Vol 92, No 7 (2020)

Editorial
Immunosupressive therapy of aplastic anemia patients: successes and failures (single center experiment 2007–2016)
Mikhaylova E.A., Fidarova Z.T., Abramova A.V., Luchkin A.V., Troitskaya V.V., Dvirnyk V.N., Galtseva I.V., Kliasova G.A., Kovrigina A.M., Kulikov S.M., Chabaeva Y.А., Parovichnikova E.N., Savchenko V.G., Obukhova T.N.
Abstract

Treatment programs for patients with acquired aplastic anemia include two main therapeutic options: allogeneic bone marrow transplantation and combined immunosuppressive therapy (IST). However, combined IST remains the method of choice for most adult AA patients. This study included 120 AA patients who received IST at the National Research Center for Hematology in 2007–2016. The analysis was applied to 120 patients. Median age was 25 (17–65) years, M/F: 66/54, SAA/NSAA: 66%/34%. Effectiveness of IST was carried out in 120 patients with AA. This group did not include 8 SAA patients who died during the first 3 months from the start of treatment from severe infectious complications (early deaths – 6.2%) and 2 AA patients who dropped out of surveillance. The observation time was 55 (6–120) months. Paroxysmal nocturnal hemoglobinuria (PNH clone) was detected in 67% of AA patients. The median PNH clone size (granulocytes) was 2.5 (0.01–99.5)%. The treatment was according to the classical protocol of combined IST: horse antithymocytic globulin and cyclosporin A. Most of patients (87%) responded to combined immunosuppressive therapy. To achieve a positive response, it was sufficient to conduct one course of ATG to 64% of patients, two courses of ATG – 24% of patients and 2% of patients responded only after the third course of ATG. A positive response after the first course was obtained in 64% of patients included in the analysis. Most of the responding patients (93%) achieve a positive response after 3–6 months from the start of treatment. Therefore, the 3rd–6th months after the first course of ATG in the absence of an answer to the first line of therapy can be considered the optimal time for the second course of ATG. This tactic allows to get an answer in another 58% of patients who did not respond to the first course of ATG. The probability of an overall 10-year survival rate was 90% (95% confidence interval 83.6–96.2).

Terapevticheskii arkhiv. 2020;92(7):4-9
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Consensuns
Monoclonal gammopathy of renal significance: consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment
Smirnov A.V., Afanasyev B.V., Poddubnaya I.V., Dobronravov V.A., Khrabrova M.S., Zakharova E.V., Nikitin E.A., Lysenko (Kozlovskaya) L.V., Bobkova I.N., Rameev V.V., Batyushin M.M., Moiseev I.S., Darskaya E.I., Pirogova O.V., Mendeleeva L.P., Biryukova L.S.
Abstract

Monoclonal gammopathy of renal significance (MGRS) is a new nosology in modern nephrology and oncohematology. MGRS is defined as kidney injury due to nephrotoxic monoclonal immunoglobulin produced by the B-cell line clone which does not reach the hematological criteria for specific treatment initiation. Monoclonal protein’s pathological effects on kidney parenchyma result in irreversible decline of kidney function till the end stage renal disease that in line with the position of International Consensus of hematologists and nephrologists determinates critical necessity for clone specific treatment in patients with MGRS despite the absence of hematological indications for treatment initiation. Main challenge of MGRS in Russian Federation is an inaccessibility of an in-time diagnostic and appropriate treatment for the great majority of patients due to the following reasons: 1) limited knowledge about the MGRS among hematologists and nephrologists; 2) lack of necessary diagnostic resources in most health-care facilities; 3) lack of approved clinical recommendations and medical economic standards for treatment of this pathological entity. Consensus document comprises the opinion of experts – leading nephrologists and hematologists of Russian Federation – on the problem of MGRS including the incoherence in nosology classification, diagnostics approach and rationale for clone specific treatment. Consensus document is based on conclusions and agreements reached during the conference of leading nephrologists and hematologists of Russia which was held in the framework of symposia “Plasma cell dyscrasias and lymphoproliferative diseases: modern approaches to therapy”, 15–16 of March 2019, Pavlov First Saint Petersburg State Medical University. The present Consensus is intended to define the principal practical steps to resolve the problem of MGRS in Russian Federation that are summarized as final clauses.

