A rare case of acute basophilic leukemia transformed from high risk myelodysplastic syndrome

Abstract

Acute basophilic leukemia (ABL) transformed from myelodysplastic syndrome is exceedingly rare. We report the case of a 73-year-old man with ABL which transformed from IPSS-M High risk MDS. The patient had a history of metastatic castration-sensitive prostate cancer. Further investigations demonstrated circulating blasts on peripheral blood smear. Upon bone marrow examination, a diagnosis of ABL arising from underlying MDS was established, characterized by cytogenetic analysis demonstrating trisomy 8 (+ 8), with the additional copy of chromosome 8 present in the form of a ring chromosome, and a WT1 frameshift mutation. The patient was treated with azacitidine and venetoclax, followed by best supportive care after disease progression. This case highlights the rare occurrence of ABL secondary to MDS and provides insight into the diagnostic challenges, clonal evolution, and therapeutic limitations associated with this aggressive entity.

Introduction

Myelodysplastic syndrome (MDS) is a neoplastic myeloid proliferation characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a variable risk of transformation to acute myeloid leukemia (AML) [1]. The progression of MDS to secondary AML (sAML) represents a critical progression of the disease and is associated with poorer prognosis and increased therapeutic resistance compared with de novo AML [2]. Among the AML subtypes, acute basophilic leukemia (ABL) is exceptionally rare [3, 4]. It is defined by a proliferation of immature blasts with basophilic differentiation and is often associated with aggressive clinical behavior and, in some cases, symptoms related to histamine release [5]. Here, we report a rare case of ABL arising from underlying MDS. We describe the clinical presentation, diagnostic challenges, cytogenetic and molecular features, and therapeutic course. To the best of our knowledge, this represents the sixth reported case of ABL transformed from MDS.

Case presentation

A 73-year-old Chinese man with a history of metastatic castration-sensitive prostate cancer after palliative radiotherapy to the thoracic spine (T9-11; 20 Gy in 5 fractions) and maintained on Enzalutamide presented with pancytopenia, with a hemoglobin level of 10.1 g/dL, a white blood cell count of 3.9 × 10⁹/L, and a platelet count of 128 × 10⁹/L. His Eastern Cooperative Oncology Group (ECOG) performance status was 0, indicating fully active function without restriction. He denied fevers, night sweats, weight loss, bleeding, or recurrent infections. No symptoms of histamine release (flushing, pruritus, wheezing, or abdominal cramping) were present.

He was referred to our hematology department after his peripheral blood smear (PBS) demonstrated 3% circulating myeloblasts. Dysplastic neutrophils and giant platelets were observed. The initial bone marrow aspirate (BMA) was pauciparticulate and hemodiluted. Some dysplastic neutrophils showed pelgeroid morphology with bilobed nuclei (Fig. 1) suggestive of a myelodysplastic process. Occasional myeloblasts with high nuclear-cytoplasmic ratio and prominent nucleoli were also observed. A marrow fragment with an attached fibrin clot contained atypical mononuclear cells with ovoid nuclei not resembling hematopoietic cells, raising concern for a bone marrow infiltration with carcinoma. However, interpretation was limited by post-radiotherapy hypocellularity. Trephine biopsy was hypocellular with 5% cellularity. Reticulin fibrosis was graded as 0/4. No abnormal cellular infiltrate noted. Focal areas of increased CD117 + cells without corresponding CD34 expression were noted, suspicious of blasts; however, their nature was indeterminate in the context of hypocellularity. Flow cytometry revealed a hypocellular marrow with an increased population of CD34 + myeloblast (3%) and a markedly expanded population of basophils (35%). These basophils showed dim CD117; however, their phenotype was largely similar to that of normal basophils. Minor phenotypic aberrations were observed in both populations, and an atypical post-radiotherapy reaction could not be excluded. Chromosomal karyotyping revealed a normal cell line with an abnormal clone demonstrating a ring chromosome 8 in 16 of 20 metaphases. Fluorescence in situ hybridization (FISH) for MDS showed trisomy 8. Next-generation sequencing (NGS) identified a WT1 mutation with a variant allele frequency (VAF) of 6%.

Fig. 1.

Morphologic, immunophenotypic, and cytogenetic features of MDS transforming to ABL

According to the WHO 2022 classification, the patient met criteria for Myelodysplastic syndrome with low blasts (bone marrow blasts 3%, peripheral blasts 3%). The IPSS-R score (based on cytopenias, blast counts, and cytogenetics) was calculated as high risk (score > 6). The IPSS-M confirmed high-risk disease with a predicted overall survival (OS) of 1.7 years and leukemia-free survival (LFS) of 1.5 years, given the patient’s presentation of pancytopenia, 3% blasts and WT1 mutation. In view of the patient’s background of prostate cancer, he was not eligible for stem cell transplant (SCT). Azacitidine therapy was offered; however, the patient opted for best supportive care and received regular red blood cell and platelet transfusions.

