Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature.

Philadelphia (Ph) chromosome (9;22)(q34;q11) comprises 90-95 % of chronic myeloid leukemia (CML), while 5-10 % of CML have translocations involving three or more chromosomes. The outcome of treating patients harbouring complex Ph-positive cytogenetics with tyrosine kinase inhibitors (TKI) is unclear. In the present systematic review, we aim to summarise the response of patients with complex Ph-positive cytogenetics to treatment with TKI therapy. We collated all available literature from databases such as PubMed, Google Scholar, Web of Science database, Cochrane library, Scopus and Embase (up until January 31st, 2024), which describe cases of patients with CML, harbouring complex Ph-positive variations (three and four-way translocations), and summarised their response to TKI therapy. The studies were screened for the following criteria: documented TKI intervention and outcome (whether CR was achieved). Studies that did not report the same, were excluded. Additionally, we report a case from our center of a 55-year-old patient with CML, positive for the Ph-chromosome, harbouring a three-way translocation involving chromosome 15 i.e. 46XX, t(9;15;22) (q34;p11;q11). Identification of BCR::ABL and involvement of chromosome 15 was carried out using conventional cytogenetics, fluorescence in situ hybridization (FISH), and quantitative PCR (qPCR). Based on the inclusion criteria, a total of 15 studies were included from which a total of 87 cases were covered. Overall, we identified 38 unique complex three- and four-way translocations across 87 Ph-positive cases and found that 85 patients with complex Ph-positive cytogenetics achieved complete remission upon treatment and did not appear to have a lesser response to TKI therapy.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.

Comparison between Conventional Cytogenetics and Interphase Fluorescence in situ Hybridization (FISH) for Patients with Multiple Myeloma

BACKGROUND: For patients with multiple myeloma (MM), different strategies are used to detect chromosomal abnormalities (CA). There have been a few studies that have directly compared FISH with conventional cytogenetics (CC) for the detection of CA. In this study, we employed a combined approach of metaphase cytogenetics and interphase FISH to investigate the genetic basis for the great heterogeneity observed in the clinical behavior of 28 MM patients. METHODS: Cytogenetic analysis was performed via traditional metaphase karyotype analysis. The FISH studies were done using DNA probes to detect translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and deletions of 17p13.1 and 13q14. RESULTS: CA were detected by CC in 16 patients (57.1%) and by FISH in 14 patients (50.0%) of the 28 patients we studied. 14q32 abnormalities and deletion abnormalities of 13q14 and 17p13.1 were detected by CC in five patients (17.9%), three patients (10.7%) and no patients (0%), respectively and these were detected by FISH in 12 (42.8%), four (14.3%) and five (17.8%), respectively, of the 28 patients we studied. The median follow-up timefor the patients was 23.85 months (range: 0.3~58.13 months). On the univariate and multivariate analyses, none of the abnormalities detected by cytogenetics and interphase FISH affected survival. CONCLUSION: On comparing the cytogenetics and interphase FISH results, we can suggest that both studies should be an essential part of the workup for the diagnosis of patients with MM. Also, both studies may complement each other to predict the prognosis.

Why Should FISH Be Done in Patients with Acute Leukemias to Detect MLL Translocation? / 대한임상병리학회지

BACKGROUND: Translocations involving the MLL gene on the long arm of chromosome 11 (11q23) are frequently observed in acute leukemia. The detection of this genetic change has a unique significance due to its implication for poor prognosis. The aim of this study was to determine the utility of fluorescence in situ hybridization (FISH) method in detecting the MLL translocation. METHODS: We applied both conventional cytogenetic analysis (CC) and MLL FISH on 289 consecutive Korean patients (children and adults) with acute leukemia and analyzed the data, placing an emphasis on the discrepancies in the results. RESULTS: Twenty-two of 289 patients (7.6%) had the 11q23/MLL translocation. In 9 cases of 22 (41%), only FISH detected the translocation. In 8 among 22 patients, a total of 19 follow-up examinations were performed, of which FISH detected a significant level of leukemia cells harboring the MLL translocation in 5 (26%) without cytogenetic evidence. Besides the MLL translocation, FISH detected submicroscopic amplification, partial deletion of the MLL gene, and trisomy 11 in 12 cases without cytogenetic evidence. CONCLUSIONS: These results demonstrate that up to 41% of the MLL translocations at initial workups and 26% during follow-up were detected by FISH without cytogenetic evidence. Thus, we recommend that MLL FISH should be performed in the diagnosis and monitoring of acute leukemia in combination with CC.