The logic of next generation sequencing wherever myeloid neoplasia is suspected

Recently, S. Vantyghem et al (Haematologica 3/1/2021, pages 701–707)1,2 published a “real-life study.” The analyses were focused on 177 patients with suspected or already confirmed myeloid neoplasias such as MDS or MPN without a final diagnosis using cytomorphology and immunophenotyping. In a first cohort, an NGS panel with 34 genes was used either to exclude or confirm a definitive diagnosis. In a second cohort, the extent to which prognostic and especially therapeutic consequences would have to be drawn if somatic mutations were detectable was investigated. I would like to introduce this study to you in this article.

The starting constellations were e.g., anemia, thrombocytopenia, neutropenia, or pancytopenia in general, but also thrombocytosis or monocytosis in other cases. Until the molecular analyses were evaluated, the ultimate diagnoses were e.g., ICUS, suspected MDS/MPN, or suspected aplastic anemia. Debatable MPNs were normal for the classic 3 driver mutations. For the patients in the second group, diagnoses based on morphology and cytogenetics were already at hand, mostly classified as low-risk by a relevant scoring system.

NGS revealed clonal hematopoiesis with at least one somatic mutation in a third of the patients of the first group. The genes ASXL1, TET2, and DNMT3A were the most frequently affected. These are of course also found in clonal hematopoiesis of indeterminate potential (CHIP). Detection of already noticeable blood changes should lead to more closely-knit follow-ups. However, a lack of evidence of any somatic mutations could also represent a valuable gain in clinical information. In 33% of cases the diagnosis was confirmed by positive findings, while in a further 50% malignant disease was almost completely excluded by negative findings. If the constellation is unclear, the authors suggest including such results in clinical decision-making in order to mitigate any diagnostic or therapeutic uncertainties.

For the second cohort, in addition to prognostically relevant mutations such as ASXL1 or RUNX1, therapeutically important mutations such as those in SF3B1 could be demonstrated. Overall, the authors therefore assume that where the constellation is unclear, the clinical reliability of the diagnosis and the informing of patients will be improved in 83% of the cases examined, while in 19% of the investigated cases (cohort 2), prognostically and/or therapeutically relevant information becomes available. The publication also deals with the question of the extent to which the information contained here from the myeloid NGS panel can be relevant not only clinically and therapeutically, but also for overall cost calculations. Repeated and further diagnostic measures or sometimes even unnecessary treatment (e.g., allogeneic transplantation) could be avoided by excluding clonal alterations. Further comparative analyses were suggested. In view of the falling costs for sequencing, it can already be assumed that not only the clinical gain for patients but also the economic benefit will make an earlier use of NGS-assisted molecular screening feasible in the future.

1 Vantyghem S, Peterlin P, Thepot S, Menard A, Dubruille V, Debord C, Guillaume T, Garnier A, Le Bourgeois A, Wuilleme S, Godon C, Theisen O, Eveillard M, Delaunay J, Maisonneuve H, Morineau N, Villemagne B, Vigouroux S, Subiger F, Lestang E, Loirat M, Parcelier A, Godmer P, Mercier M, Trebouet A, Luque Paz D, Le Calloch R, Le Clech L, Bossard C, Moreau A, Ugo V, Hunault M, Moreau P, Le Gouill S, Chevallier P, Bene MC, Le Bris Y. Diagnosis and prognosis are supported by integrated assessment of next-generation sequencing in chronic myeloid malignancies. A real-life study. Haematologica. 2021;106(3):701-707.
2 Haferlach T. The time has come for next-generation sequencing in routine diagnostic workup in hematology. Haematologica. 2021;106(3):659-661.

The author

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Prof. Dr. med. Dr. phil. Torsten Haferlach

Executive management
Internist, Hematologist and Oncologist
Deputy Head of Cytomorphology

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