DIAGNOSIS AND TREATMENT OF MULTIPLE MYELO
The article considers the features and possibilities of flow cytometric diagnostics of plasma cell neoplasms, taking into account the classification of lymphoid and hematopoietic tissue tumors of the World Health Organization, revision of 2017 and the NCCN clinical recommendations, 2021. Standardized flow cytometric protocols (the Euro-Flow conception) and algorithms for both the diagnosis of plasma cell tumors and the detection of minimal residual disease in plasma cell myeloma are described.
Multiple myeloma is a tumor of plasma cells, one of the most common malignant blood diseases. It is preceded by a stage called monoclonal gammopathy of undetermined significance, from which true multiple myeloma develops in only a small percentage of cases. It was assumed that this process is associated with the accumulation of genetic mutations, but in recent years there is increasing evidence that the bone marrow microenvironment plays a key role in progression and that it can become a target for therapy that prevents the myeloma development. The review considers the role of mesenchymal stem cells, immune system cells, endotheliocytes, fibroblasts, adipocytes, osteoclasts and osteoblasts in multiple myeloma progression, as well as the impact of the sympathetic nervous system and microbiome composition.
A brief review focuses on the radiation diagnostics methods used in the examination of patients with myeloma and plasmacytoma. Modern imaging techniques, such as positron emission tomography combined with computed tomography (PET/CT) and magnetic resonance imaging, facilitate diagnosis and allow assessing the extent of the process and efficiency of treatment performed. Moreover, each of these methods has its own advantages and disadvantages. The most promising is PET/CT, which has sensitivity and specificity comparable to magnetic resonance imaging, while having unique advantages.
Background. Multiple myeloma (MM) is a kind of malignancy from malignant plasma cells with high intra- and interpatient variability, because of complex clonal evolution of tumor cells. Positron emission tomography combined with computed tomography with 18F-fluorodeoxyglucose (18F-FDG-PET/CT) plays a major role in MM visualization, but there are evidences of non-FDG-avid cases of MM. Taking into account the increasing role of 18F-FDG-PET/CT in MM, special criteria for risk-group stratification was elaborated. These criteria are based on comparison of radiotracer uptake in tumor tissue, mediastinal blood pool and liver.
Objective: the study of 18F-FDG uptake in MM and solitary plasmacytoma before antitumor treatment to assess the applicability of criteria based on the ratio of activity in tumor tissue and liver.
Materials and methods. We reviewed 65 18F-FDG-PET/CT scans of patients with MM and solitary plasmacytoma before treatment.
Results. In our cohort we identified 2 tumor cases of a plasma cell nature, which amounted to 2 % among all B-NHLs. In one case, the process was located in the nasal cavity and clinically manifested itself with nosebleeds. The second case is a lesion of the mouth floor, primarily with the ulcer formation. In the first cases, at diagnosis, the immunohistochemistry (IHC) test was performed after patient’s chemotherapy and radiation treatment, which distorted the tumor immunophenotype. In the second cases with extensive process in maxillary sinuses, a complete and very detailed IHC test was carried out; however the data did not allow for a definitive diagnosis. Difficulties apparently arose in the interpretation of CD38 expression – main marker of plasmacytic line cells, as well as due to the unusual morphology.
Conclusion. Therefore, 5-point scale is eligible for MM tumor assessment in 52 % of patients and feasible in 32 % of patients, but in 16 % patients alternative criteria are required.
Background. Extramedullary plasmacytoma (EP) of soft tissues, which in most cases affects the organs of the head and neck region, is a relatively rare malignant tumor. Until now, there are no consensus approaches to the diagnosis and treatment of EP. Differentiating EP from other types of non-Hodgkin’s lymphomas is difficult. There are difficulties in the differential diagnosis of EP and carcinomas in the head and neck region. Given the rare occurrence of this nosological form, the frequency of diagnostic errors is quite high, which dictates the need for a thorough description of each head and neck EP case.
Objective of the study: analysis of possible difficulties and reasons for incorrect interpretation of diagnostic data, and treatment for head and neck EP.
Materials and methods. Clinical and morphoimmunological data of 97 primary patients with B-cell non-Hodgkin’s lymphomas (B-NHLs) of the head-neck region were analyzed.
Results. In our cohort we identified 2 tumor cases of a plasma cell nature, which amounted to 2 % among all B-NHLs. In one case, the process was located in the nasal cavity and clinically manifested itself with nosebleeds. The second case is a lesion of the mouth floor, primarily with the ulcer formation. In the first cases, at diagnosis, the immunohistochemistry (IHC) test was performed after patient’s chemotherapy and radiation treatment, which distorted the tumor immunophenotype. In the second cases with extensive process in maxillary sinuses, a complete and very detailed IHC test was carried out; however the data did not allow for a definitive diagnosis. Difficulties apparently arose in the interpretation of CD38 expression – main marker of plasmacytic line cells, as well as due to the unusual morphology.
