Vol 93, No 7 (2021)

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Development of program therapy for patients with acute myeloid leukemia under the age of 60 years, based on the principles of differentiated effects

Parovichnikova E.N., Lukianova I.A., Troitskaya V.V., Drokov M.Y., Kuzmina L.A., Sokolov A.N., Kokhno A.V., Fidarova Z.T., Galtseva I.V., Davydova Y.O., Kashlakova A.I., Gribanova E.O., Zvonkov E.E., Sysoeva E.P., Dvirnyk V.N., Obukhova T.N., Sudarikov A.B., Sidorova Y.V., Kulikov S.M., Chabaeva Y.A., Savchenko V.G.


Aim. To analyze the results of treatment in patients with acute myeloid leukemia (AML) within protocols AML-17 and modified AML-17 (mOML-17) as part of two consecutive pilot studies in order to develop the best treatment strategy for AML patients aged below 60 years.

Materials and methods. The study included 89 AML patients who were aged below 60 years and received treatment within the AML-17 and mOML-17 protocols. Cytogenetic and molecular genetic studies were performed in all patients. The presence of mutations in the FLT3, NPM1, CEBPa genes was assessed by fragment analysis. 35 patients underwent a study for mutTP53, mutRUNX1 using next generation sequencing (NGS). The minimum residual population of tumor cells was evaluated by multicolor flow cytometry. Statistical analysis was performed using the procedures of the SAS 9.3 package.

Results. Complete remission (CR) was achieved in 89.7% of patients treated with intensive chemotherapy (CT) courses and in 52.4% of patients treated with low-dose CT courses. 8.8% of intensively treated patients were refractory to therapy, and 38% did not respond to low-dose exposure. The early mortality rate was 3%. The overall survival and disease-free 3-year survival for patients included in 2 consecutive studies was were 60% and 67%, respectively. The level of minimal residual disease (MRD) after the first course of induction CT was an important prognostic indicator. The three-year relapse-free survival for patients in whom CR was achieved after the first course of induction CT and in whom MRD was not detected (MRD-negative status was obtained) was 90% compared to 43% for patients who were MRD positive after the first course of induction CT (p=0.00001).

Conclusion. The key factor that significantly affects the long-term results of therapy is the rate of MRD after the first course of induction CT.

Terapevticheskii arkhiv. 2021;93(7):753-762
pages 753-762 views

Original articles

Li–Fraumeni syndrome in adult patients with acute lymphoblastic leukemia

Zarubina K.I., Parovichnikova E.N., Surin V.L., Pshenichnikova O.S., Gavrilina O.A., Isinova G.A., Troitskaya V.V., Sokolov A.N., Galtseva I.V., Kapranov N.M., Davydova J.O., Obukhova T.N., Nikulina E.E., Sudarikov A.B., Savchenko V.G.


Background. Li–Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome.

Aim. Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL.

Materials and methods. TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants).

Results. TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 – B-cell ALL (n=3), T-cell ALL (n=1) – investigated patients.

Conclusion. Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS.

Terapevticheskii arkhiv. 2021;93(7):763-769
pages 763-769 views

Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice

Vorobyev V.I., Gemdzhian E.G., Fedorova L.V., Mikhailova N.B., Ilyasov R.K., Kaleikina L.P., Trubyakova O.S., Kaplanov K.D., Melnichenko E.V., Martynova E.V., Yakovleva E.P., Li O.Y., Tarasenko E.V., Chumakova E.P., Bulieva N.B., Nesterova E.S., Margolin O.V., Zherebtsova V.A., Butaev L.S., Ptushkin V.V.


Background. Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients’ outcomes, but relapse is inevitable. In phase II–III clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL.

Aim. To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials.

Materials and methods. The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 2–4, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity.

Results. From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG>2 – 18%, blastoid variant (or Ki67>40% or WBC>50×109/l) – 43%. The median number of previous treatment lines was 2 (1–11). The ORR was 78.4% (CRR – 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p<0.001), the median OS – 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months.

The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity – 15%, arrhythmia – 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications.

Conclusion. Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

Terapevticheskii arkhiv. 2021;93(7):770-777
pages 770-777 views

Allogeneic hematopoietic stem cell transplantation in patients with multiple myeloma

Firsova M.V., Mendeleeva L.P., Parovichnikova E.N., Solovev M.V., Kuzmina L.A., Risinskaya N.V., Abramova T.V., Galtseva I.V., Savchenko V.G.


Aim. To analyze the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related HLA-identical donor in patients with multiple myeloma (MM).

Materials and methods. From 2013 to 2018, the study included 8 patients (6 men, 2 women) aged from 27 to 55 years (median 39 years) with MM who underwent allo-HSCT from a related HLA-identical donor (7 patients – after auto-HSCT, in 1 case – without previous auto-transplantation). All patients required 2 or more lines of induction therapy, while the achieved antitumor effect was unstable. Before allo-HSCT, complete and very good partial remission was determined in isolated cases, in 4 patients the response was regarded as partial remission, stabilization – in 1 observation, progression – in 1 patient. All patients underwent reduced intensity conditioning (fludarabine 30 mg/m2 × 6 days + busulfan 4 mg/kg × 2 days). Immunosuppressive therapy included the administration of antithymocyte globulin and post-transplant cyclophosphamide.