Throughout the first seven months of clinical course, the patient remained infection-free with no hospitalizations. His ECOG remained at 0.

Seven months later, the patient presented to our hospital with weakness, lethargy, mild left occipital headache, difficulty standing and walking. His ECOG was 1 (ambulatory but with some limitations). He had no fevers, bleeding, or infections.

His anemia and thrombocytopenia worsened. His PBS showed prominent basophilia, 5% blasts and worsening cytopenias. The combination of a low reticulocyte count of 56.5, a markedly elevated Lactate dehydrogenase (LDH) of 532, and a low haptoglobin of less than 30 points to ineffective hematopoiesis as the cause, not peripheral hemolysis, consistent with IPSS-M High risk MDS. His BMA was hemodiluted but showed hypercellular fragments. The slide displayed 66% basophilia, an increase in blasts to 10% and megaloblastic erythroblast maturation. Trephine biopsy revealed equivocal CD34 and CD117 staining in some areas. Reticulin deposition was graded 3+/4. The progression to grade 3 reticulin fibrosis likely contributed to the increasing difficulty in marrow aspiration and reflected advancing disease. Flow cytometry revealed an infiltration of 77% CD123+/CD203c+ basophils with aberrantly decreased heterogeneous CD11b expression and partially increased CD117 expression, while retaining a typical CD13+/CD33+/CD35+/CD45 dim phenotype. Additionally, 6% CD34+/ CD117 + myeloblast were identified, having an aberrant expression of CD15-heterogeneous/CD38-dim/CD7-partial and nuTDT-dim. Chromosomal karyotyping again demonstrated a ring chromosome 8 seen in 17 of 20 metaphases. Repeat NGS showed a persistence of WT1 mutation with 10% VAF.

The overall findings including dominant basophilic population (77%) with aberrant immunophenotype, increase in blasts to 10%, and persistence of clonal abnormalities, were consistent with transformation from MDS to ABL. Per WHO 2022, ABL is classified as a distinct subtype of AML, not otherwise specified (AML-NOS) with basophilic differentiation. Per ELN 2022, given the adverse-risk features (WT1 mutation, ring chromosome 8/trisomy 8, secondary etiology from MDS), the disease was categorized as adverse risk.

Although the patient had a low ECOG of 1 at transformation and had no active infections, intensive chemotherapy regimens such as CPX-351 or 7 + 3 were deemed unsuitable for this rare ABL subtype. First, ABL is notoriously chemoresistant, and no published data support CPX-351 (also unavailable in Singapore) in ABL specifically. Second, his active metastatic castration-sensitive prostate cancer required ongoing enzalutamide therapy, with concerns for drug-drug interactions and overlapping toxicities. Third, the presence of grade 3 marrow reticulin fibrosis at transformation is associated with poor marrow recovery following intensive chemotherapy. Fourth, the patient declined intensive intravenous chemotherapy after detailed discussion of risks. Therefore, azacitidine and venetoclax were selected as a less toxic, orally convenient option, acknowledging the lack of standard-of-care therapy for ABL.

The patient developed a fever secondary to a nosocomial infection while on posaconazole prophylaxis. The infection was treated before continuing azacitidine and venetoclax. Post-treatment, the patient’s PBS showed myelocytes, 50% basophilia, some immature looking basophiles and occasional myeloblasts, suggesting persistent disease. BMA reassessment after the first cycle of azacitidine and venetoclax was aparticulate, but blast counts increased to 10%. Prominent basophilia and immature basophils were observed. The aspirate displayed pelgroid neutrophils and hemosiderin-laden macrophages with no mast cells identified. This finding is consistent with ineffective erythropoiesis and intramedullary destruction of red blood cell precursors, confirming the underlying pathophysiology of this patient’s IPSS-M High risk MDS. Trephine showed increased reticulin staining with focal increased intersection (1–2+/4). Flow cytometry revealed 60% infiltration by CD123+/CD203c+ basophils. The basophils showed similar aberrant phenotype to the prior sample (CD11b-heterogeneous/CD117partial expression) and a small 3% population of CD34het/CD117 + myeloblasts expressing the previous aberrant CD15-heterogeneous/CD38dim/CD7partial phenotype. Chromosomal karyotyping again showed a ring chromosome, indicating persistent disease.

