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• W3147925311 abstract "BCR/ABL1 rearrangement or t(9;22)(q34.1;q11.2) is the most common recurrent cytogenetic abnormality seen in B/myeloid mixed phenotype acute leukemia (MPAL) but is also present in ~50% of adult B-ALL (Swerdlow et al., 2017). Both entities can demonstrate B lymphoblasts with aberrant myeloid expression; however, an important immunophenotypic finding that distinguishes MPAL from B-ALL with aberrant myeloid expression is reciprocal intensities of myeloid and lymphoid markers. This pattern is emphasized as the most recognizable feature of MPAL in the WHO classification but there are few examples in the literature demonstrating its practical application. Herein, we highlight this signature inverse expression characteristic using a case of MPAL B/myeloid with BCR/ABL1. Detailed methodology and antibody panels have been previously described in Cytometry B (DOI: 10.1002/cyto.b.21979). In brief, sodium heparin anticoagulated bone marrow (BM) was processed within 6 h of collection. BM specimens were washed twice using 37°C phosphate-buffered saline and adjusted to ~10 × 109/L. One hundred microliter were stained using antibody panels per DOI: 10.1002/cyto.b.21979. Specifically, the markers presented here included: CD10-APC-AF700 (ALB1), CD13-PE (SJ1D1) CD19-APC-AF700 (J3-119), CD19-APC-A750 (J3-119), CD19-ECD (J3-119), CD33-PC5.5 (D3HL60.251) CD34-PC7 (581), CD45-KO (J.33) CD117-APC (104D2D1) cCD79a-APC (HM47) and cMPO-PE (CLB-MPO-1), all antibodies from Beckman Coulter (BC). For surface staining, cells were incubated for 15 min in the dark at room temperature, and then lysed using VersaLyse (BC, ref. A09777) and IOTest-3 fixative (BC, ref. A07800). For intracellular staining BC IntraPrep™ reagent kit (BC, ref. A07802) was used according to manufacturer's instructions. After washing, samples were suspended in IOTest-3 Fixative (BC, ref. A07800) and PBS. A minimum of 50 × 103 CD45+ events were acquired on a Navios™ Flow cytometer (BC) within 1 h of preparation. Listmode data files were analyzed using Kaluza analysis software (BC, v1.3). Fluorochrome abbreviations: Phycoerythrin (PE), Phycoerythrin Texas Red-X (ECD), Phycoerythrin Cyanin 7 (PC7), Allophycocyanin (APC), Allophycocyanin Alexa Fluor 700 (APC-AF700), Allophycocyanin Alexa Fluor 750 (APCAF750) and Krome Orange (KO). A previously healthy 25-year-old male presented to medical attention with a 3-week history of progressive exertional dyspnea along with a new rash on his chest and shins. Physical examination was notable for mild tachycardia, pallor, and a petechial rash. Initial blood work revealed marked leukocytosis with a blast count of 134 × 109/L (83% blasts), profound anemia and thrombocytopenia. BM studies revealed 91% blasts by morphology with minimal granulocyte maturation. Blasts showed variable morphology ranging from small blasts with high nuclear/cytoplasmic ratio to medium-sized blasts with prominent nucleoli and granules, but no Auer rods. The trephine biopsy showed almost 100% cellularity with normal hematopoiesis replaced by a dense blast infiltrate. Comprehensive flow cytometry was performed using four 10 color panels, routine at our institution for evaluation of new acute leukemia. Panel 1 showed a large CD34 positive blast population in the CD45-dim low side scatter region with partial expression of CD117 alongside variable expression of CD13 and CD33. Such strong expression of myeloid markers initially suggested a myeloid leukemia (Figure 1a–d). Uniformly positive CD19, however, then broadened the differential diagnosis to B-ALL with aberrant myeloid expression, AML with aberrant CD19 (e.g., AML with t(8;21)(q22;q22.1), or B/myeloid MPAL (Figure 1e). The next sequence of markers demonstrated a large proportion of the blasts expressed CD10 and CD79a (Figure 1f,i), meeting WHO criteria for assigning at least a B lineage with a small proportion of the blasts being MPO positive (2.95%; Figure 1g). Cytoplasmic CD3 was negative (not shown), narrowing the differential to B-ALL with aberrant myeloid expression or B/myeloid MPAL. While MPO was only weakly/partially expressed, importantly MPAL-defining