Two articles are case series reporting 2 patients each [23, 24]. Although these case reports and series helped recognize the problem and potential outcomes of RAI treatment, they lack any statistical power due to their sample size. We omitted non-English language reports from our search criteria, and as a result, we may have missed articles with additional details and reports. A further limitation of case reports is the potential lack of full data.

Of the 14 patients included, the majority were male (9/14), and more than half were under the age of 60 (12/14). Most of the cases (10/14) involved individuals who were younger than 50 years old, with a mean age of 42.7 years and a mode of 35, 51, 48, and 27 years old.

The primary thyroid tumor, for which RAI was administered, was classified as papillary (6/14), follicular (2/14), or mixed papillary-follicular (3/14) carcinoma. One patient had adenocarcinoma, and data were not available for another case. Additionally, 1 patient was diagnosed with Graves’ disease.

The vast majority of subjects included underwent surgical interventions alongside RAI treatment, with only 1 case missing data and 1 case of Graves’ disease. In most cases, total or subtotal thyroidectomy was performed as the primary intervention. Additionally, 2 patients also received external beam radiation as part of their treatment regimen.

The recorded doses of RAI (I¹³¹), expressed in millicurie (mCi), exhibited significant variation throughout the study. As outlined in Table 1, the range of recorded doses extended from 15.32 mCi to 850 mCi, with a mean dose of 287.78 mCi. The modal doses were 15.32, 30, 32.6, 56, 103, 130, 166, 230, 346, 390, 410, 600, 670, and 850 mCi. Similarly, the interval between exposure to I¹³¹ and the onset of CML showed varying lengths, ranging from 10 months to 14 years. The median duration was approximately 5.5 years.

With respect to the chromosomal abnormality, several cases within the study did not provide comprehensive details regarding the chromosomal abnormalities observed. However, none of the reports reviewed mentioned any accompanying chromosome abnormalities other than the Philadelphia chromosome. Among the 14 cases examined, 5 cases reported chromosomal abnormalities as t(9;22) but without further information regarding the breaking point. Meanwhile, 6 cases provided more extensive descriptions of the abnormalities, which were recorded as t(9; 22) (q34;q11.2), t(9;22)(q34;q11), or t(9;22) (e14a2 BCR-ABL1 gene fusion).

The available data regarding treatment and follow-up for t-CML were generally inadequate in most cases. There was no uniform approach to treatment, with various options employed, such as hydroxyurea, interferon-alpha, busulfan, myleran, and tyrosine kinase inhibitors, including imatinib, dasatinib, and nilotinib. However, 2 cases reported complete cytogenic response achieved at the 6-month mark with the use of dasatinib and nilotinib therapy, respectively. Meanwhile, 3 cases noted WBC count stabilization and normalization following treatment with hydroxyurea (2 cases) and imatinib (1 case). Furthermore, 3 cases indicated that the patients were prepared for allogenic stem cell transplantation.

Differentiated thyroid cancer represents the bulk of thyroid cancers. Papillary thyroid cancer (PTC) compromises about 85% of cases compared to about 12% with follicular thyroid cancer characteristics [25]. Data from the Surveillance, Epidemiology and End Results Program (SEER) revealed that the adjusted incidence for PTC has more than doubled between 2000 and 2018, rising from 6.4 to 13.1 per 100,000 population [26]. Approximately 1.2 percent of men and women will be diagnosed with thyroid cancer at some point during their lifetime, based on 2016–2018 data [27].

In the form of I¹³¹ sodium iodide, RAI therapy is administered orally, usually as an adjunct to total thyroidectomy in patients with well-differentiated thyroid cancer. The radionuclide I¹³¹ is a β- and γ-emitting radionuclide with a physical half-life of 8.1 days [28]. Therefore, when indicated, as per American Thyroid Association guidelines, it may be given for (a) remnant ablation, (b) adjuvant therapy, or (c) treatment of persistent disease [25].