Post cycle 2 of azacitidine and venetoclax, the patient continued to exhibit anemia and thrombocytopenia. PBS showed a rising peripheral blast count of 25% with occasional immature basophils. The increasing myeloblast counts indicates disease progression. A repeat BM reassessment revealed a clotted, hemodiluted aspirate and persistent morphological features of ABL. The aspirate revealed hypocellularity with trilineage hypoplasia and medium-sized immature cells are also observed. Trephine reticulin was 2+/4. Flow cytometry demonstrated a significant increase and expansion of the proportion of CD34+/CD117 + myeloblast (19%) which were CD13++/CD33 + and demonstrated new aberrancies of HLADR-/CD64 partial/nuTDT dim expression. CD123+/CD203 + basophils remained increased (13%) with up to 40% of basophils expressing CD117 and partial loss of maturation markers such as CD11b and CD35 suggesting phenotypic immaturity. Monocytes demonstrated aberrant CD56+. Chromosomal karyotyping continued to show ring chromosome 8 with an increase to 18 of 20 metaphases confirming refractory disease. A diagnosis of ABL with increased myeloblast was made. After two cycles of azacitidine and venetoclax without response, treatment was discontinued and the patient transitioned to best supportive care. Five months later, he succumbed to disease.

Discussion

This case illustrates several diagnostically and biologically challenging aspects of ABL, including its evolution from myelodysplastic syndrome (MDS), overlapping immunophenotypic features with reactive basophilia, and refractoriness to hypomethylating agent-based therapy.

In this patient, the initial presentation with pancytopenia, dysplastic myeloid features, hypocellular marrow, and trisomy 8 supported a diagnosis of MDS, possibly therapy-related given prior radiotherapy. Ionizing radiation is a recognized risk factor for secondary myeloid neoplasms and the presence of ring chromosome 8 with trisomy 8 further supports a clonal myeloid process [6, 7]. Although metastatic prostate carcinoma and post-radiotherapy marrow hypoplasia complicated the initial interpretation, the presence of cytogenetic abnormalities and emergence of abnormal basophilia supported the diagnosis of a clonal disorder consistent with an underlying diagnosis of MDS [8–10]. The progression from MDS to ABL in this case is notable, as ABL more commonly arises in association with chronic myeloid neoplasms, particularly chronic myeloid leukemia in blast phase or in exceedingly rare cases, de novo [11, 12]. Transformation from MDS to ABL is exceedingly rare and sparsely reported. Published literature consistently highlighted poor prognosis, with survival ranging from 2 months to 6 months. The patients were originally diagnosed with different MDS subtypes, including refractory anemia, refractory anemia with excess blasts and refractory cytopenia with multilineage dysplasia. Patients exhibited diverse complex karyotypes, including complex karyotypes such as monosomy 7 (− 7), 46,XY, del(5)(q31q35), and − 7 with add(1)(q21) [13–17]. Our case extends this list, being the only reported case of a patient with trisomy ring chromosome 8 who has survived 10 months. This underscores the importance of recognizing abnormal basophilic populations in MDS patients, particularly when accompanied by cytogenetic evolution and increasing blast counts.

Immunophenotypic characterization played a critical role in diagnosis. The basophilic population consistently expressed CD123 and CD203c, markers considered highly sensitive and relatively specific for basophilic lineage. Normal basophils are typically negative for CD117, and the presence of dim or aberrant CD117 expression represents an important clue to basophilic neoplasia rather than reactive basophilia, as previously described [18]. Aberrant expression patterns, including partial CD117 expression and loss of maturation markers such as CD11b and CD35, supported the presence of immature and neoplastic basophils rather than reactive basophilia. Although mast cells also express CD203c, they can be readily distinguished from basophils by their lack of CD123 expression and their characteristically bright CD117 (c-KIT) expression, allowing exclusion of mast cell disease in this case [19].

Molecular studies revealed a persistent WT1 frameshift mutation that doubled in VAF over seven months provided molecular evidence of clonal evolution and disease progression. WT1 mutations have been associated with high-risk myeloid neoplasms, disease progression, and poor prognosis, particularly in secondary AML [20]. The mutation alongside a presentation of pancytopenia and blast observations gave rise to a categorisation of IPSS-M high risk [21]. The additional variants detected in ANKRD26 and PBX1 were of uncertain significance but may reflect clonal hematopoiesis or age-related genomic instability rather than direct leukemogenic drivers. Importantly, no targetable mutations were identified, limiting therapeutic options [22]. Ring chromosome 8, which in this case resulted in trisomy 8 and was formed by breakage and fusion of both arms of chromosome 8, is a rare abnormality in MDS and AML and has been associated with genomic instability and poor prognosis [23].

