Prognostic impact of TP53 mutation, monosomal karyotype, and prior myeloid disorder in nonremission acute myeloid leukemia at allo-HSCT

Najima, Yuho; Sadato, Daichi; Harada, Yuka; Oboki, Keisuke; Hirama, Chizuko; Toya, Takashi; Doki, Noriko; Haraguchi, Kazutoshi; Yoshifuji, Kota; Akiyama, Miho; Inamoto, Kyoko; Igarashi, Aiko; Kobayashi, Takeshi; Kakihana, Kazuhiko; Okuyama, Yoshiki; Sakamaki, Hisashi; Harada, Hironori

doi:10.1038/s41409-020-01016-9

Cited by 12 publications

(12 citation statements)

References 54 publications

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“…In the evolving landscape of genetic stratification, these scoring systems are likely to be refined, and the long term impact of novel salvage options from targeted therapies remains to be seen ( 37 , 38 ). One recent study underlined the particularly poor outcome of patients with TP53 mutant AML, when they were transplanted with active disease ( 39 ). A challenge in assessments of such genetic risk factors will be the clonal evolution which occurs in patients with AML following treatment ( 40 ).…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

2021

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Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.

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Section: Introductionmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

2021

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“…Gene variants were detected using HaplotypeCaller (for high frequency variants) and Mutect2 (for low frequency variants) included in GATK [12]. Gene variants obtained from HaplotypeCaller were filtered with the parameters of quality/depth, mapping quality, and strand bias to exclude false-positive variants as previously described [13]. Variants were detected using the tumor-only mode or the panel of normal mode on Mutect2.…”

Section: Detection Of Variants and Fusion Genesmentioning

confidence: 99%

Archival bone marrow smears are useful in targeted next-generation sequencing for diagnosing myeloid neoplasms

et al. 2021

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Gene abnormalities, including mutations and fusions, are important determinants in the molecular diagnosis of myeloid neoplasms. The use of bone marrow (BM) smears as a source of DNA and RNA for next-generation sequencing (NGS) enables molecular diagnosis to be done with small amounts of bone marrow and is especially useful for patients without stocked cells, DNA or RNA. The present study aimed to analyze the quality of DNA and RNA derived from smear samples and the utility of NGS for diagnosing myeloid neoplasms. Targeted DNA sequencing using paired BM cells and smears yielded sequencing data of adequate quality for variant calling. The detected variants were analyzed using the bioinformatics approach to detect mutations reliably and increase sensitivity. Noise deriving from variants with extremely low variant allele frequency (VAF) was detected in smear sample data and removed by filtering. Consequently, various driver gene mutations were detected across a wide range of allele frequencies in patients with myeloid neoplasms. Moreover, targeted RNA sequencing successfully detected fusion genes using smear-derived, very low-quality RNA, even in a patient with a normal karyotype. These findings demonstrated that smear samples can be used for clinical molecular diagnosis with adequate noise-reduction methods even if the DNA and RNA quality is inferior.

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“…method 1; for all online suppl. material, see www.karger.com/doi/10.1159/000516347) [20]. However, there were no myelodysplastic syndrome-associated somatic mutations in hematopoietic cells.…”

Section: Case Reportmentioning

confidence: 99%

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia

et al. 2021

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Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.

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Prognostic impact of TP53 mutation, monosomal karyotype, and prior myeloid disorder in nonremission acute myeloid leukemia at allo-HSCT

Cited by 12 publications

References 54 publications

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: Who, When, and How?

Archival bone marrow smears are useful in targeted next-generation sequencing for diagnosing myeloid neoplasms

Successful Cord Blood Transplantation for Idiopathic CD4<sup>+</sup> Lymphocytopenia

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