Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase

Hehlmann, Rüdiger; Lauseker, Michael; Saußele, Susanne; Pfirrmann, Markus; Krause, Stefan W.; Kolb, Hans‐Jochem; Neubauer, Andreas; Hossfeld, Dieter K.; Nerl, Christoph; Gratwohl, Aloïs; Baerlocher, Gabriela M.; Heim, Dominik; Bruemmendorf, Tim H.; Fabarius, Alice; Haferlach, Claudia; Schlegelberger, Brigitte; Müller, Martin C.; Jeromin, Sabine; Proetel, Ulrike; Kohlbrenner, Katharina; Voskanyan, Astghik; Rinaldetti, Sébastien; Seifarth, Wolfgang; Spieß, Birgit; Balleisen, Leopold; Goebeler, Marie-Elisabeth; Hänel, Mathias; Ho, Anthony D.; Dengler, Jolanta; Falge, Christiane; Kanz, Lothar; Köhne, C. A.; Burchert, Andreas; Kneba, Michael; Stegelmann, Frank; Köhne, C.-H.; Lindemann, Hans‐Walter; Waller, Cornelius F.; Pfreundschuh, Michael; Spiekermann, Karsten; Berdel, Wolfgang E.; Müller, L.; Edinger, Matthias; Mayer, Jiřı́; Beelen, Dietrich W.; Hertenstein, Bernd; Fuchs, Roland J.; Wernli, Martin; Schlegel, Frank; Schlag, Rudolph; Wit, Maike de; Trümper, Lorenz; Hebarth, H; Hahn, Markus; Thomalla, Jörg; Scheid, Christof; Schafhausen, Philippe; Verbeek, Walter; Eckart, Michael J.; Gaßmann, W.; Pezzutto, Antonio; Brossart, Peter; Geer, Thomas; Bildat, Stephan; Schäfer, E.; Hochhaus, Andreas; Hasford, Joerg

doi:10.1182/blood.v130.suppl_1.897.897

Cited by 8 publications

(5 citation statements)

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“…The results suggest that ZNF208 variations may have a substantial impact on the progression of HBV. The study found that ZNF208 polymorphisms significantly increased susceptibility to HBV infection (P = 0.008) [50]. Furthermore, a scientific investigation has asserted that mutations in the ZNF208 gene are associated with an inclination towards developing esophageal cancer [58].…”

Section: Discussionmentioning

confidence: 96%

“…The relationship between CML advancement and the development of a lethal blast crisis can be attributed to ZNF208, a member of the biologically significant group of genes known as Zinc Finger Proteins. The human genome contains a large number of zinc finger (ZNF) genes, with around 500-600 members [50]. These proteins have a role in controlling genes and the process of development, and they have remained mostly the same throughout evolution [51].…”

Section: Discussionmentioning

confidence: 99%

“…The ZNF208 gene is situated on Chromosome 19 in the p12 region [55]. It interacts with DNA and regulates the process of gene transcription [50,56]. Furthermore, additional research has demonstrated a correlation between ZNF208 and various other medical conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, incorporation of next-generation sequencing, and other high-throughput techniques have refined the discovery and validation of diagnostic and prognostic biomarkers and their incorporation into precision medicine [43][44][45][46][47][48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

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A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia

Alanazi,

Siyal,

Basit

et al. 2024

Preprint

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The hallmark of Chronic Myeloid Leukemia (CML) is Philadelphia chromosome t(9:22), which leads to formation of BCR-ABL1 fusion oncogene. BCR-ABL1 induces genetic instability, causing the progression of chronic myeloid leukemia (CML) from the manageable Chronic Phase (CP-CML) to the accelerated phase (AP-CML) and ultimately to the lethal blast crisis (BC-CML). The precise mechanism responsible for CML progression are not well comprehended, and there is a lack of specific molecular biomarkers for advanced phase CML. Mutations in transcription factors (TFs) have a significant role in cancer initiation, relapses, invasion, metastasis, and resistance to anti-cancer drugs. Recently, our group reported association of a novel transcription factor, ZNF208, with CML progression and there was a dire need for clinical validation of this novel biomarker. Therefore, the aim of this study was to clinically validate mutated ZNF208 as a novel biomarker for CML progression in a larger cohort of AP- and BC-CML patients using control-case studies. A total of 73 CML patients (N=73) from King Saud University Medical City Riyadh and King Abdulaziz National Guard Hospital, Al-Ahsa, Saudi Arabia were enrolled in the study (2020-2023) , with the experimental group (cases) consisting of patients AP-CML (n=20) and BC-CML (n=12). The controls consisted of age/sex matched CP-CML (n=41). The study was approved by Research Ethics Committees of participating institutes and all patients provided informed consent for the study. Clinical evaluations for patients were conducted according to the guidelines established by the European LeukemiaNet in 2020. Targeted resequencing of ZNF 208 was employed using Illumina NextSeq500 instrument (Illumina, San Diego, CA, USA) and mutations confirmed using Sanger sequencing. Both next generation sequencing as well as Sanger sequencing identified a novel missense mutation (c.64G>A) in novel ZNF208 . in 56 (93.3) and12 (100) CP-, AP- and BC-CML patients respectively, while in none (0%) of CP-CML patients or healthy controls from genomic databases (p=0.0001). Therefore, our studies show that ZNF208 mutation (c.64G>A) is novel and very specific biomarker for AP-and BC-CML patients. ZNF208 and other such proteins may cause carcinogenesis by interacting with KAP-1 repressor to silence many target genes and thus may prove to be novel drug targets as well. Therefore, we recommend carrying out prospective clinical trials for further clinical validation of this biomarker for its utilization in clinical decision, investigating its precise role in cancer pathogenesis and investigate its potential for novel drug target in advanced phase CML patients.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia

Alanazi,

Siyal,

Basit

et al. 2024

Preprint

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“…The 10-year major MMR and MR4.5 rates were 93 and 63%, respectively, with imatinib [27]. Several studies comparing imatinib 400 vs. 800 mg failed to show the survival benefit of imatinib 800 mg over 400 mg [28][29][30]. Therefore, imatinib at a dose of 400 mg daily is recommended for treating patients with newly diagnosed CML-CP.…”

Section: Frontline Therapymentioning

confidence: 99%

Current status and novel strategy of CML

Morita

Sasaki

2021

Int J Hematol

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The advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the outcome of patients with chronic myeloid leukemia (CML). Currently, four TKIs are available for the frontline treatment, including the first-generation TKI (imatinib) and the second-generation TKIs (dasatinib, nilotinib, and bosutinib). The second-generation TKIs lead to a faster and deeper molecular response without a survival benefit compared with imatinib. However, the opportunity for the treatment discontinuation and functional cure requires the achievement of durable deep molecular remission. Therefore, the secondgeneration TKIs should be considered as initial therapy for chronic-phase CML. Switch of therapy is warranted in case of treatment failure, including resistance and/or intolerance. The life expectancy of patients with CML is approaching that of the general population. Given an expected lifespan, future perspectives should consider the strategy for the optimal choice of TKIs, allowing for long-duration of effective TKI therapy with less toxicity to aim for a functional cure. A novel prediction approach such as artificial intelligence-driven analysis on the accumulated data from clinical trials paves a promising path for the personalized recommendation on frontline TKIs and precise survival prediction.

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Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

2018

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CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long-term survival, because of the availability of effective salvage therapies. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.

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Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase

Cited by 8 publications

References 0 publications

A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia

A retrospective case-control study for Clinical Validation of mutated ZNF208 as a novel biomarker of fatal blast crisis in Chronic Myeloid Leukemia

Current status and novel strategy of CML

Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

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