inverse co-expression patterns between myeloid and lymphoid markers were evident. MPO was only expressed in the cells brightest for the myeloid marker CD33 and dimmest for the B lineage associated marker CD79a (Figure 1i,j, black backgating on MPO+). A similar negative inverse correlation could be demonstrated for CD10 and CD33 (Figure 1k,l, black backgating on CD117+); however, CD19 intensity did not vary. Similar to MPO, CD117 was only expressed in cells that were strongly positive for CD33, but negative for CD10. Given these phenotypic associations, we inferred that MPO was expressed in CD19+ cells positive for the myeloid markers CD33 and CD117, but negative for B cell markers CD10 and CD79a. Based on this characteristic inverse B-lymphoid and myeloid expression pattern, a preliminary diagnosis of MPAL, B/myeloid was communicated to the treatment team the day of the BM biopsy. Subsequent cytogenetics results demonstrated t(9;22)(q34.1;q11.2) in 19/20 metaphases and a p210 BCR/ABL1 transcript by molecular. A final WHO classification of MPAL with t(9;22)(q34.1;q11.2) was made. Next generation sequencing results detected a variant of uncertain significance (VUS) in RUNX1 leading to the duplication of a valine residue at position 119 (RUNX1c.356_358dupTGG/p.Val119dup), variant allele frequency 47%. The patient was started on a tyrosine kinase inhibitor based B-ALL regimen and eventually went on to receive an allogeneic stem cell transplant and is currently in remission. Acute leukemias are increasingly classified by recurrent molecular/cytogenetic abnormalities. In this case, t(9;22)(q34.1;q11.2); BCR/ABL1 did not assist with distinguishing MPAL from B-ALL since it a common finding in both entities. In fact, BCR/ABL1 in cases such as this one may create more ambiguity since it is known to be associated with aberrant myeloid expression in B-ALL. The presence of a BCR/ABL1 p210 isoform and mixed phenotype blasts also raises the possibility of chronic myeloid leukemia (CML) presenting in a mixed blast crisis. In our case this was unlikely based on the acute clinical history and absence of other suggestive features of CML such as splenomegaly, peripheral granulocytosis, or residual granulocyte maturation. Given the controversies related to isolated MPO expression in otherwise typical B-ALL presentations, this case helps emphasize the value of additional aberrant myeloid markers, particularly when the pattern of B-lymphoid and myeloid markers are inversely correlated. The fact that lineage defining MPO expression clearly followed this pattern made it highly unlikely that the MPO staining was non-specific. Other phenotypic support for MPAL included CD117 positivity, which in contrast to CD13 and CD33, is rare in B-ALL. It is likely that additional genetic events occur that ultimately determine the dominant blast lineage(s) at presentation since BCR/ABL1 may be detected in de novo ALL, AML, MPAL and blast phase CML. The added finding of a RUNX1 mutation in this case (albeit classified as a VUS) is interesting as emerging evidence suggests that RUNX1 can play a role in the pathogenesis of MPAL, and specifically seems to be enriched in B/myeloid MPAL (Takahashi et al., 2018). In the tyrosine kinase inhibitor era the clinical impact of distinguishing MPAL, B-myeloid with BCR/ABL1, and B-ALL with BCR/ABL1 remains unclear; however, the categorization as MPAL in a young patient may favor allotransplant consolidation where feasible, regardless of measurable residual disease. This highlights the therapeutic importance of accurate flow cytometric interpretation and awareness of the distinguishing features between these two subtypes of acute leukemia." @default.
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• W3147925311 date "2021-03-29" @default.
• W3147925311 modified "2023-09-25" @default.
• W3147925311 title "Lymphoid blasts with aberrant myeloid marker expression and <scp>BCR</scp>/<scp>ABL1</scp>: Is it mixed phenotype acute leukemia or B lymphoblastic leukemia?" @default.
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• W3147925311 doi "https://doi.org/10.1002/cyto.b.22002" @default.
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