Review Article2022-09-01 Diagnostic Hematology

Unreliable Automated Complete Blood Count Results: Causes, Recognition, and Resolution

Gene Gulati, Ph.D., Guldeep Uppal, M.D., and Jerald Gong, M.D.

Ann Lab Med 2022; 42(5): 515-530

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Abstract : Automated hematology analyzers generate accurate complete blood counts (CBC) results on nearly all specimens. However, every laboratory encounters, at times, some specimens that yield no or inaccurate result(s) for one or more CBC parameters even when the analyzer is functioning properly and the manufacturer’s instructions are followed to the letter. Inaccurate results, which may adversely affect patient care, are clinically unreliable and require the attention of laboratory professionals. Laboratory professionals must recognize unreliable results, determine the possible cause(s), and be acquainted with the ways to obtain reliable results on such specimens. We present a concise overview of the known causes of unreliable automated CBC results, ways to recognize them, and means commonly utilized to obtain reliable results. Some examples of unreliable automated CBC results are also illustrated. Pertinent analyzer-specific information can be found in the manufacturers’ operating manuals.

Review Article2022-05-01 Diagnostic Hematology

Myelodysplastic Syndromes with Bone Marrow Fibrosis: An Update

Akriti G. Jain , M.D., Ling Zhang , M.D., John M. Bennett , M.D., and Rami Komrokji , M.D.

Ann Lab Med 2022; 42(3): 299-305

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Abstract : Myelodysplastic syndrome (MDS) is a diverse hematological malignancy with a wide spectrum of presentations and implications. Treatment strategies for patients with MDS heavily rely on prognostic scoring systems, such as the revised international prognostic scoring system (IPSS-R). Bone marrow fibrosis (BMF) has been identified as an independent risk factor for poor survival in patients with MDS, irrespective of the IPSS-R risk category. However, BMF is not widely included in scoring systems and is not always considered by clinicians when making treatment decisions for patients. In this review, we discuss the available literature about the presentation and prognosis of patients with MDS and concurrent BMF. The prognostic impact of BMF should be factored in when deciding on transplant candidacy, especially for intermediate-risk patients.

Original Article2022-07-01 Diagnostic Hematology

Digital Morphology Analyzer Sysmex DI-60 vs. Manual Counting for White Blood Cell Differentials in Leukopenic Samples: A Comparative Assessment of Risk and Turnaround Time

Minjeong Nam , M.D., Ph.D., Sumi Yoon , M.D., Mina Hur , M.D., Ph.D., Gun Hyuk Lee , M.D., Hanah Kim , M.D., Ph.D., Mikyoung Park , M.D., Ph.D., and Hyeong Nyeon Kim , M.D.

Ann Lab Med 2022; 42(4): 398-405

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Abstract : Background: Digital morphology (DM) analyzers are increasingly being used for white blood cell (WBC) differentials. We assessed the laboratory efficiency of the Sysmex DI-60 system (DI-60; Sysmex, Kobe, Japan) in comparison with manual counting in leukopenic samples. Methods: In total, 40 peripheral blood smear samples were divided into normal, mild leukopenia, moderate leukopenia, and severe leukopenia groups based on WBC count. In each group, the risk and turnaround time (TAT) were compared between DI-60 and manual counting. Risk was determined by failure mode and effect analysis using the risk priority number (RPN) score, and TAT was recorded for the analytical phase. Results: Overall, DI-60 showed a five-fold lower risk (70 vs. 350 RPN) and longer TAT than manual counting. In severe leukopenic samples, DI-60 showed a shorter TAT/slide and a remarkably lower cell count/slide than manual counting. In all samples, the TAT/cell for DI-60 was substantially longer than that for manual counting (DI-60 vs. manual: total, 1.8 vs. 1.0 sec; normal, 1.5 vs. 0.7 sec; mild leukopenia, 1.9 vs. 0.9 sec; moderate leukopenia, 1.8 vs. 1.0 sec; severe leukopenia, 28.8 vs. 19.0 sec). Conclusions: This is the first comparative assessment of risk and TAT between DI-60 and manual counting in leukopenic samples. DI-60 decreases the laboratory risk and improves patient safety, but requires more time to count fewer cells, especially in severe leukopenic samples. DM analyzers should be applied selectively depending on the WBC count to optimize laboratory efficiency.

