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Molekulare Diversität der akuten lymphoblastischen Leukämie

Innovationen in Diagnostik und Therapie

Molecular diversity in acute lymphoblastic leukemia

New developments for diagnosis and therapy

  • Leitthema
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Die Onkologie Aims and scope

Zusammenfassung

Hintergrund

In der akuten lymphoblastischen Leukämie (ALL) werden über 20 molekulare Subtypen, basierend auf genomischem Treiber und zugehörigem Genexpressionsprofil, unterschieden.

Ziel

Diese molekulare Diversität wurde hinsichtlich ihrer Implikationen für Diagnostik und Therapie analysiert.

Material und Methoden

Dazu wurde eine gezielte Literaturrecherche durchgeführt und um eigene Analysen aus GMALL-Patientenkohorten (German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia) ergänzt.

Ergebnisse und Diskussion

Die Transkriptomsequenzierung (RNA-Seq) ermöglich für > 90 % der ALL-Patienten eine zuverlässige Zuordnung zu einer von über 20 Subgruppen mit einer einzigen Methode. Die klinischen Phänotypen sind noch unzureichend charakterisiert. Prognostische Relevanz zeichnet sich für Therapieansprechen und Gesamtüberleben ab. Alter und Geschlecht bestimmen die Selektion leukämogener Treiber mit. Rückgrat der ALL-Therapie bleibt die risikostratifizierte Polychemotherapie, ergänzt durch antiköperbasierte und zelluläre Immuntherapien sowie die allogene Stammzelltransplantation. Neben der Standard-Tyrosinkinaseinhibitor(TKI)-Therapie für die BCR::ABL1-positive ALL weisen Fallserien auf Wirksamkeit von spezifischen TKI für den Ph-like-ALL-Subtyp bei Vorliegen einer ABL-Klasse-Genfusion oder bei Fusionen mit NTR-Kinasen hin. Wichtigstes Integral für das Therapieansprechen bleibt die minimale Resterkrankung (MRD). Sie ist nicht nur stärkster unabhängiger Prognosefaktor, sondern auch Indikator eines drohenden Rezidivs. Richtungsweisend für weitere Therapieoptimierung werden molekulare Diagnostik (genomischem Treiber, Genregulation/Transkriptom, MRD) sowie der Einsatz etablierter und neuer zielgerichteter Ansätze sein.

Abstract

Background

In acute lymphoblastic leukemia (ALL), more than 20 molecular subtypes have been distinguished based on the genomic driver and corresponding gene expression profile.

Purpose

To analyze this molecular diversity with respect to its implications for diagnosis and therapy.

Materials and methods

A targeted literature search was performed and complemented by our own analyses from GMALL (German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia) patient cohorts.

Results and discussion

Transcriptome sequencing (RNA-Seq) allows reliable allocation to one of more than 20 subgroups for > 90% of ALL patients using a single method. The respective clinical phenotypes are still insufficiently characterized. Prognostic relevance for therapy response and overall survival is emerging. Age and gender contribute to the selection of leukemogenic drivers. The backbone of ALL therapy remains risk-stratified polychemotherapy, supplemented by antibody-based and cellular immunotherapies and allogeneic stem cell transplantation. In addition to standard tyrosine kinase inhibitor (TKI) therapy for BCR::ABL1-positive ALL, case series indicate efficacy of specific TKIs for the Ph-like ALL subtype in the presence of ABL class gene fusion or fusions with NTR kinases. The most important factor for the analysis of treatment response remains minimal residual disease (MRD). It is not only the strongest independent prognostic factor, but also an indicator of impending relapse. Molecular diagnostics (genomic driver, gene regulation/transcriptome, MRD) and the use of established and new targeted approaches will be crucial for further therapy optimization.

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  1. Klinik für Innere Medizin II, Hämatologie und Onkologie, Universitäres Cancer Center Schleswig-Holstein, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, 24105, Kiel, Deutschland

    Lorenz Bastian & Claudia D. Baldus

  2. Klinik für Innere Medizin II, Sektion für hämatologische Spezialdiagnostik, Universitäres Cancer Center Schleswig-Holstein, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland

    Monika Brüggemann

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L. Bastian, M. Brüggemann und C.D. Baldus geben an, dass kein Interessenkonflikt besteht.

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Bastian, L., Brüggemann, M. & Baldus, C.D. Molekulare Diversität der akuten lymphoblastischen Leukämie. Onkologie 28, 492–503 (2022). https://doi.org/10.1007/s00761-022-01165-0

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