A 53‐year‐old woman with a history of longstanding mild leukopenia and thrombocytopenia presented with pancytopenia and 49% blasts. Peripheral blood showed leukocytes 61 × 109/L, neutropenia 1.2 × 109/L, anemia 80 g/L, and thrombocytopenia 10 × 109/L with dysplastic hypogranular granulocytes. Bone marrow aspirate illustrated granulocytic dysplasia (Figure 1, panel A) and two blast populations: small‐to‐intermediate and large‐sized blasts. No significant erythroid or megakaryocytic dysplasia was identified. Flow cytometry revealed 87.76% blasts expressing CD34+/CD117+/HLADR+/TdT+/CD13+/CD33+/CD38+/cMPO+ (variable); a subset of blasts (11%) expressed CD19+ (dim)/CD10+/CD22+ (strong)/CD79+ (strong) (Figure 1, panel B). Bone marrow biopsy (Figure 1, panel C) showed sheets of CD34+/CD117+/TdT+ (Figure 1, panel C, inset)/MPO+ blasts (Figure 1, panel D); a subset was positive for PAX5+/CD79+ (Figure 1, panel E). A diagnosis of Mixed‐phenotype acute leukemia (MPAL), B/Myeloid, was contemplated. Cytogenetics and Optical Genome Mapping (OGM) revealed normal karyotype (NK). Next generation sequencing (NGS) identified SRSF2 (VAF:51.1%), ASXL1 (VAF:48.6%), and FLT3‐TKD (VAF:36.0%), plus CBL/PTPN11/KDM6A/NRAS mutations. Given the SRSF2/ASXL1 co‐mutations, MDS‐associated mutations or AML, myelodysplasia‐related (AML‐MR) defining mutations per WHO HAME5, a diagnosis of AML‐MR was rendered per WHO HAEM5's suggestions. The patient received ALL‐based induction therapy and midostaurin given the mixed B‐lineage immunophenotype and institutional practice patterns for MPAL‐like presentations. Unfortunately, the treatment failed with refractory leukemia (28% blasts). Salvage therapy with MEC demonstrated complete morphological remission; the patient was on bridging INDAC for bone marrow transplant.
FIGURE 1.
(A) Bone marrow aspirate shows increased blasts with small‐to‐intermediate and large‐sized blasts, some with hand mirror form and granulocytic dysplasia with hypogranular cytoplasm. (B) Flow cytometry shows blasts were CD34+, CD19+ (dim), CD10+, CD22+, CD79a+, TdT+, and cMPO+ (variable). (C) Bone marrow Biopsy shows diffuse infiltration of blasts, TdT+ (C, inset). The blasts were MPO+ (D) and CD79+ (E).
Although SRSF2, ASXL1, FLT3, and NRAS individually are reported enriched in MPAL, their co‐mutations in MPAL are rare. SRSF2/ASXL1 co‐mutations, granulocytic dysplasia, dim CD19+, and failed first induction suggest AML‐like MPAL [1, 2]. FLT3‐TKD offers a therapeutic target. The current classifications (both WHO‐HAEM5 and ICC) are ambiguous regarding the categorization of acute leukemias of ambiguous lineage (ALAL), including MPAL when MDS‐associated mutations are present. They recommend excluding cases with ambiguous immunophenotypes from the ALAL category if they harbor MDS‐associated mutations, suggesting these cases may be more appropriately classified as AML‐MR. Recent studies [2, 3] demonstrated ALAL harboring MDS‐associated mutations exhibit a biological, clinical, and prognostic similarity comparable to that of AML‐MR rather than MPAL, supporting this recommendation. Future large‐scale studies including integrative genomic and transcriptomic profiling, in addition to NGS and OGM, may be required to further clarify diagnostic and therapeutic implications.
Author Contributions
Dr. Zhaodong Xu prepared the manuscript and figure; Dr. Monika Hudoba revised the manuscript and contributed to the diagnosis.
Funding
The authors have nothing to report.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.