Results. Severe acute GVHD (grade 3–4) was observed in 3 (37.5%) cases, which resulted in death in 1 case. A stable antitumor response was achieved in 5 (62.5%) patients, complete remission lasts for 29–86 months after allo-HSCT. Specific therapy for these patients is not carried out. The 7-year progression-free survival rate was 75%, the 7-year overall survival rate was 84%, with a median follow-up of 65 months. The transplant-related mortality was 12.5%.

Conclusion. Allo-HSCT is considered as an alternative method of therapy for young patients with aggressive MM. Allo-HSCT in MM in some cases leads to long-term immunological control of the tumor.

Terapevticheskii arkhiv. 2021;93(7):778-784
pages 778-784 views

Carfilzomib, lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience

Zherebtsova V.A., Vorobyev V.I., Gemdzhian E.G., Ulyanova M.A., Chernikov M.V., Ivanova V.L., Vinogradova O.Y., Ptushkin V.V.


Background. Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial.

Aim. Analysis of efficacy and safety of KRd in routine clinical practice.

Materials and methods. The prospective analysis included patients with MM who received at least one line of previous therapy. The inclusion criteria were relapse/progression; refractoriness; lack of very good partial response (VGPR) and more after the first line of therapy. Since February 2016, we used KRd like in ASPIRE trial, since October 2019, carfilzomib has been used at a dose of 56 mg/m2 on days 1, 8 and 15. Autologous hematopoietic stem cell transplantation (autoHSCT), consolidation (KRd) and maintenance therapy (Rd) were regarded as one line of therapy.

Results and discussion. We evaluated 77 patients with median age at the time of diagnosis is 55 (30–72) years. For 56% (n=43) of patients KRd was applied as the second line (group 1), for 44% (n=34) – as the third and more (group 2). In 23/43 patients from group 1, an early change in therapy was made due to insufficient effectiveness (after 2–4 courses of VCD or PAD). KRd served as a "bridge" to autoHSCT in 25 (32%) patients (21 of 25 in group 1). Another 7 patients underwent collection of autoHSC (all from group 1).

The overall response rate (ORR) was 80.5%, with 33.8% complete response (CR) and 26% VGPR. ORR in group 1 was 98% versus 65.6% in group 2; 24-month overall survival (OS) was 70%, progression free survival (PFS) – 49.8%. In group 1, 24-month OS was 85.6% versus 50.0% in group 2, 24-month PFS was 67.8% versus 25.5% (p=0.01).

Conclusion. Our analysis confirmed the high efficiency of KRd in the treatment of RRMM in real-life practice. Early correction of therapy with insufficient effectiveness of the first line made it possible to implement the strategy of high-dose consolidation and autoHSCT in a larger percentage of patients with MM.

Terapevticheskii arkhiv. 2021;93(7):785-792
pages 785-792 views

Clinical notes

Multiple primary tumor of hematopoietic tissue: myeloid sarcoma in combination with mantle cell lymphoma. Case report

Gavrilina O.A., Dubov V.S., Troitskaya V.V., Kovrigina A.M., Dvirnyk V.N., Galtseva I.V., Sudarikov A.B., Obukhova T.N., Parovichnikova E.N., Savchenko V.G.


The prevalence of multiple primary tumors has significantly increased last time. The question of choosing the optimal tactics of therapy today not fully resolved. Particular interest is the simultaneous detection of two neoplasms of similar origin in one study biopsy material. This publication presents a case of simultaneous diagnosis of myeloid sarcoma and mantle cell lymphoma in a 65-year-old patient, which required use of two different chemotherapy protocols. This example shows the need to use an extended diagnostic approach at all stages of the therapy, which allows choosing right tactics of therapy and achieving complete remission of two neoplasms.

Terapevticheskii arkhiv. 2021;93(7):793-799
pages 793-799 views

Thrombosis in patients with myeloproliferative neoplasms. Case report

Melikyan A.L., Subortseva I.N., Gilyazitdinova E.A., Koloshejnova T.I., Shashkina K.S., Egorova E.K., Kovrigina A.M., Sudarikov A.B., Gorgidze L.A.


Thrombotic complications are the most significant factors determining the prognosis in myeloproliferative neoplasms. Markers for assessing the risk of thrombosis are the number of leukocytes, platelets, hemoglobin level, hematocrit, age, molecular status, history of thrombosis, obesity, arterial hypertension, hyperlipidemia, hereditary or acquired thrombophilia. The pathogenesis of thrombosis in patients with myeloproliferative neoplasms is complex and multifactorial. In most cases, the etiological factor remains unknown. Currently, antiplatelet and anticoagulant therapy is carried out on an individual basis. The algorithm for primary and secondary (after thrombosis) prevention requires development and testing. We present a clinical case of repeated arterial and venous thrombotic complications in a patient with primary myelofibrosis.