Terapevticheskii arkhiv. 2020;92(7):10-22
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Original articles
Multipotent mesenchymal stromal cells application for acute graft versus host disease treatment
Kuzmina L.A., Petinati N.A., Vasilieva V.A., Dovydenko M.V., Drokov M.Y., Davydova Y.O., Kapranov N.M., Sats N.V., Chabaeva Y.A., Kulikov S.M., Gaponova T.V., Drize N.I., Parovichnikova E.N., Savchenko V.G.
Abstract

Aim. Analysis of the effectiveness of the MSCs aministration as the second- or third-line therapy of acute GVHD (aGVHD) resistant to glucocorticosteroid treatment.

Materials and methods. The study included 35 patients who received MSCs obtained from the bone marrow of healthy donors as a treatment of steroid-resistant aGVHD. The clinical parameters of patients, MSCs’ cultural characteristics, the MSC expression profile for various genes including those involved in immunomodulation, expression of cells’ surface markers, the source of MSCs, as well as the frequency and number of MSC administrations were analyzed.

Results. Response to therapy was achieved in 74% of cases, a complete response was reached in 13 (37%) patients, partial response/clinical improvement was demonstrated in 13 (37%). This treatment was ineffective in 9 patients. The prediction of a group of patients with good response to MSC therapy turned to be impossible. The differences between the effective and ineffective for the GVHD treatment MSCs samples were found. The effective ones were characterized with a decreased total MSCs production and an increase in the main histocompatibility complex and PDL-1 antigens expression.

Conclusion. These data allow to select optimal samples for aGVHD treatment that can improve clinical results. aGVHD treatment with MSCs has shown efficacy comparable to other treatment approaches. Given the low percentage of complications and the absence of significant adverse effects, MSC therapy seems to be one of the optimal approaches to the treatment of resistant forms of GVHD.

Terapevticheskii arkhiv. 2020;92(7):23-30
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Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways
Zarubina K.I., Parovichnikova E.N., Surin V.L., Pshenichnikova O.S., Gavrilina O.A., Isinova G.A., Troitskaia V.V., Sokolov A.N., Gal’tseva I.V., Kapranov N.M., Davydova I.O., Obukhova T.N., Sudarikov A.B., Savchenko V.G.
Abstract

Issue. The study of activating mutations (NRASKRASFLT3JAK2CRLF2 genes) of RAS/RAF/MEK/ERK and JAK/STAT signaling pathways in B-cell acute lymphoblastic leukemia (B-ALL) in adult patients which are included in Russian multicenter clinical trials.

Materials and methods. Within the multicenter study there were 119 adult patients included with de novo B-ALL. The study was considered as prospective and retrospective. The group with BCR-ABL1-negative B-ALL consisted of up to 93 patients (45 male and 48 female, at the age of 17 to 59, the median age – 31), they were treated according to the protocols ALL-2009, ALL-2016. The median follow-up lasted for 19 months (1–119). The group with BCR-ABL1-positive B-ALL with up to 26 patients (10 male and 16 female, at the age of 23 to 78, the median age 34 years) was included in the study as well. The treatment was carried out according to the protocols ALL-2009 and ALL-2012 in combination with tyrosine kinase inhibitors. The median follow-up lasted for 23 months (4–120). The molecular analysis of activating mutations in NRASKRAS genes (RAS/RAF/MEK/ERK signaling pathway) and JAK2CRLF2 genes (JAK/STAT signaling cascade) was performed via Sanger sequencing. The internal tandem duplications (ITDs) in FLT3 gene were studied by fragment analysis. The evaluation of CRLF2 expression was fulfilled via flow cytometry.