Conclusion. The described diagnostic situations dictate the need for a comprehensive algorithm in the diagnosis of head and neck tumors. It is advisable to perform an extended morpho-immunophenotypic study of the tumor (IHC, immunocytology, flow cytometry, etc.), if a tumor of a plasma cell nature is suspected, a morpho-immunological study of the bone marrow is indicated.
In most publications on relapsed and refractory multiple myeloma, the term double-refractory refers to the loss of response to lenalidomide and proteasome inhibitors. The prognosis in the case of double-refractory multiple myeloma is poor. Usually, these are severely pretreated patients who have accumulated drug toxicity after 2 or more lines of therapy, with limited reserves of bone marrow hematopoiesis and often decompensated comorbidities. A partial solution to the problem was to use certain new drugs that have demonstrated activity as monotherapy or in combination with dexamethasone in this group of patients. This review is aimed to provide a critical review of recent clinical studies addressing this issue. According to the recent European Hematology Association and European Society for Medical Oncology (EHA-ESMO) 2021 guidelines for the diagnosis and treatment of double-refractory multiple myeloma, triple combinations should be considered, including monoclonal antibodies (elotuzumab (Elo), isatuximab (Isa), daratumumab (Dara)), dexamethasone and pomalidomide (Elo-Pd, Isa-Pd, Dara-Pd) or carfilzomib (Isa-Kd, Dara-Kd). In Russia, as of March 2021, the first two regimens were approved (Elo-Pd, Isa-Pd). Elotuzumab was tested in combination with pomalidomide in the randomized phase II ELOQUENT-3 trial (Elo-Pd vs. Pd; n = 177). Median progression-free survival was 10.3 months on Elo-Pd vs. 4.7 months on Pd (hazard ratio 0.54; 95 % confidence interval 0.34–0.86; р = 0.008). Elo-Pd superiority was observed in all subgroups, including patients with double-refractory MM, high-risk cytogenetic aberrations del17p, t(4;14), t(14;16), and increased serum LDH. The Isa-Pd triplet was approved in the randomized phase III ICARIA-MM study (Isa-Pd vs. Pd; n = 307). The median progression-free survival in this protocol was 11.5 months in the Isa-Pd group vs. 6.5 months in the Pd group (hazard ratio 0.596; 95 % confidence interval 0.44–0.81; р = 0.001). Isa-Pd triplet superiority was demonstrated in all unfavorable prognostic subgroups, including lenalidomide-refractory patients, patients with high-risk cytogenetics, and doublerefractory patients. New triplets with monoclonal antibodies represent an important option for the treatment of doublerefractory multiple myeloma.
Objective of the study: analysis of AL-amyloidosis (AL-A) diagnostics in real clinical practice and to determine the main approaches for the earlier detection of this disease.
Materials and methods. A retrospective analysis of medical records of 34 patients with newly diagnosed AL-A.
Results. The median time from first symptoms appearance to the diagnosis was more than 2 years. Most often, the pathological process in AL-A involves the kidneys, heart and gastrointestinal tract; moreover, at the time of diagnosis, most patients already have an injury of 2 or more organs. In half of the patients, a biopsy of the damaging organ was performed to verify the diagnosis; according to our data, histological examination of “easily accessible” locus not less informative. Symptoms characteristic of amyloidosis, such as periorbital purpura or macroglossia, are observed in a small part of patients and refer to late manifestations of the disease.
Conclusion. The versatility of AL-A manifestations leads to a late diagnosis, which affects overall survival. The main signs were highlighted that should alert doctors in relation to this pathology.
HEMATOLOGIC MALIGNANCIES: TREATMENT
Background. Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive tumors of the lymphatic system. Despite the frequency of occurrence, there is no single algorithm for treating DLBCL patients with poor prognostic factors. R-CHOP therapy does not allow achieving long-term complete remissions. Therefore, there is a need for second and subsequent lines of therapy. At the same time, the effectiveness of each subsequent therapy is low, while the toxicity increases. There are many randomized trials of the DLBCL treatment; however, there are only a few studies on the comparative efficacy of high-dose chemotherapy at the induction stage.
The objective of the study: the evaluation of the effectiveness and toxicity of R-DA-EPOCH and R-mNHL-BFM-90 induction courses in DLBCL patients with poor prognostic factors in a randomized multicenter clinical trial “DLBCL-2015”.
Materials and methods. As of April 2021, 140 patients from 13 medical institutions in Russia were included in the randomized multicenter clinical trial DLBCL-2015. As part of this study, the analysis of pharmacoeconomic factors and effectiveness of combined immunochemotherapy R-DA-EPOCH and R-mNHL-BFM-90 in patients with prognostically unfavorable DLBCL had been performed. From January 2018 to April 2021, this study included 41 patients (21 men, 20 women) with a newly diagnosed DLBCL, with 2 or more factors of an unfavorable prognosis, who were treated at the National Research Center for Hematology of the Ministry of Health of the Russian Federation. Of these, 21 patients received R-DA-EPOCH, and 20, R-mNHL-BFM-90 therapy. Median age for R-DA-EPOCH patients was 52 years (range 30–64); for R-mNHL-BFM-90 patients, 40 years (range 18–60). All patients had high-intermediate and high risk according to the international (IPI) and age-adjusted (aaIPI) prognostic index. The primary protocol endpoints were rates of complete remission, partial remission, disease progression, and hematologic and non-hematologic toxicity. Side effects were assessed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) criteria.
