Alaa Fadhil Alwan

BACKGROUND: Myeloproliferative neoplasms (MPNs) are clonal disorders affecting myeloid progenitor cells, with thrombotic events being a major cause of mortality and morbidity. Increased mean platelet volume (MPV) has been linked to higher thrombosis risk. JAK2V617F is the most common mutation in MPNs. OBJECTIVES: This study aimed to explore the association between JAK2V617F status and MPV in MPNs patients. MATERIALS AND METHODS: A cross-sectional study was conducted on MPN patients, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Full blood count, including MPV, was measured using an automated hematology analyzer, and JAK2V617F mutation was detected by Amplification refractory mutation system-polymerase chain reaction. RESULTS: Eighty-five patients (43 PV, 24 ET, 18 PMF) were analyzed. The mean MPV was 8.89 fL. MPV correlated positively with age (r = 0.245; P = 0.025). No significant MPV differences were found among PV, ET, and PMF (P = 0.7344). JAK2V617F-mutated patients were older in PV and ET but not in PMF. MPV did not differ by JAK2V617F status in PV (P = 0.3648) or ET (P = 0.4705) but was higher in JAK2V617F-mutated PMF (P = 0.0175). JAK2V617F-mutated PV patients had a higher thrombosis frequency, and MPV was significantly higher in thrombotic MPN patients (P = 0.0328), particularly in PV (P = 0.0254). CONCLUSION: MPV is similar across MPN subtypes but correlates with age. JAK2V617F mutation is linked to increased MPV in PMF and a higher thrombosis frequency in PV. MPV and JAK2V617F may serve as thrombotic risk biomarkers, warranting further research

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL)

BACKGROUND: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm caused by genetic abnormality resulted in BCR-ABL1 fusion gene, leading to constitutive tyrosine kinase activity. Despite improved treatment outcomes of tyrosine kinase inhibitors (TKIs), resistance to these agents due to mutations in targeted BCR-ABL gene is still a challenge. Bosutinib is consider one of TKI, it inhibit both Sarcoma kinase and Ablson kinase (SRC/ABL), It is approved for patients for whom frontline TKIs is failed or undergo adverse effects. OBJECTIVE: This study aims to evaluate the efficacy of bosutinib as a second-line treatment for CML patients who have previously failed or experienced intolerance to other TKIs. MATERIALS AND METHODS: A cross-sectional study was conducted from October 2021 to December 2023 at the National Center of Hematology. Thirty CML patients were enrolled, all of whom had received bosutinib following failure or intolerance to prior TKI treatments (imatinib and/or nilotinib). Data collected included patient demographics, prior treatment history, and laboratory results. BCR-ABL levels were quantitatively measured using polymerase chain reaction at baseline and 6 months posttreatment. Statistical analyses included paired t-tests and correlation assessments. RESULTS: The study included 30 CML patients (12 males and 18 females) with a median age of 49.5 years. Most patients (60%) had received imatinib only prior to bosutinib. A significant decrease in mean BCR-ABL levels was observed after 6 months of bosutinib treatment (P < 0.0001), with 53% of patients achieving optimal molecular response as per the European LeukemiaNet criteria. Correlation analyses indicated significant relationships between BCR-ABL level and white blood cell count (P = 0.006) and between treatment duration and hemoglobin level (P = 0.001). In addition, patients previously treated solely with imatinib responded to bosutinib significantly better than those who had received both imatinib and nilotinib (P = 0.0272). CONCLUSION: Bosutinib demonstrated significant efficacy as a second-line treatment for CML in patients who showed failure response to prior TKI therapies. These findings support bosutinib usage in managing CML, particularly in patients with a history of single TKI treatment, and underscore the necessity for ongoing research into resistance mechanisms and alternative therapies.

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27⁺CD45RO⁻ CD8⁺ T cells.