Journal pre-proofs

We report a clinical case of a rare, aggressive variant of cyclin D1-negative mantle cell lymphoma in a 71-year-old female patient with a congenital disorder classified as a 46,XY disorder of sex development (DSD). Histological and immunohistochemistry examination revealed that diffusely infiltrating the lymph node tissue atypical cells express SOX11, do not express cyclin D1, and have a Ki-67 proliferative activity index of up to 70%. The cytogenomic profile of the tumor did not reveal the t(11;14)(q13;q32)CCND1::IGH translocation, but there were multiple clonal chromosomal alterations, including a deletion of the 17p13(TP53) locus and rearranged of the 14q32(IGH) locus. Simultaneously, the patient was found to have XY(SRY+) gonosomal complement in bone marrow cells, peripheral blood lymphocytes, and buccal epithelial cells, which led to the diagnosis of a congenital condition belonging to the 46,XY DSD group. The patient received four courses of VR-CAP to treat the underlying disease. Given the aggressive course of the disease and the development of adverse events during bortezomib treatment, treatment with ibrutinib was continued. However, after a brief partial remission, the disease progression caused the patient's death.
We discuss the clinical manifestations, course, diagnosis, and treatment of the disease, and explores a possible association between DSD and certain types of hematological malignancies.

INTRODUCTION.
Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell chronic lymphoproliferative disorders (B-CLPD), significantly improving survival rates and quality of life for patients. The development of drug resistance to first-generation BTK inhibitors has led to the development of more advanced agents for the treatment of ibrutinib-resistant patients.

OBJECTIVE.
To systematize current data on the effects of BTK inhibitors on T-lymphocytes and tumor microenvironment cells in CLPD.

MATERIALS AND METHODS.
A systematic review was performed using stepwise search algorithms in electronic databases (Scopus, PubMed, Web of Science, ScienceDirect) using the keywords “tumor microenvironment,” “BTK,” “ibrutinib,” “T-cells,” “solid tumor,” and “lymphoma.” Studies were searched from the introduction of the first BTK inhibitor in 2009 to 2025.

RESULTS.
Covalent BTK inhibitors have demonstrated high therapeutic efficacy, but the development of resistance is often due to point mutations in the BTK binding site, particularly the C481S mutation. Non-covalent BTK inhibitors are able to retain activity against mutated forms of Bruton's tyrosine kinase, and proteolytic degraders allow for the selective destruction of the BTK protein regardless of its mutational status. It is also known that BTK inhibitors have a significant effect on the tumor microenvironment, reducing the number and suppressing the activity of myeloid suppressor cells, promoting a change in the polarization of macrophages from a pro-neoplastic (M2) to an anti-neoplastic (M1) phenotype, and also enhancing the functional activity of T-lymphocytes, changing the balance from Th2 to Th1.

CONCLUSION.
The immunomodulatory properties of BTK inhibitors contribute to the formation of an antitumor immune response and can be successfully used in combination therapeutic regimens, including the treatment of infections and inflammatory diseases, including COVID-19.

Rationale.
The growing need for specialized medical care in the field of transfusiology, the limited number of beds in round-the-clock specialized hospitals, the increase in the number of comorbid patients in need of transfusion replacement therapy require measures to optimize the organization of transfusion care.

Hematological profile. Methods.
The medical records of 1282 hematological patients hospitalized in the day hospital for the period 2017-2024 were analyzed.

Outcomes.
The day hospital of the State Budgetary Healthcare Institution of the Novosibirsk Region "Novosibirsk Clinical Blood Center" is the only specialized transfusion day hospital in the Russian Federation, created on the basis of a blood service institution, providing medical care on an outpatient basis. For the period 2017-2024 replacement therapy with donor blood components was performed on 1847 patients with hematological and oncological profiles, including 1282 patients with a hematological profile, including oncohematology. During the study period, 7500 transfusions of donor blood components were performed in order to correct the anemic syndrome, including 6495 transfusions of erythrocyte-containing components, and 1005 transfusions of platelet concentrate. Clinical efficacy in hematological patients was achieved in 99.2% of cases of erythrocyte-containing blood components, in 87.4% of cases of platelet-containing components.

Conclusion.
The results obtained indicate the possibility of providing specialized transfusion medical care to hematological patients with anemia and thrombocytopenia on an outpatient basis, which is confirmed by the correction of pathological manifestations and the achievement of clinical efficacy in the form of relief of anemia and thrombocytopenic syndromes, but it has its own fundamental features.