Terapevticheskii arkhiv. 2021;93(7):800-804
pages 800-804 views

Repeated haploidentical allogeneic hematopoietic stem cell transplantation with TCR αβ/CD19 depletion in patient with primary myelofibrosis. Case report

Kolgaeva E.I., Vasilyeva V.A., Kuzmina L.A., Drokov M.Y., Dovydenko M.V., Konova Z.V., Chebotarev D.I., Kovrigina A.M., Kamelskih D.V., Gaponova T.V., Sokolova M.A., Subortseva I.N., Melikyan A.L., Maschan M.A., Parovichnikova E.N., Savchenko V.G.


Indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with primary myelofibrosis are intermediate-2 and high-risk group of DIPSS (Dynamic International Prognostic Scoring System), beginning of the disease in childhood. The other adverse factors affect engraftment and survival after allo-HSCT, example partialy matched donor. But the result of allo-HSCT from matched related donors and result of allo-HSCT from haploidentical donors are comparable. The method for haploidentical hematopoietic stem cell transplantation is αβT-cell-depletion. This is clinical case of αβT-cell-depleted haploidentical hematopoietic stem cell transplantation in patient with primary myelofibrosis, the diagnosis was established in childhood.

Terapevticheskii arkhiv. 2021;93(7):805-810
pages 805-810 views

Extracorporeal cytokine removal in chimeric antigen receptor T-cell therapy associated cytokine release syndrome in patient with acute lymphoblastic leukemia. Case report

Shchekina A.E., Galstyan G.M., Gavrilina O.A., Arapova N.M., Bronyakina S.I., Kotova E.S., Troitskaya V.V., Parovichnikova E.N., Maschan M.A., Savchenko V.G.


Сytokine release syndrome is the common complication of CAR-T therapy. We report a case of patient with B-cell acute lymphoblastic leukemia developing сytokine release syndrome with shock and multiple organ failure and requiring cytokine removal and hemodiafiltration. Remission of the disease was achieved after CAR-T therapy.

Terapevticheskii arkhiv. 2021;93(7):811-817
pages 811-817 views

A case report of familial dyskeratosis congenital. Case report

Luchkin A.V., Mikhailova E.A., Fidarova Z.T., Troitskaya V.V., Galtseva I.V., Kovrigina A.M., Glinkina S.A., Dvirnyk V.N., Raykina E.V., Pavlova A.V., Demina I.A., Parovichnikova E.N.


Dyskeratosis congenita (DC) is a hereditary syndrome of bone marrow failure, which develops because of telomeres’ defects and combines with cancer predisposition. Its classical clinical features are skin pigmentation, nail dystrophy, oral leukoplakia (“skin-mucosa triad”). The goal is to describe the algorithm of diagnosis, clinical specificities of DC and specific treatment for cases of DC in one family. The present report includes descriptions of diagnosis and treatment of family members diagnosed for the first time as having a DC. The report shows an importance of all diagnostic stages: from a medical history and clinical picture to an application of modern high-tech diagnostic methods (flow-FISH, NGS). The report underlines an importance of diagnosis of all family members for excluding an asymptomatic form after a case of DC has been already detected in that family. A high frequency of a toxicity and secondary neoplasia makes it necessary to realize an individual approach at treatment of each patient with DC (the earliest start of androgen treatment, prompt decision of implementation of allogenic hematopoietic stem cell transplantation). The knowledge of pathogenesis, clinical features and principles of diagnosis and therapy of this disease is relevant to pediatricians and hematologists.

Terapevticheskii arkhiv. 2021;93(7):818-825
pages 818-825 views


Treatment of thrombotic thrombocytopenic purpura

Galstyan G.M., Maschan A.A., Klebanova E.E., Kalinina I.I.


The review discusses approaches to treatment of congenital thrombotic thrombocytopenic purpura (TTP) or Upshaw-Schulman syndrome. In congenital TTP, plasma transfusions are sufficient. Such treatment options as plasma exchange, administration of clotting factor VIII concentrate, recombinant ADAMTS13, are also used. Separately discussed issues of management of patients with TTP during pregnancy, and pediatric patients with TTP.

Terapevticheskii arkhiv. 2021;93(7):826-829
pages 826-829 views

History of medicine

Gaucher disease: achievements and prospects

Ponomarev R.V., Lukina E.A.


Gaucher disease (GD) is the most common lysosomal storage disorder, resulting from a deficiency in the activity of a lysosomal enzyme – glucocerebrosidase, which is involved in the catabolism of sphingolipids. The phenomenal progress in understanding the pathogenesis and development of specific therapy of this disease over the past 60 years dramatically changed the clinical phenotype of GD, turning a severe progressive disorder into an asymptomatic metabolic defect. The evolution of the understanding of GD associated with fundamental discoveries in the field of cell biology, biochemistry and genetics may be of interest to a wide audience – as a model of the effective work of the scientific community in the treatment of rare metabolic pathology.

Terapevticheskii arkhiv. 2021;93(7):830-836
pages 830-836 views

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