The choice of azacitidine and venetoclax for our patient was guided by his risk profile, treatment ineligibility, age and molecular landscape. Although his initial marrow was markedly hypocellular (5% cellularity), immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine was contraindicated. IST is generally reserved for hypoplastic MDS patients with favorable features, such as absence of high-risk mutations, presence of a PNH clone, or HLA-DR15 positivity, and without excess blasts. Our patient, by contrast, was classified as IPSS-M High-risk, carrying a clonal cytogenetic abnormality (trisomy ring chromosome 8), a pathogenic WT1 mutation, and 3% peripheral blast. Collectively, these factors predict poor IST response and instead favor hypomethylating agent (HMA)-based therapy [24, 25]. Furthermore, his disease was actively transforming from high-risk MDS to sAML. In this setting, venetoclax combined with an HMA has demonstrated activity and is widely used, particularly in older or transplant-ineligible patients, owing to its lower intensity compared with regimens such as CPX-351 or 7 + 3 [26, 27]. Our 73-year-old patient was ineligible for stem cell transplantation due to both his advanced age and active metastatic prostate cancer. However, it must be acknowledged that data on venetoclax efficacy in ABL specifically are extremely limited, and no prospective studies have addressed this rare subtype [28]. Adding to the therapeutic complexity, molecular profiling revealed no actionable mutations (e.g., IDH1/2, FLT3, KIT), thereby excluding targeted inhibitors such as ivosidenib, enasidenib, gilteritinib, or avapritinib. Moreover, no clinical trials of novel oral targeted agents were available at the time of treatment [29]. Compounding these challenges, the presence of grade 3 reticulin fibrosis at transformation, a finding independently associated with poor survival in MDS patients, likely contributed to his unfavorable outcome [30]. Despite two cycles of azacitidine and venetoclax, the disease proved ultimately refractory, with persistent basophilic infiltration, rising blast counts, and increasing cytogenetic burden. These findings collectively highlight the intrinsic chemoresistance of ABL and the current absence of a standard-of-care therapy for this entity [31]. Given the refractory disease course, limited evidence-based therapeutic options, and the patient’s preference, the transition to best supportive care was deemed appropriate.

This case offers four clinically actionable lessons for evaluating atypical myeloid disorders. First, although persistent or dominant basophilia may occasionally be reactive, it should nevertheless prompt careful evaluation for an underlying clonal basophilic neoplasm, particularly in patients with MDS or prior cytotoxic exposure. Second, multiparametric flow cytometry with basophil-specific markers such as CD123 and CD203c is essential for accurate diagnosis, as it helps distinguish basophilic blasts from myeloblasts and other myeloid neoplasms. Third, this case demonstrates that ABL may evolve dynamically, with shifting proportions of basophils and myeloblasts over time. This necessitates serial immunophenotypic and cytogenetic assessments to capture disease evolution and guide timely therapeutic adjustments. Finally, therapeutic innovation is urgently needed. There remains a critical need for improved molecular characterization and targeted therapeutic strategies for this rare and aggressive leukemia. Current treatment paradigms are largely extrapolated from other AML subtypes and fail to address the unique biological drivers of ABL.

Conclusion

This case highlights the rare transformation of MDS to ABL, particularly in the context of prior radiotherapy. It illustrates the diagnostic challenges posed by overlapping reactive and neoplastic basophilia and emphasizes the importance of comprehensive immunophenotypic, cytogenetic, and molecular evaluation. Given the aggressive and refractory nature of secondary ABL, further studies are needed to elucidate its pathogenesis and to develop effective therapeutic strategies.

Author contributions

CAG: Conceptualization of case report, initial drafting, data collection and analysis, writing, editing and supervision.YYH: Conceptualization of case report, initial drafting, data collection and analysis, writing, editingWYJ: Data analysis, writing, editing and supervisionSH: Data collection and analysisXWA: Data collection and analysis, writing, editing and supervision.PWEC: Data collection and analysisKGEL: Data collection and analysisJEIL: Data collection and analysisSYL: Data collection and analysis, writing, editing and supervision.BEF: Conceptualization of case report, initial drafting, data collection and analysis, writing, editing and supervision.

Funding

No funding was required for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Statement of ethics

This study followed the principles of the Declaration of Helsinki, and informed consent was obtained from the patient’s family for publication of this case report. Ethics approval by the National Healthcare Group was not required for publication of case reports.

Consent to publish

Informed consent was obtained from the patient for publication of this case report and for the use of accompanying images.

Competing interests

Bingwen Eugene Fan is corresponding author of this article and also acts as an Editorial Board member for the journal.