Oncologists are required to provide guidance to laboratories on their patients’ suspected diseases via the ICD-10 box on the test requisition form. This process drives laboratories down certain paths, often causing misdiagnosis. Precipio’s unique Omnia methodology includes a comprehensive assessment of the patient’s history, prior test results and other important information, providing an alternate hypothesis that often, as in the case presented below, leads to the uncovering of a disease not suspected by the oncologist.
Acute myeloid leukemia, myelodysplasia-related (AML-MR) is a type of acute myeloid leukemia (AML) that is characterized by the presence of genetic mutations that are also found in myelodysplastic syndromes (MDS). By definition, AML presents as an acute condition that requires immediate intervention. If AML is not clinically suspected, required testing to confirm AML will not be ordered; or more comprehensive testing that may help with AML diagnosis will be reported at a surface level such as a reporting of blasts on a flow cytometry work up.1
In this case, using Precipio’s Omnia approach, additional clinical information was used to identify a rare variant of HCL (BRAF mutation* negative), and early AML, a clinical scenario that may warrant faster, more aggressive intervention.
A case of a 91 year-old male patient was presented for Omnia work up to rule out hairy cell leukemia. Initial laboratory investigations indicated pancytopenia, prompting further evaluation. (Table 1)
The patient had flow cytometry on peripheral blood showing monoclonal kappa light chain restricted B-cells, co-expressing CD11c, CD22, and CD103, while negative for CD25. The Differential analysis showed, lymphocytes 32.9%, monocytes 3%, granulocytes 54.9%, CD45 (dim) 9.1%, CD45 (Neg) 0.6%, while plasma cells were not detected. (Table 2) These results suggested a Hairy cell leukemia variant.
Table 1: Blood Work Up
|MPV ( μm3)||6.2-12.1||9|
Table 2: Blood smear, manual differential
|Other Cells %||0||2|
|Tear drop cells||None||1+|
Case Work Up &Results:
The bone marrow biopsy, including core and clot samples, revealed a high-grade myeloid neoplasm with increased blasts, estimated at 15-20% of the total cell population. Notably, concurrent low-level involvement of B cell lymphoma, specifically the hairy cell leukemia variant, was identified, comprising approximately 10% of the cell population. Additionally, mild kappa light chain predominant plasmacytosis was observed, accounting for approximately 5% of the cell population.
Further cytogenetic analysis was performed to assess the genetic abnormalities associated with the patient’s condition. Results demonstrated a complex karyotype, including deletions in chromosomes 5q and 20q. Fluorescence in situ hybridization (FISH) testing for AML, MDS, MZL, and LPD revealed additional abnormalities, such as 20q deletion, 5q deletion, RUNX1T1 deletion, and CBFB deletion.
To gain a comprehensive understanding of the genetic landscape, molecular testing using the HemeScreen™ AML panel was performed. The panel tested negative for mutations in IDH1, IDH2, FLT3, KIT, NPM1, CEBPA, as well as BRAF mutation. However, NGS-177 analysis uncovered somatic mutations in the TP53, ABL1, RB1, CRLF2, ERG, and SF3B1 genes. The structural chromosomal abnormalities 5q- and 20q- were also detected. The presence of bi-allelic TP53 mutations and the complex karyotype supported a diagnosis of AML-MR.
The presence of bi-allelic TP53 and RB1 mutations suggests a poor prognosis. The presence of SF3B1 mutations is associated with a favorable prognosis. The prognostic implications of CRLF2 and ERG mutations in AML are currently unknown.
Therapeutic options for TP53-mutated AML include Aurora kinase A inhibitors, Wee1 inhibitors, Chk1 inhibitors, kevetrin, APR-246, nutlins, and potentially gene therapy approaches. Potential therapeutic strategies of RB1 mutations include Aurora A kinase inhibitors or BCL2 inhibitors in combination with cisplatin-based therapy. Spliceosome modifiers have shown promise in targeting SF3B1-mutated cells specifically.
AML-MR is a subtype that is more common in older individuals. It is less responsive to chemotherapy, and it has lower remission and survival rates than non-MR types of AML.
As part of the Omnia process, appropriate additional testing and communication allowed for proper classification of the variant form of hairy cell leukemia, and more importantly, a diagnosis of emerging AML.
While prognosis in this case is not favorable, by working with Precipio hematopathology team, the treating physician was able to make better informed treatment decisions. Prior lab work-ups from other reference labs failed to uncover this HCL variant and emerging AML condition.
*: BRAF: oncogenic v-raf murine sarcoma viral oncogene homolog B1
This presentation is intended for educational purposes only and does not replace independent professional judgment. This document contains proprietary information belonging to Precipio, Inc. No use or disclosure of the information contained herein is permitted without the prior written consent of Precipio Inc.