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KMT2A Amplification in Two Adult Patients with B-Cell Acute Lymphoblastic Leukemia

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
The KMT2A gene, located on chromosome 11q23, encodes a lysine methyltransferase critical for regulating gene expression in hematopoiesis. KMT2A rearrangements are commonly seen in myeloid and lymphoid malignancies, including acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL). However, KMT2A amplification is rare, occurring in approximately 1% of AML cases and even less frequently in B-ALL, with only a few reported cases. Given the rarity, documenting and analyzing KMT2A amplification in B-ALL is critical for improving diagnostic and therapeutic strategies. This report describes two adult B-ALL cases with KMT2A amplification and reviews nine additional cases (seven adults and two children), highlighting the clinical and genetic features of this aggressive subtype.

 

Case Presentation
Patient 1: A 58-year-old male with spondylolisthesis, hypertension, hyperlipidemia, gastroesophageal reflux disease (GERD), and anxiety/depression was transferred from an outside hospital for suspected newly diagnosed acute leukemia.

Patient 2: A 66-year-old female with type 2 diabetes mellitus, GERD, hypertension, obstructive sleep apnea, and hyperlipidemia was admitted with concern for newly diagnosed acute leukemia.

 

Diagnostic Workup
Patient 1: Flow cytometry of the bone marrow aspirate demonstrated 54.11% leukemic blasts that were positive for CD13dim, CD19, CD22dim, CD34, CD38, CD45, CD58, nTdT, and negative for NK/T, other myeloid, and monocytic cell markers, leading to a diagnosis of B-ALL. B-ALL FISH analysis showed KMT2A amplification with 6~18 copies detected in 68.5% of interphase bone marrow cells. G-banded chromosome analysis showed a complex karyotype involving multiple chromosomes (3, 5, 6, 10, 11, 13, 14, 15, 16, 17, 20, 21, 22). The myeloid panel NGS analysis detected a clinically significant TP53 missense variant (c.524G>A, p.Arg175His) with a 91% variant allele frequency.

Patient 2: Flow cytometry of the peripheral blood demonstrated 89.71% leukemic blasts that were positive for CD10, CD13, CD19, CD22dim, CD34, CD38, CD58, nTdT, and negative for NK/T, other myeloid, and monocytic cell markers, supporting a diagnosis of B-ALL. B-ALL FISH analysis showed KMT2A amplification with 8~11 copies in 87.5% of interphase peripheral blood cells. G-banded chromosome analysis was unsuccessful, but limited analysis indicated additional material on the q arm of chromosome 11q23. FISH analysis of the TP53 gene showed no deletion. The Ph-like B-ALL FISH panel identified a CRLF2 gene rearrangement in 85% of interphase peripheral blood cells, marking the first documented case of KMT2A amplification in an adult with de novo Ph-like B-ALL.

 

Treatment and Management
Both patients began induction chemotherapy. However, Patient 1 developed infections, respiratory failure, and encephalopathy, while Patient 2 developed septic shock, lactic acidosis, bacteremia, acute kidney injury requiring continuous renal replacement therapy, and non-ST elevation myocardial infarction.

 

Outcome and Follow-Up
Both patients passed away, Patient 1 after 2 months of hospitalization despite maximum support, and Patient 2 after 4 days due to multiorgan failure.

 

Discussion
Patient 1 had KMT2A amplification, a complex karyotype, and a clinically significant TP53 variant, while Patient 2 presented with KMT2A amplification and CRLF2 gene rearrangement, marking the first documented case of KMT2A amplification in an adult with de novo Ph-like B-ALL. Both cases progressed rapidly with poor outcomes, underscoring the risk associated with KMT2A amplification, especially when combined with other adverse genetic markers. A review of nine published cases of KMT2A amplification in B-ALL shows a tendency toward older adults, marked by aggressive disease, and treatment resistance.

 

Conclusion
The two cases underscore the highly aggressive nature of KMT2A-amplified B-ALL, a rare and challenging subtype. This highlights the need for genetic profiling to enhance risk stratification and personalize treatment. Due to the limited number of documented cases and treatment options, there is an urgent need for further research to develop more effective management strategies for KMT2A-amplified B-ALL.

 

Agenda

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