Results. Activating mutations in NRASKRASFLT3 genes were found in 22 (23.6%) patients with BCR-ABL1-negative B-ALL. In total, 23 mutations were revealed in the NRAS (n=9), KRAS (n=12), and FLT3 (n=2) genes, according to statistics that was significantly more frequent than with BCR-ABL1-positive B-ALL, these genes mutations were not identified in patients (p=0.007).

The frequency of mutations detection in KRAS and NRAS genes in patients with BCR-ABL1-negative B-ALL was comparable as 12.9% (12 of 93) to 9.7% (9 of 93), respectively (p=0.488). One patient was simultaneously revealed 2 mutations in the KRAS gene (in codons 13 and 61). FLT3-ITD mutations were detected in 3.5% (2 of 57) cases of BCR-ABL1-negative B-ALL. In patients with BCR-ABL1-positive B-ALL FLT3-ITD mutations were not assessed. Violations in the JAK/STAT signaling cascade were detected in 4 (4.3%) patients with BCR-ABL1-negative B-ALL. They were represented by the missense mutations of JAK2 gene (n=3) and the overexpression of CRLF2 (n=2); in one patient were detected the overexpression of CRLF2 and a mutation in JAK2 gene simultaneously. No mutations were found in CRLF2 gene. In patients with BCR-ABL1-positive B-ALL no JAK2 mutations were detected. As long as analyzing demographic and clinical laboratory parameters between groups of patients with and without mutations, there were no statistically significant differences obtained. In the analyzed groups of patients, long-term therapy results did not differentiate according to the mutations presence in NRASKRASFLT3JAK2 genes. Also, substantive differences were not shown in the rate of the negative status achievement of the minimum residual disease between patients with and without activating mutations in the control points of the protocol (on the 70th, 133rd and 190th days).

Conclusion. NRASKRASFLT3JAK2 activating mutations do not affect the long-term results of the therapy and the rate of the negative status achievement of the minimum residual disease in patients with BCR-ABL1-negative B-ALL treated by the Russian multicenter clinical trials.

Terapevticheskii arkhiv. 2020;92(7):31-42
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Fecal microbiota transplantation for graft-versus-host disease in children and adults: methods, clinical effects, safety
Goloshchapov O.V., Chukhlovin A.B., Bakin E.A., Stanevich O.V., Klementeva R.V., Shcherbakov A.A., Shvetsov A.N., Suvorova M.A., Bondarenko S.N., Kucher M.A., Kulagin A.D., Zubarovskaya L.S., Moiseev I.S.
Abstract

Aim. Was to evaluate clinical efficacy, adverse events and changes in the gut microbiome after fecal microbiota transplantation (FMT) in patients with gastrointestinal (GI) form of graft-versus-host disease (GVHD).

Materials and methods. The prospective single-center study in R.M. Gorbacheva institute included 27 patients with GI GVHD after allogeneic stem cell transplantation. 19 patients received FMT, 8 patients received placebo. Clinical scales for GI autoimmune diseases were used to evaluate response. Microbiome alterations were assessed with multiplex PCR.

Results. After FMT higher overall bacterial mass (р=0.00088), higher bacterial numbers of Bifidobacterium spp. (р=0.021), Escherichia coli (р=0.049) and Bacteroides fragilis gr. (р=0.000043) compared to placebo group. Also higher bacterial mass was observed in patients with clinical response (р=0.0057). The bacterial mass after procedure in non-responders was compared to the placebo group (р=0.31). Partial response of GVHD was achieved faster in the FMT group compared to placebo (median 4 days vs 48 days, p=0.014). Complete response was observed in 8 (42%), 14 (74%) and 16 (84%) at 30, 60 and 90 days respectively, while in the placebo group only 0%, 1 (13%) and 4 (50%) achieved complete response at the same time points. The incidence and severity of adverse events was comparable between FMT and the placebo group.