Results. By the end of 6 induction courses, the frequency of achieving complete remission on R-mNHL-BFM-90 therapy was 100 % (20/20) compared to R-DA-EPOCH, where the complete remission rate was 71.4 % (15/21) (p = 0.0097), partial remission and progression were 14.3 % (n = 3) and 14.3 % (n = 3), respectively. Hematological toxicity on therapy according to the R-mNHL-BFM-90 scheme exceeded that on R-DA-EPOCH in terms of myelotoxic agranulocytosis (p = 0.0536), anemia (p = 0.0464) and thrombocytopenia grade III–IV (p = 0.0206). When assessing non-hematological toxicity at the compared courses, no statistically significant differences were noted, all complications occurred with the same frequency.
Conclusion. Treatment according to the R-mNHL-BFM-90 protocol is highly effective as first line therapy in high-intermediate and high-risk DLBCL patients. The hematologic toxicity is higher on the R-mNHL-BFM-90 than on the R-DA-EPOCH therapy, but it is acceptable. Non-hematological toxicity in both programs is comparable.
Background. Actually, treatment results of Hodgkin lymphoma (HL) are the most dramatic oncohematology achievements, therefore modern treatment protocols designed to toxicity reduction with the same high level of patients’ survival. Time of complete response occupies a central position in the prognostic factors for HL and helps to find a group of patients whose treatment could be de-escalated.
Objective: to evaluate the efficacy of original domestic risk-adopted protocol RDC POG-HL 2003 with treatment de-escalation and refused radiation therapy (RT) for early-responded patients.
Materials and methods. 192 patients were enrolled in prospective RDC POG-HL 2003 protocol from February 2003 to November 2020. Median age was 12.8 years (from 3 to 17). Local stages (IA–IIA) were diagnosed in 48 (25 %) patients, disseminated (IIB–IVB) – in 144 (75 %) cases. For local (IA–IIA) stages by RCD POG-HL 2003 treatment included DBVE + RT, for disseminated (IIB–IVB) – BEACOPP escalated (esc.) + RT. In case of 70 % and more tumor reduction after 4 induction courses of BEACOPP-esc., the following treatment included less intensive schemes (ABVD, COPP/ABV). Because of high risk of breast cancer in girls after mediastinal RT, it was possible to omit a RT in case of early response.
Results. All patients with local stages are alive by the time of study end. Event- and relapse-free survivals in this group were 97.8 ± 2.5 % (median follow up 181.9 ± 4.8 months). Event-free survival for disseminated stages patients was 90.3 ± 3.3 % (median follow up 179.1 ± 4.2 months), relapse-free survival – 93.5 ± 2.1 % (median follow up 191.7 ± 2.3 months) and overall survival – 97.9 ± 1.2 % (median follow up 196.3 ± 2.6 months). In 48 (25 %) patients it was possible to omit RT without reducing survival rates.
Conclusion. Differentiated HL treatment with respect to disease stage and time of complete response is a key to success of treatment. Such approach permits us to reduce cumulative therapy toxicity by its de-escalation and, in some cases, to omit RT.
Background. Lymphomas are a heterogeneous group of the lymphoid and hematopoietic system tumors. Neoplastic process often develops in head and neck area, including the integumentary tissues, orbit, nasal cavity, paranasal sinuses, oral cavity, pharynx, salivary glands, thyroid gland, as well as neck lymph nodes. The difficulties of head and neck lymphomas diagnosis are significant, since very often there is a combined non-tumor pathology. The high heterogeneity of lymphomas in the head and neck area requires structuring knowledge about their epidemiology and clinical manifestations.
Objective: to study the epidemiological and clinical features of the head and neck lymphoproliferative diseases, which will lead to an improvement in diagnostic quality of this nosology’s.
Materials and methods. The frequency of head and neck lymphoproliferative diseases detection was estimated based on the study of epicrisis and clinical data of 174 patients hospitalized at the N.N. Blokhin National Medical Research Center of Oncology in the period from 2000 to 2020.
Results. Taking into account the modern clinical and morphological classification of lymphomas of the World Health Organization (2017), information about the features of localization, characteristic signs of extranodal foci and lymph nodes is presented. Detection frequency of various subtypes non-Hodgkin’s and Hodgkin’s lymphomas were determined on a sufficient cohort of patients.
Conclusion. Based on the analysis of clinical and morphological features of head and neck lymphomas, epidemiological and clinical features are described in detail, and differences in the symptoms and clinical manifestations of non-Hodgkin’s and Hodgkin’s lymphomas with a predominant head and neck involvement are revealed.
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ISSN 2413-4023 (Online)