Original Article2022-09-01 Diagnostic Hematology

Clinical Utility of Next-Generation Flow-Based Minimal Residual Disease Assessment in Patients with Multiple Myeloma

Hyun-Young Kim , M.D., In Young Yoo , M.D., Dae Jin Lim , M.T., Hee-Jin Kim , M.D., Sun-Hee Kim , M.D., Sang Eun Yoon , M.D., Seok Jin Kim , M.D., Duck Cho , M.D., and Kihyun Kim , M.D.

Ann Lab Med 2022; 42(5): 558-565

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Abstract : Background: Minimal residual disease (MRD) is an important prognostic factor for evaluating a deeper treatment response in patients with multiple myeloma (MM). We evaluated the clinical utility of next-generation flow (NGF)-based MRD assessment in a heterogeneous MM patient population. Methods: Patients with suspected morphological remission after or during MM treatment were prospectively enrolled. In total, 108 bone marrow samples from 90 patients were analyzed using NGF-based MRD assessment according to the EuroFlow protocol, and progression-free survival (PFS) was evaluated according to the International Myeloma Working Group response status, cytogenetic risk, and MRD status. Results: The overall MRD-positive rate was 31.5% (34/108 samples), and MRD-positive patients showed a lower PFS than MRD-negative patients (P=0.005). MRD-positive patients showed inferior PFS than MRD-negative in patients with stringent complete remission (sCR)/complete remission (P=0.014) and high-risk cytogenetic abnormalities (P=0.016). MRD was assessed twice in 18 patients with a median interval of 12 months. Sustained MRD negativity was only observed in patients with sustained sCR, and their PFS was superior to that of patients who were not MRD-negative (P=0.035). Conclusions: Clinical application of NGF-based MRD assessment can provide valuable information for predicting disease progression in patients with MM in remission, including those with high-risk cytogenetic abnormalities.

Original Article2023-03-01 Diagnostic Hematology

Clinical, Mutational, and Transcriptomic Characteristics in Elderly Korean Individuals With Clonal Hematopoiesis Driver Mutations

Inki Moon , M.D., M.S., Min Gyu Kong , M.D., M.S., Young Sok Ji , M.D., M.S., Se Hyung Kim , M.D., Ph.D., Seong Kyu Park , M.D., Ph.D., Jon Suh , M.D., Ph.D., and Mi-Ae Jang , M.D., Ph.D.

Ann Lab Med 2023; 43(2): 145-152

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Abstract : Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of blood cells originating from somatically mutated hematopoietic stem cells, is common among the elderly and is associated with an increased risk of hematologic malignancies. We investigated the clinical, mutational, and transcriptomic characteristics in elderly Korean individuals with CHIP mutations. Methods: We investigated CHIP in 90 elderly individuals aged ≥60 years with normal complete blood counts at a tertiary-care hospital in Korea between June 2021 and February 2022. Clinical and laboratory data were prospectively obtained. Targeted next-generation sequencing of 49 myeloid malignancy driver genes and massively parallel RNA sequencing were performed to explore the molecular spectrum and transcriptomic characteristics of CHIP mutations. Results: We detected 51 mutations in 10 genes in 37 (41%) of the study individuals. CHIP prevalence increased with age. CHIP mutations were observed with high prevalence in DNMT3A (26 individuals) and TET2 (eight individuals) and were also found in various other genes, including KDM6A, SMC3, TP53, BRAF, PPM1D, SRSF2, STAG1, and ZRSR2. Baseline characteristics, including age, confounding diseases, and blood cell parameters, showed no significant differences. Using mRNA sequencing, we characterized the altered gene expression profile, implicating neutrophil degranulation and innate immune system dysregulation. Conclusions: Somatic CHIP driver mutations are common among the elderly in Korea and are detected in various genes, including DNMT3A and TET2. Our study highlights that chronic dysregulation of innate immune signaling is associated with the pathogenesis of various diseases, including hematologic malignancies.

Brief Communication2022-09-01 Diagnostic Hematology

Clinical and Genomic Profiles of Korean Patients with MECOM Rearrangement and the t(3;21)(q26.2;q22.1) Translocation

Jikyo Lee , M.D., Sung Min Kim , B.S., Soonok Kim , M.T., Jiwon Yun , M.D., Dajeong Jeong , M.D., Young Eun Lee , M.D., Eun-Youn Roh , M.D., Ph.D., and Dong Soon Lee , M.D., Ph.D.