Conclusion. FMT in patients with refractory GI GVHD was associated with favorable clinical outcomes and recovery in certain marker bacterial populations. Multiplex PCR can be used to assess an engraftment of a donor microbiota. FMT in GI GVHD was not associated with life-threatening adverse events, but further studies are required to validate clinical efficacy.

Terapevticheskii arkhiv. 2020;92(7):43-54
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Informativeness of whole-body diffusion-weighted magnetic resonance imaging and positron emission tomography with computed tomography in follicular lymphoma
Nesterova E.S., Yatsyk G.A., Lutsik N.S., Kravchenko S.K., Sudarikov A.B., Krasil‘nikova I.V., Gemdzhian E.G., Kovrigina A.M.
Abstract

Aim. This study conducted the possibilities of diffusion-weighted magnetic resonance imaging of the whole body – diffusion WB-MRI (in comparison with positron emission tomography with computed tomography – PET/CT) in assessing the volume and prevalence of the tumor, as well as determining bone marrow (BM) damage (for various cytological types) in the diagnosis and staging of the disease in patients with FL.

Materials and methods. A prospective comparative search study included 15 patients (4 men and 11 women, with a median age of 53 years) with newly diagnosed FL. Patients have not received antitumor chemotherapy previously. After the diagnosis was established, all patients (with the blindness of both the cases themselves and some specialists regarding the results of other specialists) were examined by PET/CT and diffusion WB-MRI, after which a BM examination was performed (histological examination and determination of B-cell clonality in BM puncture by PCR). Using the diffusion WB-MRI method, the prevalence of tumor lesion (nodal and extranodal foci) in each patient was estimated, and the total tumor volume was calculated, BM lesion was detected, and BM lesion volume was calculated. For lesions of different localization, the measured diffusion coefficient (DC) of the diffusion WB-MRI and the standardized rate of accumulation of the radiopharmaceutical in tissues (SUV) of the PET/CT method were determined and compared with each other (for the same areas). Statistical analysis was performed using the estimate of agreement (by Cohen’s kappa coefficient and asymptotic test) of the results of the compared methods.

Results. Estimates of the prevalence of tumor damage (lymph nodes and extranodal foci) using the diffusion WB-MRI and PET/CT methods were the same. High DC and SUV were observed in the peripheral lymph nodes, extranodal foci and bulky, low DC and SUV – in the foci of BM. All 4 methods successfully determined BM damage, however, the diffusion WB-MRI had comparatively less negative results. The highest values of SUV and CD were noted in cases of the 3 grade of FL. Using the diffusion WB-MRI method, the prevalence of tumor lesion was assessed in each patient (nodal and extranodal foci were detected) and the total tumor volume was calculated, BM lesion detection was performed, and the volume of BM lesion was calculated. It is important to note that with the help of diffusion WB-MRI, it was possible to measure separately the total tumor volume (46–2025 cm3) and separately the volume of bulky (25–1358 cm3). The diffusion WB-MRI allowed us to differentiate the volume of tumor tissue (reduced as a result of treatment) and residual (fibrous-adipose) tissue in residual formations (which averaged 21% of the initial volume). The predictors of a poor antitumor response were the maximum SUV values (more than 14.0) and the minimum DC values (0.5¥10-3 mm2/s) in the BM foci.

Conclusion. The diffusion WB-MRI allows for detailed visualization of BM lesions and surrounding soft tissues both in the debut of the FL and in the process of tracking the effectiveness of chemotherapy, which makes it possible to use it along with PET/CT. Diffusion WB-MRI allows to separately evaluate the volume of true tumor tissue and residual tissue. Cases of the 3 grade of FL (including the transformation of FL into diffuse B-large cell lymphoma) are isolated due to low DC values (and high SUV values) in the tumor tissue. BM foci of FL lesion also have (in comparison with nodal and extranodal foci) lower DC values. The predictors of a poor antitumor response were high (from 14.0 or more) SUV valuesin the tumor (and especially in bulky), and low (about 0.5¥103 mm2/s) DC values of BM foci. The PET/CT and diffusion WB-MRI have proven to be reliable diagnostic tools for establishing the stage of FL and detecting BM damage. Diffusion WB-MRI for FL is an informative first-line diagnostic method that allows regular monitoring of the disease and early detection of foci of relapse and disease progression.

