Clinical utility of genomic profiling of <scp>AML</scp> using paraffin‐embedded bone marrow clots: <scp>HM‐SCREEN‐Japan</scp> 01

Hosono, Naoko; Chi, SungGi; Yamauchi, Takahiro; Fukushima, Kentaro; Shibayama, Hirohiko; Katagiri, Seiji; Gotoh, Akihiko; Eguchi, Motoki; Morishita, Takanobu; Ogasawara, Reiki; Kondo, Takeshi; Yanada, Masamitsu; Yamamoto, Kazuhito; Kobayashi, Tsutomu; Kuroda, Junya; Usuki, Kensuke; Utsu, Yoshikazu; Yoshimitsu, Makoto; Ishitsuka, Kenji; Ono, Takaaki; Takahashi, Naoto; Iyama, Satoshi; Kojima, Kensuke; Nakamura, Yukinori; Fukuhara, Suguru; Izutsu, Koji; Abutani, Hikaru; Yamauchi, Nobuhiko; Yuda, Junichiro; Minami, Yosuke

doi:10.1111/cas.15746

Cited by 3 publications

(1 citation statement)

References 22 publications

(42 reference statements)

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“…Bone marrow (BM) examination revealed myeloperoxidase-positive leukemic cells and extensive BM necrosis ( Figure 1A–C ). Cytogenetic analysis of 24 metaphases showed a normal karyotype; however, molecular analysis of the patient by next-generation sequencing (NGS) conducted in Hematologic Malignancy (HM)-SCREEN-Japan-01 (UMIN000035233) 8 identified FLT3 -ITD, DNMT3A, IDH2 , and NPM1 mutations ( Table 1 ). She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR).…”

Section: Case Presentationmentioning

confidence: 99%

Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy

Katagiri¹,

Furuya²,

Akahane³

et al. 2023

OTT

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We performed sequential molecular analyses of a 75-year-old woman with de novo FLT3 -ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, FLT3 -ITD, NPM1, DNMT3A , and IDH2 mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. FLT3 -ITD and NPM1 mutations were persistently positive, and the patient received gilteritinib therapy. Although the FLT3 -ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and CBL mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the FLT3 -ITD clone was detected again. Gilteritinib treatment was restarted, and FLT3 -ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) FLT3 -ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.

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Section: Case Presentationmentioning

confidence: 99%

Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy

Katagiri¹,

Furuya²,

Akahane³

et al. 2023

OTT

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Targeted NGS on sequential bone marrow biopsies aids in the evaluation of cytopenias and monocytosis and documents clonal evolution—a proof of principle study

Nann,

Rau,

Mahmutovic

et al. 2023

Virchows Arch

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Differential diagnosis of clonal versus reactive cytopenia and monocytosis, respectively, frequently presents a diagnostic challenge. With the two recent classifications of myeloid disorders, mutational analysis has gained importance as a diagnostic tool. However, reports on its utility on trephine bone marrow biopsies (BMB) are sparse. The aim of our proof of principle study was to determine the suitability of targeted sequencing for the longitudinal evaluation of cytopenia and monocytosis and demonstration of clonal evolution on sequential BMB. Seventy-seven EDTA-decalcified BMB of 33 patients with peripheral cytopenia and/or monocytosis, including at least one follow-up biopsy/patient, were included. Initial morphological diagnoses were idiopathic cytopenia of undetermined significance (ICUS, 8 cases), MDS (without blast increase, 7 cases), MDS with increased blasts/excess blasts (MDS-IB/EB) (11 cases), and CMML (7 cases). Thirty-one genes relevant for myeloid disorders were examined using two custom AmpliSeq NGS panels. Mutations were found in the initial BMB of 5/8 cases of ICUS, thus changing the diagnosis to clonal cytopenia of unknown significance (CCUS), 5/7 MDS, 10/11 MDS-IB/EB, and 7/7 CMML. Clonal evolution was observed in 14/33 (42%) cases, mostly associated with disease progression. None of the wild-type patients acquired mutations during follow-up. NGS-based mutation profiling is a robust diagnostic tool for BMB and provides valuable additional information, especially for cases with no/minimal dysplasia, and for better risk stratification of MDS. Tracking variant allele frequency and appearance of mutations over time allows for observing clonal evolution or relapse.

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Clinical utility of genomic profiling of AML using paraffin‐embedded bone marrow clots: HM‐SCREEN‐Japan 01

et al. 2023

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Next‐generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)‐SCREEN‐Japan 01 is a multicenter study to detect actionable mutations using paraffin‐embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R‐AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High‐quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1 ‐ RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R‐AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP5 3 mutations had a poor prognosis. As for the detection of actionable mutations, 38% ( n = 69) of patients had useful genetic mutation ( FLT3 ‐ ITD / TKD , IDH1 / 2 , and DNMT3A R822 ) for treatment selection. Comprehensive genomic profiling using paraffin‐embedded BM clot specimens successfully identified leukemic‐associated genes that can be used as therapeutic targets.

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Clinical utility of genomic profiling of AML using paraffin‐embedded bone marrow clots: HM‐SCREEN‐Japan 01

Cited by 3 publications

References 22 publications

Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy

Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy

Targeted NGS on sequential bone marrow biopsies aids in the evaluation of cytopenias and monocytosis and documents clonal evolution—a proof of principle study

Clinical utility of genomic profiling of AML using paraffin‐embedded bone marrow clots: HM‐SCREEN‐Japan 01

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