Secondary acute myelomonocytic leukemia in untreated follicular lymphoma: A case report

INTRODUCTION

Follicular lymphoma (FL) is an indolent B-cell neoplasm, accounting for roughly 20% of lymphomas diagnosed in Japan.^[1] Although it generally progresses slowly and carries a favorable prognosis, FL has been linked to an elevated risk of developing secondary malignancies, including both hematologic and non-hematologic cancers.^[2] In current clinical practice, patients with low tumor burden and no minimal symptoms are often managed using a “watch-and-wait” approach, delaying immediate treatment until disease progression.^[3] While widely accepted, this strategy requires careful long-term monitoring, since disease transformation or secondary neoplasms can arise during the observation.

Here, we report a rare case of acute myelomonocytic leukemia (AMMoL) developing only 8 months after initial surveillance for untreated FL, emphasizing the need for ongoing vigilance even under conservative management.

CASE REPORT

A man in his 70s, with a 15-year history of diabetes and 5 years of maintenance dialysis, underwent a routine health check in December, year 20 XX, during which a 20 mm reddish depressed lesion was detected in the gastric antrum. He was admitted for endoscopic submucosal dissection (ESD) in March, year 20XX+1. Pre-operative imaging revealed left axillary lymphadenopathy. A lymph node biopsy in April, year 20XX+1, showed diffuse proliferation of small atypical lymphoid-like cells. Immunohistochemistry was positive for leukocyte common antigen (LCA) and CD20, and negative for CD3, diagnosed as stage 1 FL. Observation was chosen as the management strategy. Complete blood count counts from December 20XX to January 20XX+2 have been presented in Figure 1. The progression of anemia observed in March and September 20XX+1 was considered to be associated with the effects of ESD and subsequent bleeding. In April 20XX+1, at the diagnosis of FL, no leukemic cells were observed [Figure 1]. In December, year 20XX+1, peripheral blood tests revealed monocytosis (6.3 × 10³/μL, monocytes 24%) and the presence of blast-like cells (2%: Counted as “Other”) [Figures 1 and 2, Table 1]. Bone marrow aspiration showed that blasts accounted for 32% of cells, with 20.6% promonocytes. These cells were partly positive for both naphthol AS-D chloroacetate and a-naphthyl butyrate staining, supporting a diagnosis of AMMoL [Figure 2]. Flow cytometric analysis indicated that the blasts expressed CD4, CD33, CD56, CD64, CD11b, CD11c, myeloperoxidase, and human leukocyte antigen-DR isotype, and were mostly negative for CD14 and CD34 [Figure 3]. These features were consistent with the flow cytometric features of AMMoL.^[4] Cytogenetic analysis revealed trisomy 11 (47, XY, +11 (20/20 metaphases). Due to the patient’s advanced age and impaired cardiac function (ejection fraction 31%), intensive chemotherapy was deemed unsuitable. Venetoclax plus azacitidine was considered; however, due to infection control issues and worsening cardiac status, therapy could not be initiated. The patient was transferred to another facility for the best supportive care.

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Figure 1:

Trends in peripheral blood counts from October 20XX to January 20XX+2. (a) Changes in white blood cell count and differential. (b) Changes in hemoglobin, platelet, and red blood cell counts. Promyelo: Promyelocyte, Myelo: Myelocyte, Metamyelo: Metamyelocyte, Stab: Stab neutrophils, Seg: Segmented neutrophils, Eo: Eosinophils, Baso: Basophils, Lymph: Lymphocytes, Mono: Monocytes, WBC: White blood cells, RBC: Red blood cells.

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Figure 2:

(a-b) Morphological images of peripheral blood, and (c-f) bone marrow at initial diagnosis. (a-c) Morphological image with ×100 magnification. (b and d-f) ×400 magnification. (a-d) May-Giemsa staining. (e) Peroxidase staining. (f) Esterase double staining, stained with naphthol AS-D chloroacetate staining and alfa-naphthyl butyrate staining.

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Figure 3:

Flow cytometric analysis of bone marrow cells at diagnosis. (a) The left panel shows the leukemic population identified as the CD45 dim blast cluster, which was used for subsequent immunophenotypic analysis. (b) The right panels display representative staining results for two selected antibodies. Flow cytometric analysis demonstrated that the blasts were positive for CD4, CD13, CD33, CD56, CD64, CD11b, MPO, CD11c, and HLA-DR, and negative for CD14 and CD34. CD: Cluster of differentiation, HLA-DR: Human leukocyte antigen-DR isotype, MPO: Myeloperoxidase.

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DISCUSSION

Dinnessen et al.^[2] reported that among 13,652 FL patients, 1762 (12%) developed secondary malignancies over a median follow-up of 5.5 years, including 65 acute myeloid leukemia (AML) cases. The incidence of second primary malignancies (SPMs) was 42% higher than in the general population. Common SPMs included skin squamous cell carcinoma, lung cancer, and AML, suggesting links to immune dysregulation and DNA damage from prior treatments. Giri et al.^[5] studied 15,517 FL patients over a median of 71 months and found that 9.9% developed SPMs, with a standardized incidence ratio (SIR) of 1.08 and an absolute excess risk of 11.3/10,000 person-years. Risks were particularly elevated for Hodgkin lymphoma (SIR 5.85), AML (SIR 4.88), and certain solid tumors; age >65 years (SIR 1.57), male sex (SIR 1.43), and prior radiation (SIR 1.24) were notable risk factors. These findings highlight the need for risk-adapted surveillance strategies and long-term follow-up in FL survivorship care. Another study of 19,326 grade I-II FL patients demonstrated that initial chemotherapy (49.36%) or radiotherapy (14.95%) significantly increased the risk of developing myeloid neoplasms, including myelodysplastic syndrome (MDS) (hazard ratio (HR) 1.85), AML (HR 2.22), and AML-Myelodysplasia-Related Changes (MRC) (HR 3.42),^[6] highlighting the rarity of secondary AML (s-AML) in untreated cases.

Cytogenetic analysis in this patient revealed trisomy 11. Eisfeld et al.^[7] reported that among 1,625 AML patients, 23 (1.4%) had isolated +11; up to 90% had mixed lineage leukemia (MLL) partial tandem duplication (MLL-partial tandem duplication (PTD)), and frequent mutations in DNA methyltransferase 3A (DNMT3A), U2 small nuclear RNA auxiliary factor 1 (U2AF1), Fms-like tyrosine kinase 3 – Internal Tandem Duplication (FLT3-ITD), and Isocitrate Dehydrogenase 2 (IDH2) were observed. MLL-PTD is often found in myeloid dysplasia syndromes, s-AML, and de novo AML. The presence of an MLL rearrangement generally indicates poor prognosis.^[8] These molecular features may be involved in the pathogenesis of +11 AML.

FL typically follows an indolent course, allowing many patients to be observed without immediate therapy. In this case, AMMoL developed only 8 months after FL diagnosis, notably without any prior chemotherapy. This unusually early transformation underscores the importance of careful monitoring, even in patients with FL managed by watchful waiting.

We report a rare case of secondary AMMoL emerging during the observation period, only 8 months after the diagnosis of FL. This unusually early occurrence highlights the importance of close surveillance even in FL patients managed conservatively.

CONCLUSIONS

We report an exceptionally rare case of secondary AMMoL developing only eight months after the diagnosis of chemotherapy-naïve FL. This case highlights that even in patients managed conservatively with a “watch-and-wait” strategy, early leukemic transformation can occur. Vigilant and continuous surveillance is therefore essential for timely detection of secondary hematologic malignancies in FL patients, regardless of initial treatment strategy.