Acute promyelocytic leukemia (APL) is a distinct subtype of AML characterized classically by the balanced translocation t(15;17)(q24;q21), resulting in the PML-RARA fusion gene [1]. This entity corresponds to “AML with PML-RARA” in the World Health Organization classification and the recent International Consensus Classification [2].

Variant RARA rearrangements account for approximately 1–2% of APL cases and involve alternative partner genes such as ZBTB16 (PLZF), NPM1, NUMA1, and STAT5B [3]. Among these, t(11;17)(q23;q21), resulting in the ZBTB16-RARA fusion, is one of the most well-described variants [4]. These cases often show atypical morphology, aberrant immunophenotype, and resistance to all-trans retinoic acid (ATRA), making early recognition clinically critical [5].

A 9-year-old female child presented with fever, generalized weakness, gum hypertrophy, and bicytopenia for two weeks. There was no prior significant medical history. Examination revealed pallor, petechiae, and mild hepatosplenomegaly. Hematological Findings: Complete blood count showed: • Hemoglobin: 6.8 g/dL • Total leukocyte count: 48,000/µL • Platelet count: 22,000/µL Peripheral smear demonstrated circulating blasts (38%) with moderate cytoplasm and irregular nuclear contours. Classic hypergranular promyelocytes or multiple Auer rod bundles (“faggot cells”) were not identified. Bone Marrow Findings Morphology Bone marrow aspirate was markedly hypercellular with approximately 70% blasts. The blasts were medium to large in size with irregular to folded nuclei, fine chromatin, occasional nucleoli, and moderate cytoplasm. Some cells exhibited monocytic features including nuclear indentation and cytoplasmic vacuolation. Cytochemical staining showed variable myeloperoxidase positivity. Cytochemistry: Blasts were positive in MPO stain and negative in PAS stain. Based on morphology and cytochemistry, a diagnosis of AML with monocytic differentiation was considered. Flow Cytometry / Immunophenotype Multiparametric flow cytometry revealed a blast population expressing: In the blast region: Positive markers: Strong: CD15, CD33, CD38, cyMPO Moderate: CD4, CD11c, CD34, CD56, CD64, CD117, CD123, HLADR Dim: CD13, CD14, CD36, CD71, CD303, CD304 Negative markers: CD7, CD19, CD41a, CD61, nTDT, cyCD3 and cyCD79a In the Promonocytic and monocytic region: Positive markers: Strong: CD11c, CD14, CD15, CD33, CD38, CD64, HLA-DR Moderate: CD4, CD34, CD36, CD56, CD117, CD123, cyMPO Dim: CD13, CD71, CD303, CD304 Negative markers: CD7, CD19, CD41a, CD61, nTDT, cyCD3 and cyCD79a The immunophenotypic profile was consistent with acute myelomonocytic leukemia (AML with monocytic differentiation). Cytogenetic Analysis Fluorescence in-situ hybridisation (FISH) FISH-AML panel test was performed on bone marrow aspirate and demonstrated: Fluorescence in situ hybridisation analysis was performed with AML panel which included BCR/ABL1, PML-RARA, KMT2A (MLL), RUNX1-RUNX1T1 (AML/ETO) and CBFB probes [Metasystem]. 200 interphase cells were scored for each probe or probe confirmation. FISH results analysed showed: 1. BCR/ABL1 t(9;22) – Translocation not detected 2. KMT2A Gene (11q23) – Rearrangement detected 3. PML/RARA t(15;17) – Translocation not detected 4. RUNX1-RUNX1T1 t(8;21) – Translocation not detected 5. CBFB inv(16) – Rearrangement not detected Conventional karyotyping of bone marrow cells demonstrated: Report: 46,XX, t(11;17)(q23;q21)[13]/46,XX[1] ISCN 2024 Thirteen analysed metaphases revealed translocation between chromosome 11 and 17 at the break points q23 and q21 respectively. Finding was in favour of Acute Promyelocytic Leukemia with variant translocation and normal karyotype in one metaphase. Figure 1: FISH analysis of KMT2A Gene (11q23) break-apart probe. The white arrows depict the rearrangement of the KMT2A Gene. Case no.: AML 04/26. Figure 2: Fish analysis of PML/RARA t(15;17) break-apart probe. No translocation is seen in PML/RARA t(15;17) probe. Case no.: AML 04/26. Figure 3: G-Banding Karyotype analysis of the case CG-14-2026. 46,XX,t(11;17)(q23;q21)[13]/46,XX[1] ISCN 2024. The red arrows depict the t(11 ;17) translocation in the ‘q’ arms of the chromosomes 11 and 17 respectively. Figure 4: Bone marrow image showing atypical blast morphology in increased number lacking auer rods, consistent with AML with monocytic differentiation. Figure 5: Bone marrow image demonstrating atypical cells / blasts in myeloperoxidase positive staining.

APL is characterised by RARA rearrangements that disrupt retinoic acid signaling and block myeloid differentiation [1]. While t(15;17) is the hallmark abnormality, variant RARA rearrangements constitute a small but clinically significant subset [3].

This translocation is known to involve the RARA gene on chromosome 17 and ZBTB16 (formerly PLZF) on chromosome 11, consistent with a variant form of APL.

The t(11;17)(q23;q21) translocation results in the ZBTB16-RARA fusion gene [4]. Unlike classical PML-RARA APL, these cases frequently:

• Exhibit atypical morphology
• May show increased numbers of regular granules rather than heavy hypergranularity.
• Often lack typical Auer rods
• Demonstrate variable HLA-DR expression
• Show resistance to ATRA ( All Trans Retinoic Acid) therapy [5,6]

In the present case, morphology and immunophenotype initially suggested AML with monocytic differentiation. The presence of HLA-DR positivity and monocytic markers further supported this impression. In molecular cytogenetics, FISH revealed NO translocation or rearrangements, However, conventional karyotype revealed a defining RARA rearrangement with the partner gene ZBTB16.

This case highlights several key diagnostic lessons:

1. Morphology alone may be misleading in variant APL.
2. Flow cytometry profiles may deviate from classical APL patterns.
3. Conventional karyotyping remains critical in suspected AML cases.
4. Accurate identification impacts therapy, as ZBTB16-RARA APL is often resistant to all trans retinoic acid and may require conventional AML-type chemotherapy [5,6].

In paediatric populations, variant APL is particularly rare, and literature describing such presentations remains limited [7].

We report a rare case of variant APL with t(11;17)(q23;q21) in a 9-year-old female child presenting with morphologic and immunophenotypic features suggestive of AML with monocytic differentiation. This case underscores the importance of an integrated diagnostic approach incorporating morphology, flow cytometry, and cytogenetics for accurate classification and appropriate therapeutic decision-making.

Conflicts of Interest: Nil.

Funding: Self-funded.