Short- and long-term side effects related to RAI have been observed. Our concern is the risk of secondary malignancies, specifically leukemia. For example, one report of over 30,000 patients treated with RAI for thyroid malignancy found a statistically significant increased risk of leukemia as a second malignancy in patients who received radioiodine (excess risk 2.78 per 10,000 person-year) than those who did not (excess risk 0.04 per 10,000 person-year) [29]. Likewise, another study of nearly 7,000 patients examined the risk of secondary malignancies among patients who received I¹³¹ and those who did not; relative risk (RR) was 2.5 for I¹³¹ versus no I¹³¹[30]. Moreover, a systematic review and meta-analysis report found that the RR of leukemia was increased for thyroid cancer survivors treated with RAI (RR = 2.5 [95% CI 1.13, 5.53, p = 0.024]) relative to those not treated with RAI [31]. Other studies have also suggested an increased incidence of hematologic and leukemic malignancies following treatment of differentiated thyroid cancers [32, 35].

Although the studies mentioned earlier concluded that therapy-related leukemia is increased following RAI therapy, the details of which type of myeloid leukemia were not given and the risk was increased within the first 10 years following exposure to I¹³¹. A linear relationship between the cumulative dose of I¹³¹ and the risk of leukemia, in particular, was observed [30]. In addition, a dose higher than 100 mCi was observed to increase the risk of developing secondary leukemias [30, 33]. Although the dose of radiation delivered to the thyroid tissue through I¹³¹ is 1,000- to 10,000-fold higher than that delivered to other tissues, a reasonable justification for the linear relationship is that an increased dose of I¹³¹ would increase absorption by the bone marrow depending on the amount of remnant thyroid tissue reflected by the radioiodine uptake. For example, a dose of 100 mCi of RAI to a patient with 0% uptake would result in an absorbed dose of 0.13 Gy to the bone marrow [36]. While a dose of 108 mCi would result in 0.14 absorption if the uptake is 5%, a dose of 131 would result in 0.17 Gy absorption if the uptake is 10% [36].

The precise mechanism through which RAI provokes leukemia is largely unclear. However, a probable explanation is that RAI induces oxidative stress via the formation of reactive oxygen species, resulting in structural and functional damage to the cellular membrane, DNA strand breakage, DNA base alterations, and eventually cancer development in the instances of inadequate repair of damage [33].

In this review, the largest of the t-CML was diagnosed in the initial 10 years after RAI therapy, and most of them received a dose exceeding 100 mCi. Other factors may have contributed to incidence. Possibilities include genetic predisposition, exposure to other therapies, dietary and environmental factors, and surveillance bias. Many questions remain open. For example, the more significant part of the subjects had PTC histopathology but not follicular in our review. Is there a relationship between PTC and the emergence of leukemia? This question is relevant because some reports have mentioned that PTC has a mutation of the RET protooncogene, which has been linked to leukemia, prostate cancer, and breast cancer.

Although there may be underreporting of t-CML following RAI, this should not discourage researchers from arranging comprehensive studies to address the association and the determinants that may have a role. This review can be considered as groundwork for future investigations. Our group is addressing the unmet clinical needs and addressing the unanswered questions in CML like the association of AIHA [37] and tuberculosis with CML [38], the reactivation of hepatitis B with CML [39], ophthalmic manifestations as initial presentation in patients with CML [40], bariatric surgeries in patients with CML [41], and the effects of intermittent fasting on CML [42].

In summary, the risk of leukemia, namely, t-CML, seems to be extremely low based on current reports and does not present a contraindication to RAI therapy. However, it may be wise to include this risk in the risk-benefit discussion with the patients before initiating this therapy. Long-term follow-up for patients who underwent RAI is advisable for doses over 100 mCi with a complete blood count, possibly yearly, for the first 10 years. The new onset of significant leukocytosis post RAI exposure should raise the suspicion for leukemia and warn further investigation. Further studies are needed to establish or refute a causal relationship.

We wish to show our gratitude to the Internal Medicine Residency Program for their scientific support and Qatar National Library Open Access Program for funding this article.

Ethical approval and consent were not required as this study was based on publicly available data.

Each author declares that he has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangement, etc.) that might pose a conflict of interest in connection with the submitted article.

This study was funded by Qatar National Library.

Yousef Mohammed Ali Hailan, Husam Nabil Al-Duabi, and Mohamed A. Yassin: performed writing, editing, and final approval of the concept.

Data are available on reasonable request. All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.