Terapevticheskii arkhiv. 2020;92(7):55-62
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Morphological and immunohistochemical predictors of renal response to therapy patients with myeloma cast nephropathy and dialysis-dependent acute kidney injury
Rekhtina I.G., Kazarina E.V., Stolyarevich E.S., Kovrigina A.M., Dvirnyk V.N., Kulikov S.M., Mendeleeva L.P.
Abstract

Aim. Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy.

Materials and methods. Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and á-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission.

Results. Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively; p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively; p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN.

Conclusion. If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.

Terapevticheskii arkhiv. 2020;92(7):63-69
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Autologous haematopoietic stem cell transplantation in patients with multiple myeloma complicated by dialysis-dependent renal failure
Firsova M.V., Mendeleeva L.P., Solovev M.V., Rekhtina I.G., Pokrovskaya O.S., Urnova E.S., Soboleva N.P., Dvirnyk V.N., Klyasova G.A., Kuzmina L.A., Savchenko V.G.
Abstract

Aim. To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with dialysis-dependent renal failure.

Materials and methods. During a period from May 2010 to December 2016 fourteen MM patients with dialysis-dependent renal failure aged 48 to 65 years underwent auto-HSCT. After the induction therapy complete response, very good partial response, partial response were documented in 64, 29, 7% of patients, respectively. In no case was a renal response achieved. Haematopoietic stem cell mobilization in most patients (13/14) was performed according to the scheme: G-CSF 10 μg/kg. Melphalan in 3 dosages was used as pre-transplant conditioning: 100, 140 and 200 mg/m2; 13 patients underwent a single and in one case underwent a tandem auto-HSCT against the background of hemodialysis. Evaluation of the antitumor and renal response was assessed on the 100th day after auto-HSCT. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100–200 mg/m2), 13 patients underwent a single and one patient underwent a tandem auto-HSCT. At +100 days after auto-HSCT, an antitumor response and renal response were assessed.

Results. The period of agranulocytosis after auto-HSCT was from 5 to 12 days (median 8,5) and was accompanied by infectious complications, cardiac and neurological dysfunctions. At +100 days after auto-HSCT, the complete response was confirmed in 71% patients and very good partial response was confirmed in 29% patients. The minimal renal response was registered in 2 patients (14%), hemodialysis was stopped. The transplant-related mortality was absent. After a median follow-up of 53 months 5-year progression-free survival was 59%, and overall survival was 93%.

Conclusion. Carrying out auto-HSCT in patients with dialysis-dependent renal failure contributed to the achievement of a minimal renal response in 14% of cases, which allowed these patients to stop hemodialysis. Patients whose conditioning regimen was performed using melphalan at a dose of 200 mg/m2 showed more frequent complications in the early post-transplant period compared to patients who received a lower dose of melphalan (100–140 mg/m2). Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, which in some cases contributes to independence from hemodialysis.

Terapevticheskii arkhiv. 2020;92(7):70-76
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Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy
Ptushkin V.V., Kulagin A.D., Lukina E.A., Davydkin I.L., Konstantinova T.S., Shamrai V.S., Minaeva N.V., Kudlay D.A., Gapchenko E.V., Markova O.A., Borozinets A.Y.
Abstract

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program «Development of the pharmaceutical and medical industry» for 2013–2020 was developed Elizaria (JSC GENERIUM) – the first biosimilar of the original drug eculizumab.

Aim. To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH.

