Molecular diagnostic criteria of myeloproliferative neoplasms.

INTRODUCTION: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by the driver mutations JAK2, CALR, and MPL. These mutations cause constitutive activation of JAK-STAT signaling, which is central to pathogenesis of MPNs. Next-generation sequencing has further expanded the molecular landscape allowing for improved diagnostics, prognostication, and targeted therapy. AREAS COVERED: This review aims to address current understanding of the molecular diagnosis of MPN not only through improved awareness of the driver mutations but also the disease modifying mutations. In addition, other genetic factors such as clonal hematopoiesis of indeterminate potential (CHIP), order of mutation, and mutation co-occurrence are discussed and how these factors influence disease initiation and ultimately progression. How this molecular information is incorporated into risk stratification models allowing for earlier intervention and targeted therapy in the future will be addressed further. EXPERT OPINION: The genomic landscape of the MPN has evolved in the last 15 years with integration of next-generation sequencing becoming the gold standard of MPN management. Although diagnostics and prognostication have become more personalized, additional studies are required to translate these molecular findings into targeted therapy therefore improving patient outcomes.

Imatinib Resistance in Chronic Myeloid Leukemia Associated with a D363G BCR::ABL1 Kinase Domain Mutation.

Acquired resistance to tyrosine kinase inhibitors (TKIs) remains a therapeutic challenge in the treatment of chronic myeloid leukemia (CML). The most studied reason for TKI resistance is the acquisition of mutations within the BCR::ABL1 tyrosine kinase domain (KDM) and of which the majority of which occur at seven codons within this region. A case of CML is described in which presence of a rare D363G BCR::ABL1 KDM resulted in a suboptimal response to frontline imatinib. Switching to dasatinib resulted in achieving a sustained major molecular response that was maintained after a subsequent switch to bosutinib due to the side effects. Reporting of such cases is important for the future management of any CML patients with this rare mutation.

Pyoderma gangrenosum and myeloproliferative neoplasms.

Pyoderma gangrenosum can be associated with haematological malignancies but rarely a myeloproliferative neoplasm. A review of requests for molecular detection of myeloproliferative neoplasm driver mutations in patients with pyoderma gangrenosum was performed and revealed that testing for these mutations is unwarranted in cases where there are no clinical, haematological or morphological features of a myeloproliferative neoplasm present.

Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study.

Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance.