Oncohematology

Background. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure. The introduction of anti-C5 therapy (eculizumab, ravulizumab) has significantly improved patient outcomes; however, suboptimal hematological response, breakthrough hemolysis, and inadequate disease monitoring persist in real-world clinical practice. Data on the real-world management of PNH patients in the Russian Federation are limited, justifying the need for the present study.

Aim. To evaluate the clinical and demographic characteristics, the rate and quality of hematological response, the frequency of laboratory monitoring, and the disease course features in PNH patients receiving or not receiving complement C5 inhibitors (anti-C5 therapy) in real-world clinical practice in the Russian Federation.

Materials and methods. A retrospective, non-interventional study (RADAR-PNH) was conducted and included 145 adult patients with a confirmed diagnosis of PNH. The primary analysis assessed hematological response and the frequency of key disease parameters monitoring during the 12 months following anti-C5 therapy initiation (n = 128).

Results. An optimal hematological response to anti-C5 therapy was achieved in 75 (58.6 %) of patients, including a complete response in 31 (24.2 %) and a good response in 44 (34.4 %). A suboptimal response persisted in 53 (41.4 %) of patients, including a minor response in 21 (16.4 %). Only 32 (25 %) of patients on anti-C5 therapy underwent complete regular laboratory monitoring. During the entire observation period, 43 (33.9 %) patients required red blood cell transfusions. Breakthrough intravascular hemolysis was reported in 30 (23.4 %) of patients. Five (3.9 %) patients developed thrombosis while receiving C5 inhibitor therapy.

Conclusion. The obtained data indicate a substantial proportion of patients with an incomplete hematological response, inadequate laboratory monitoring, and a persistent risk of breakthrough hemolysis and thrombosis even during targeted therapy. This study may provide a basis for systemic improvements in the diagnosis, follow-up, and treatment of PNH aimed at enhancing the quality of life and prognosis in this patient population.

Background. Despite high efficacy of chemotherapy in Hodgkin lymphoma (HL), a substantial proportion of patients (about 20 %) still experience relapse or refractory disease. This study was aimed to analyze efficacy and toxicity of most widely-used chemotherapy regimens for advanced-stage HL at a single center.

Materials and methods. The retrospective analysis included adult patients with advanced-stage HL (n = 107) who received treatment at the P. A. Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center, between 2019 and 2024.

Results. Of the 107 patients, 86 received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) or a BEACOPP-like regimen, and 21 received ABVD (doxorubicin, bleomycin, vinorelbine, dacarbazine). The overall response rate after completion of therapy was 93.5 %, and the complete metabolic response rate was 92.5 %. With a median follow-up of 26 (10–44) months, overall survival was 98.1 %, and progression-free survival was 78.5 %. Exploratory subgroup analysis showed a negative impact on progression-free survival of a high International Prognostic Score value (hazard ratio 1.13; 95 % confidence interval 2.60–6.02; p = 0.03), presence of extranodal lesions (hazard ratio 5.67; 95 % confidence interval 1.66–19.09; p = 0.006), and bone marrow involvement (hazard ratio 3.19; 95 % confidence interval 1.18–8.61; p = 0.02). Toxicity was comparable between treatment groups, although BEACOPP-like regimens were associated with higher hematologic toxicity.

Conclusion. The most commonly used chemotherapy protocols for advanced-stage HL provide only suboptimal disease control in this setting.

Langerhans cell histiocytosis (LCH) is a rare clonal myeloid neoplasm driven by constitutive activation of the MAPK signaling pathway. The principal molecular alterations are activating somatic mutations in BRAF, MAP2K1, ARAF, KRAS, and NRAS. Their identification provided the rationale for BRAF and MEK inhibitors, which place in treatment depends on age, clinical subtype, and LCH molecular profile.

Aim of the work – to analyze the molecular basis, efficacy, and safety of BRAF and MEK inhibitors in children and adults with LCH and to identify unresolved issues in molecularly targeted therapy.

In a pediatric cohort, the BRAF V600E mutation was detected in 54.6 % of patients and was associated with higher rates of resistance to first-line therapy (21.9 % vs 3.3 %) and 5-year disease reactivation (42.8 % vs 28.1 %). BRAF inhibitors are used primarily for BRAF V600E, whereas MEK inhibitors target MAP2K1 mutations and other activating alterations of the MAPK cascade. Two-year overall survival in pediatric patients with LCH, treated with BRAF and MEK inhibitors is 98 %. After end of treatment 3-year event-free survival decrease up to 62 %.

In adults the BRAF V600E mutation was detected in 38.8 %, BRAF deletions in 25.4 %, and MAP2K1 mutations in 19.4 % of patients. In all cases, complete or partial responses have been observed with the use of BRAF and MEK inhibitors, but there are no results on long-term survival in adult patients with LCH.

The main limitations of molecularly targeted therapy are frequent reactivation after discontinuation, uncertain optimal treatment duration, and adverse events. BRAF inhibitors most commonly cause cutaneous toxicity, photosensitivity, arthralgia, and QT prolongation; MEK inhibitors may cause dermatologic, gastrointestinal, cardiac, and ophthalmologic complications.

BRAF and MEK inhibitors are highly effective components of personalized therapy for LCH with activating MAPK pathway alterations. The strongest evidence concerns children with relapsed or refractory multisystem disease; first-line use in children and adults are supported mainly by observational studies and small heterogeneous cohorts. So, treatment choice should account for clinical subtype, molecular profile, risk of irreversible organ damage, and expected toxicity. Treatment sequence, combinations of BRAF and MEK inhibitors, duration, discontinuation criteria, and long-term safety require prospective evaluation.

Background. Multiple myeloma (MM) remains a chronic hematologic malignancy. However, treatment outcomes have improved significantly due to the introduction of new targeted agents and high-dose therapy with autologous hematopoietic stem cell transplantation (auto-HSCT) into clinical practice. Several researchers have demonstrated that the efficacy of high-dose chemotherapy with auto-HSCT is superior to the use of low-intensity antitumor therapy alone, even in the era of targeted agents. Despite this, disease relapses after auto-HSCT remains a major problem limiting the potential for a biological cure for MM. It is important to identify significant prognostic factors whose correction could help prevent adverse outcomes in MM treatment.

Aim. To determine the efficacy of auto-HSCT and to study progression-free survival (PFS) rates of MM patients depending on various clinical and laboratory parameters.

Materials and methods. The single-center study included 803 patients with MM aged from 19 to 69 years (median 54 years), who underwent high-dose chemotherapy followed by single or tandem auto-HSCT from June 2000 to January 2025. The diagnosis was established in accordance with the criteria adopted by the International Myeloma Working Group (IMWG) with successively revised parameters and updated in 2014. Before the collection of hematopoietic stem cells all patients received induction therapy, including chemotherapeutic agents only (VAD, EDAP) in 38 cases, bortezomib in 765 cases, lenalidomide in 217 patients, and daratumumab in 51 cases. Single high-dose chemotherapy (melphalan 140–200 mg / m²) followed by auto-HSCT was administered to 515 patients, and tandem chemotherapy was administered to 288 patients. The antitumor response was assessed (revised for the retrospective group) for all patients according to the IMWG-2016 criteria after induction therapy, before auto-HSCT, and on day 100 thereafter. The study results were statistically analyzed using MedCalc.

Results. Immunoglobulin G secretion was detected in 53 % of MM patients at disease onset, plasmacytomas were detected in 39 % of cases, and Durie–Salmon stage IIIA was diagnosed in 71 % of patients. After auto-HSCT, the rate of achieving stringent complete remission was 29 %, complete remission – 26 %, very good partial remission – 31 %, partial remission – 8 %, stabilization of disease – 2 %, and progression / relapse was recorded in 4 % of patients. A total of 320 (40 %) patients with MM showed an improvement in the antitumor response on the day 100 after the first auto-HSCT compared with the results of induction treatment. After completion of the high-dose phase, including one or two auto-HSCT, maintenance therapy was prescribed in 58 % of cases and in 42 % of cases, patients were monitored until progression without post-transplant treatment. The median PFS of patients was 36 months, while the probability of 5-year PFS was 32 %, and 10-year PFS – 20 %. The median PFS in the group of patients with standard cytogenetic risk was significantly higher and amounted to 40 months (95 % confidence interval 32–43) versus 26 months (95 % confidence interval 14–37) in the high-risk group (p < 0.05).

Based on the results of survival parameters assessment depending on the antitumor response achieved after auto-HSCT the median PFS was 104 months in case of stringent complete remission, 29 months for complete remission, 30 months for very good partial remission, 19 months for partial remission, 5 months for disease stabilization, and 4 months for progression / relapse on the day 100 after auto-HSCT (p < 0.001). Multivariate Cox regression analysis showed that the probability of disease relapse / progression after autologous stem cell transplantation was statistically significantly associated with three factors: stage III (International Staging System), failure to achieve a stringent complete remission after auto-HSCT, and the absence of maintenance therapy (p < 0.05).

Conclusion. A long-term follow-up period allows confirming the high significance of auto-HSCT in the treatment algorithm for MM patients, as the probability of maintaining remission achieved after transplantation for 10 years was 20 %.

Background. Pregnancy in patients with Ph-negative myeloproliferative neoplasms (MPN) is often accompanied by complications – both for the mother and the fetus.

Aim. To investigate complications and pregnancy outcomes in patients with Ph-negative MPN depending on the nosological form and the therapy administered during the gestational period.

Materials and methods. This retrospective study included 122 women with Ph-negative MPNs (essential thrombocythemia, polycythemia vera, and primary myelofibrosis) followed at the National Medical Research Center for Hematology from 2014 to 2024, with 165 pregnancies recorded. The structure of obstetric complications and pregnancy outcomes depending on the MPN nosological variant and treatment regimen was assessed using data extracted from medical records (outpatient charts, medical histories of childbirth).

Results. The effect of various treatment regimens on the incidence of pregnancy complications was analyzed in 122 patients with Ph-negative myeloproliferative neoplasms of reproductive age, who had a total of 165 pregnancies. In this group, the proportion of pregnancies resulting in live birth was 67.8 %. Among 120 pregnancies prolonged after the first trimester, complications were observed in 72.5 % (87 / 120) of cases. The most common of them were threatened miscarriage (20.8 %), bleeding during pregnancy or childbirth (13.3 %), preeclampsia (9.2 %); the incidence of thrombotic complications was 4.2 %.

Multivariate analysis revealed an independent protective effect of low molecular weight heparin: its inclusion in the treatment regimen reduced the probability of pregnancy complications by 68 % (odds ratio (OR) 0.32; 95 % confidence interval 0.12–0.86; p = 0.03). Acetylsalicylic acid and interferon α did not demonstrate a statistically significant independent effect (p = 0.51 and p = 0.69, respectively). In contrast to triple therapy, the interferon α + acetylsalicylic acid combination was associated with a significantly increased risk of complications (OR 3.6; p = 0.05). Other treatment regimens did not show a significant effect on the incidence of pregnancy complications.

In polycythemia vera, the three-component treatment regimen showed a tendency to reduce the incidence of pregnancy complications (OR 0.24; p = 0.07), and the results of multivariate analysis confirmed that low molecular weight heparin is the main independent protector (OR 0.31; p = 0.02)

Conclusion. The obtained data substantiate the need for a differentiated approach to choosing a therapeutic strategy in pregnant women with various forms of myeloproliferative neoplasms.

Background. Waldenström’s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with a heterogeneous tumor substrate. Methods for selection and characterizing WM tumor cells using multicolor flow cytometry vary in the literature. Since the choice of optimal gating strategy directly impacts diagnostic accuracy and tumor volume assessment, developing a unified approach is a pressing issue.

Aim. To develop an optimal gating strategy for separating the tumor substrate in WM patients before initiating specific therapy and to study the immunophenotypic characteristics of each compartment.

Materials and methods. The study included 60 patients (31 men and 29 women) with a median age of 61 years. Bone marrow was analyzed using multicolor flow cytometry. A panel of antibodies against CD19, CD20, CD22, CD27, CD38, CD45, CD138, immunoglobulin M, and the light chains of immunoglobulins κ and λ was used.

Results. A unique gating strategy was proposed in the study, including the separation of the B-cell component, plasma cells (PCs), and intermediate lymphoplasmacytic cells (LPCs). Tumor B cells were detected in the bone marrow sample of 60 patients (100 %), tumor PCs in 53 (88 %), and LPCs in 45 (75 %). In all cases, tumor B cells and PCs demonstrated monoclonal restriction by immunoglobulin light chains (κ/λ) and immunoglobulin M expression. Tumor B cells, compared to normal B cells, had lower expression of CD19, CD20, CD22, and CD27 antigens. PCs differed from normal B cells by a higher density of CD20, CD45, and immunoglobulin M heavy chain antigen expression, as well as lower expression of CD38 and CD138.

Conclusion. The three-component strategy proposed for research purposes allows for a detailed characterization of WM tumor clone heterogeneity. However, for routine clinical diagnosis, a two-component approach (B cells + PCs), based on the inclusion of LPCs in the PC-compartment, is sufficient. Despite the identified heterogeneity, in clinical practice, we recommend combining LPCs with PCs due to the similarity of their immunophenotypes and the lack of additional diagnostic value when analyzed separately. Multicolor flow cytometry is a valuable adjunctive diagnostic method for patients with suspected WM.

Background. Despite advances in the treatment of chronic myeloid leukemia (CML), the problem of resistance to tyrosine kinase inhibitors (TKIs) remains unresolved. The role of additional gene mutations (besides BCR::ABL1) in resistance development is widely discussed. These mutations may influence the development of the disease, its course, progression, and the effectiveness of targeted therapy.

Aim – to determine the spectrum and frequency of genetic abnormalities in patients with chronic phase CML at the onset of the disease and to identify genetic factors that predict the poor prognosis for the effectiveness of targeted therapy with ATP-competing TKIs.

Materials and methods. The study included 61 patients with CML diagnosed in chronic phase: 37 with a long-term stable optimal response to first-line imatinib therapy – favorable CML course (median age 61 (23–83) years, median follow-up 47 (27–78) months), and 24 with resistance to three or more 1^st- to 3^rd-generation TKIs (median age 53 (15–81) years, median follow-up 43 (13–90) months). All patients underwent standard examination and high-throughput DNA sequencing using a custom panel of 123 genes.

Results. Additional mutations in the overall cohort of patients were identified in 59 % of cases in 24 genes: in the group with a favorable CML course – in 40 % of patients, with a resistant course – in 88 %. Mutations of unfavorable significance were determined in 13 and 38 %, of uncertain significance – in 3 and 21 %, benign – in 32 and 67 %, respectively. The most common pathogenic mutations were ASXL1 (10 % of cases in the overall cohort, 5 % in the group with favorable CML, and 17 % in those with resistant CML) and KMT2C (13, 3, and 29 % in the above cohorts, respectively). The presence of additional pathogenic mutations, the number of such mutations (>1), and the presence of pathogenic mutations in the ASXL1 or KMT2C gene are statistically significantly correlated with a decrease in progression-free and overall survival. All five patients who died due to CML progression were resistant to therapy with three or more TKIs and harbored additional pathogenic mutations; three of them had two pathogenic gene mutations, one of which – in all three cases – was an ASXL1 mutation. A comparison of genetic, cytogenetic and clinical data was carried out.

Conclusion. The obtained results demonstrate the need to incorporate next-generation sequencing of patients’ genetic landscapes at diagnosis into the risk assessment of CML progression, the effectiveness of targeted therapy, and the selection of TKIs for each individual case. However, further studies in larger patient cohorts are currently needed to identify definitive prognostic markers.

Aim of the study – to develop a curriculum for a Continuing Professional Education program – specifically, a Professional Retraining (PR) program in the specialty of “Hematology” – that meets modern clinical challenges, professional and educational standards, and the expectations of the medical community.

This article presents and describes the methodological approaches to developing the curriculum for the PR program in “Hematology”, which is focused on advancing and enhancing modern technological directions for the diagnosis and treatment of blood system disorders. It also addresses clinical tasks fundamentally based on the labor functions outlined in the professional standard. The program structure is based on a modular principle with a clearly traceable practice-oriented focus. To assess the relevance and applicability of the PR program, a survey was conducted among chief freelance hematology specialists from the constituent entities of the Russian Federation, practicing hematologists, and medical university faculty.

The survey results helped identify the most significant thematic blocks, reveal differences in educational priorities, and formulate recommendations for adapting the professional retraining program according to the varying conditions of real clinical practice in medical organizations specializing in hematology.