Early Occurrence of Therapy-Related Acute Myeloid Leukemia (t-AML) with Monocytic Differentiation with Trisomy 8 Cytogenetic Abnormality after Radioactive Iodine (RAI) Treatment for Papillary Thyroid Cancer

Background: Although most t-AML occurs after chemotherapy +/- radiation, exposure to radioactive substances can be implicated, as in nuclear accidents. Thyroid cancer is the most commonly endocrine malignancy. The relative risk of second primary malignancy in thyroid cancer patients is higher in those treated with RAI than those without, with a notable 2.5-fold increase risk of leukemia. The excess leukemia risk is greater in patients < 45 yrs compared with older patients. Recent reviews have attempted to characterize cytogenetic and molecular abnormalities from RAI related t-AML. We present the case of a young woman who developed AML with monocytic differentiation and Trisomy 8 cytogenetic abnormality after RAI treatment for thyroid papillary carcinoma.

Case Presentation: A 29-year-old Chinese woman presented with worsening fatigue and menorrhagia over 3 months. Initial workup revealed pancytopenia (WBC 1.7, Hb 8.3, Hct 24, PLT 44, ANC 0.7). She had a history of papillary thyroid carcinoma, classic type, treated with total thyroidectomy followed by RAI ablation with 99 mCi of I-131 2 years prior. She had been without evidence of residual/recurrent disease since then. Her only home medication was Levothyroxine and had no other toxic exposure. Physical exam was unremarkable. Serology was negative for HIV, Hepatitis B or C. Peripheral smear showed decreased WBC count, few circulating blasts, atypical monocytes, and decreased platelets. Bone marrow aspiration and biopsy showed marked hypercellular marrow (100%) replaced by sheets of myeloid appearing-blasts, increased medium/large size CD68+ monoblasts with moderate basophilic vacuolated cytoplasm, as well as promonocytes comprising 90% of nucleated marrow cells. This was consistent with AML with monocytic differentiation. Flow Cytometry confirmed presence of HLA-DR, CD56, CD64, CD2, CD5, CD4, and CD11+ myeloblasts (27% of total cells) with increased CD56+ monocytes (23%). Cytogenetic analysis identified trisomy 8. Molecular testing was negative for FLT3 ITD and FLT3 TKD mutations by PCR, and negative for PML-RARA rearrangement by FISH.

The patient was started on induction chemotherapy with cytarabine 100 mg/m2 daily as continuous infusion on days 1-7 + Idarubicin 12 mg/m2 daily for days 1-3 (7+3 regimen). Repeat bone marrow evaluation on day 14 revealed complete histologic and cytogenetic response. She received three cycles of consolidation with high dose cytarabine 3 g/m2. She is presently awaiting identification of a matched donor for allogeneic hematopoietic stem cell transplantation.

Discussion: t-AML is a distinct subgroup of AML in 2008 WHO classification for their attributed worse outcome than their de novo counterparts with the same genetic abnormalities [except inv(16)(p13.1q22), t(16;16)(p13.1;q22) or t(15;17)(q22;q12)], suggestive of biologic differences. However, these findings are largely derived from patients who received cytotoxic treatment with topoisomerase II inhibitors, alkylating agents and/or RT. In contrast, little is known about outcome and prognosis in t-AML from RAI. We present a young woman with RAI related t-AML with monocytic differentiation and trisomy 8 after a 2-year latency who responded to standard induction and consolidation chemotherapy. To our knowledge the monocytic differentiation with Trisomy 8 was previously unreported.

Retrospective studies and case series suggest that median latency of RAI related t-AML is ~ 7 yrs, in bimodal distribution peaking at 1-3 years and later at 8-10 years. 68% of t-AML from RAI have abnormal karyotype, with chromosomes 7, 5, and 8 most commonly involved, notably del 7q. FAB M2, M3, and M4 represented the vast majority of cases. Compared to patients with other t-AML, RAI-related AML tend to have significantly inferior survival. This suggests a unique mechanism of secondary primary malignancy, possibly via the Na(+)/I(-) symporter, a membrane glycoprotein that mediates active iodide uptake in thyroid and other tissues.

Conclusion: t-AML from RAI is an under-recognized and under-reported form of AML, with unclear mechanism, wide-spectrum cytogenetic abnormalities and histology, undefined dose-risk ratio, and decreased survival. As the incidence of thyroid cancer increases, and utilization of RAI becomes more frequent, further investigation is needed to better characterize this unique entity, early detection and its optimal treatment.