Ann Lab Med 2022; 42(5): 590-596

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Abstract : The translocation (3;21)(q26.2;q22.1) is a unique cytogenetic aberration that characterizes acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) in patients with AML and myelodysplastic syndrome (MDS) or a therapy-related myeloid neoplasm. Using multigene target sequencing and FISH, we investigated the clinical and genomic profiles of patients with t(3;21) over the past 10 years. The frequency of t(3;21) among myeloid malignancies was very low (0.2%). Half of the patients had a history of cancer treatment and the remaining patients had de novo MDS. Twenty-one somatic variants were detected in patients with t(3;21), including in CBL, GATA2, and SF3B1. Recurrent variants in RUNX1 (c.1184A>C, p.Glu395Ala) at the same site were detected in two patients. None of the patients with t(3;21) harbored germline predisposition mutations for myeloid neoplasms. MECOM rearrangement was detected at a higher rate using FISH than using G-banding, suggesting that FISH is preferable for monitoring. Although survival of patients with t(3;21) is reportedly poor, the survival of patients with t(3;21) in this study was not poor when compared with that of other AML patients in Korea.

Letter to the Editor2022-03-01 Diagnostic Hematology

Concomitant Diagnosis of Primary Bone Marrow B-Cell Non-Hodgkin Lymphoma and Essential Thrombocythemia: A Case Report

Hongkyung Kim , M.D., Hye Min Kim , M.D., Jin Ju Kim , M.D., Saeam Shin , M.D., Doh Yu Hwang , M.D., Seung-Tae Lee , M.D., and Jong Rak Choi , M.D.

Ann Lab Med 2022; 42(2): 282-285

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Letter to the Editor2022-03-01 Diagnostic Hematology

Clinical Performance of Monocyte Distribution Width for Early Detection of Sepsis in Emergency Department Patients: A Prospective Study

Shinae Yu , M.D., Sae Am Song , M.D., Ph.D., Kyung Ran Jun , M.D., Ph.D., Ha Young Park , M.D., and Jeong Nyeo Lee , M.D., Ph.D.

Ann Lab Med 2022; 42(2): 286-289

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Brief Communication2022-11-01 Diagnostic Hematology

Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia with RUNX1::RUNX1T1

Sang Mee Hwang , M.D., Ph.D., Beom Joon Kim , M.D., Jee-Soo Lee , M.D., Moon-Woo Seong , M.D., Ph.D., Soo Hyun Seo , M.D., Ph.D., Jin Ho Paik , M.D., Ph.D., Sang-A Kim , M.D., Ji Yun Lee , M.D., Jeong-Ok Lee , M.D., Ph.D., Yoon Hwan Chang , M.D., Ph.D., and Soo Mee Bang , M.D., Ph.D.

Ann Lab Med 2022; 42(6): 678-682

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Abstract : Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.

Original Article2023-07-01 Diagnostic Hematology

Development of a Next-generation Sequencing-based Gene Panel Test to Detect Measurable Residual Disease in Acute Myeloid Leukemia

Jin Ju Kim , M.D., Ji Eun Jang , M.D., Hyeon Ah Lee , M.S., Mi Ri Park , B.S., Hye Won Kook , M.D., Seung-Tae Lee , M.D., Jong Rak Choi , M.D., Yoo Hong Min , M.D., Saeam Shin , M.D., and June-Won Cheong , M.D.

Ann Lab Med 2023; 43(4): 328-336

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Abstract : Background: AML is a heterogeneous disease, and despite intensive therapy, recurrence is still high in AML patients who achieve the criterion for cytomorphologic remission (residual tumor burden [measurable residual disease, MRD]0.99). The test reproducibly detected MRD in three dilution series samples, with a sensitivity of 0.25% for single-nucleotide variants. More than half of samples from patients with morphologic remission after one month of chemotherapy had detectable mutations. NGS-MRD positivity for samples collected after one month of chemotherapy tended to be associated with poor overall survival and progression-free survival. Conclusions: Our highly sensitive and accurate NGS-MRD panel can be readily used to monitor most AML patients in clinical practice, including patients without gene rearrangement. In addition, this NGS-MRD panel may allow the detection of newly emerging clones during clinical relapse, leading to more reliable prognoses of AML.