Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping.

Optical genome mapping (OGM) recently has demonstrated the potential to improve genetic diagnostics in acute myeloid leukemia (AML). In this study, OGM was utilized as a tool for the detection of genome-wide structural variants and disease monitoring. A previously unrecognized NUP98::ASH1L fusion was detected in an adult patient with secondary AML. OGM identified the fusion of NUP98 to Absent, Small, or Homeotic-Like Histone Lysine Methyltransferase (ASH1L) as result of a complex structural rearrangement between chromosomes 1 and 11. A pipeline for the measurement of rare structural variants (Rare Variant Pipeline, Bionano Genomics, San Diego, CA, USA) was used for detection. As NUP98 and other fusions are relevant for disease classification, this demonstrates the necessity for methods such as OGM for cytogenetic diagnostics in AML. Furthermore, other structural variants showed discordant variant allele frequencies at different time points over the course of the disease and treatment pressure, indicating clonal evolution. These results support OGM to be a valuable tool for primary diagnostics in AML as well as longitudinal testing for disease monitoring and deepening our understanding of genetically heterogenous diseases.

Optical Genome Mapping Reveals and Characterizes Recurrent Aberrations and New Fusion Genes in Adult ALL.

(1) Background: In acute lymphoblastic leukemia (ALL) the genetic characterization remains challenging. Due to the genetic heterogeneity of mutations in adult patients, only a small proportion of aberrations can be analyzed with standard routine diagnostics. Optical genome mapping (OGM) has recently opened up new possibilities for the characterization of structural variants on a genome-wide level, thus enabling simultaneous analysis for a broad spectrum of genetic aberrations. (2) Methods: 11 adult ALL patients were examined using OGM. (3) Results: Genetic results obtained by karyotyping and FISH were confirmed by OGM for all patients. Karyotype was redefined, and additional genetic information was obtained in 82% (9/11) of samples by OGM, previously not diagnosed by standard of care. Besides gross-structural chromosome rearrangements, e.g., ring chromosome 9 and putative isodicentric chromosome 8q, deletions in CDKN2A/2B were detected in 7/11 patients, defining an approx. 20 kb minimum region of overlap, including an alternative exon 1 of the CDKN2A gene. The results further confirm recurrent ALL aberrations (e.g., PAX5, ETV6, VPREB1, IKZF1). (4) Conclusions: Genome-wide OGM analysis enables a broad genetic characterization in adult ALL patients in one single workup compared to standard clinical testing, facilitating a detailed genetic diagnosis, risk-stratification, and target-directed treatment strategies.

Broad genomic workup including optical genome mapping uncovers a DDX3X: MLLT10 gene fusion in acute myeloid leukemia.

In acute myeloid leukemia (AML), treatment decisions are currently made according to the risk classification of the European LeukemiaNet (ELN), which is based on genetic alterations. Recently, optical genome mapping (OGM) as a novel method proved to yield a genome-wide and detailed cytogenetic characterization at the time of diagnosis. A young female patient suffered from a rather unexpected aggressive disease course under FLT3 targeted therapy in combination with induction chemotherapy. By applying a "next-generation diagnostic workup" strategy with OGM and whole-exome sequencing (WES), a DDX3X: MLLT10 gene fusion could be detected, otherwise missed by routine diagnostics. Furthermore, several aspects of lineage ambiguity not shown by standard diagnostics were unraveled such as deletions of SUZ12 and ARPP21, as well as T-cell receptor recombination. In summary, the detection of this particular gene fusion DDX3X: MLLT10 in a female AML patient and the findings of lineage ambiguity are potential explanations for the aggressive course of disease. Our study demonstrates that OGM can yield novel clinically significant results, including additional information helpful in disease monitoring and disease biology.

High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Primary CNS Lymphoma: A Retrospective Monocentric Analysis of Long-Term Outcome, Prognostic Factors, and Toxicity.

High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is reportedly an effective treatment strategy in relapsed or refractory primary CNS lymphoma (r/r PCNSL); however, only selected patients are eligible for this treatment. We retrospectively analyzed outcome, prognostic factors, and toxicity in 59 patients with r/r PCNSL planned to receive HCT-ASCT at our institution between January 2005 and December 2021 (n = 33 < 65 years; n = 26 ≥ 65 years). Median follow-up was 65 months (95% CI 21−109). Median age was 63 years (range 29−76), median Karnofsky performance score (KPS) was 80 (range 30−100). In the entire cohort of 59 patients, median overall survival (OS) was 14 months (95% CI 0−37). In 50/59 (84.7%) patients who completed HCT-ASCT, median progression free survival (PFS) was 12 months (95% CI 3−21) and median OS 30 months (95% CI 0−87). 1-year, 2-year, and 5-year OS rates of 61.2%, 52.3% and 47.1%, respectively, were observed. Six patients (10.2%) died related to treatment (1 during induction treatment, 5 post HCT-ASCT). Age was not prognostic. On univariate analysis, KPS ≥ 80 (p = 0.019) and complete or partial remission before HCT-ASCT (p = 0.026) were positive prognosticators of OS; on multivariate analysis, KPS (p = 0.043) and male gender (p = 0.039) had an impact on OS. The 5-year OS rate in patients with progressive or stable disease after induction treatment was 32.7%. In summary, HCT-ASCT was effective and feasible in this cohort of r/r PCNSL patients. Clinical state, remission status before HCT-ASCT, and gender influenced survival, whereas age did not influence outcome in this study.