Materials and methods. The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks.

Results. During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 μg/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event – in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity.

Conclusion. The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.

Terapevticheskii arkhiv. 2020;92(7):77-84
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Clinical notes
Bone disease as the first manifestation of systemic AL-amyloidosis
Mendeleeva L.P., Rekhtina I.G., Kovrigina A.M., Kostina I.E., Khyshova V.A., Arytyunyan N.K., Mamonov W.E., Savthenko V.G.
Abstract

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib weren’t detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP – 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.8–5% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (ê/ë 44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous «scarring» of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

Terapevticheskii arkhiv. 2020;92(7):85-89
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Successful use of long-term follow-up in patients with chronic myeloid leukemia with a deep molecular response at reduced doses of 2nd generation tyrosine kinase inhibitors: clinical cases and literature review
Gurianova M.A., Chelysheva E.Y., Shukhov O.A., Turkina A.G.
Abstract

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 60–70% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.

Terapevticheskii arkhiv. 2020;92(7):90-94
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The prognostic value of ASXL1 mutation in primary myelofibrosis. Literature review and clinical case description
Melikyan A.L., Subortseva I.N., Gilyazitdinova E.A., Koloshejnova T.I., Egorova E.K., Pustovaya E.I., Sudarikov A.B., Abdullaev A.O., Gorgidze L.A., Chebotarev D.I.
Abstract

Primary myelofibrosis is a myeloproliferative neoplasm that occurs de novo, characterized by clonal proliferation of stem cells, abnormal expression of cytokines, bone marrow fibrosis, hepatosplenomegaly – as a result of extramedullary hematopoiesis, symptoms of tumor intoxication, cachexemia, peripheral blood leukoerythroblastosis, leukemic progression and low survival. Primary myelofibrosis is a chronic incurable disease. The aims of therapy: preventing progression, increasing overall survival, improving quality of life. The choice of therapeutic tactics is limited. Allogenic hematopoietic stem cell transplantation is the only method that gives a chance for a cure. The role of mutations in a number of genes in the early identification of candidates for allogeneic hematopoietic stem cell transplantation is being actively studied. The article describes the clinical case of the detection of ASXL1 gene mutations in a patient with prefibrous primary myelofibrosis. The diagnosis was established on the basis of WHO criteria 2016. The examination revealed a mutation of ASXL1. Interferon alfa therapy is carried out, against the background of which clinico-hematological remission has been achieved. Despite the identified mutation, the patient is not a candidate for allogeneic hematopoietic stem cell transplantation. Given the unfavorable prognostic value of the ASXL1 mutation, the patient is subject to active dynamic observation and aggressive therapeutic tactics when signs of disease progression appear.

Terapevticheskii arkhiv. 2020;92(7):95-99
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Parvovirus B19 infection in HIV-infected patients
Petrenko A.A., Dudina G.A., Kremneva N.V., Pivnik A.V.
Abstract

Here we provide a review of the literature and a description of our own clinical case. The patient was a 32-year-old woman who had been infected with HIV for 6 years without antiretroviral therapy. The test results showed CD4 87 cells/μl, viral load 3750 copies/ml. Normochromic normocytic anemia and reticulocytopenia developed soon. In the myelogram, all erythroblasts were 0.5%. The viral load of parvovirus B19 DNA according to PCR was more than 9 million IU/ml. Pure red cell aplasia associated with parvovirus B19 was diagnosed. We started antiretroviral therapy with efavirenz, lamevudine and tenofovir. In addition to blood transfusions, we administered intravenous donor immunoglobulin with a dose increase from 5000 mg to 20 000 mg per day. After discontinuing of intravenous immunoglobulins, the laboratory test results were stable over the next 5 months: hemoglobin was more than 115 g/L, reticulocytes – more than 3%, in the myelogram all erythroblasts were 21%. However, the elimination of parvovirus B19 wasn’t achieved. The maximum decrease in viral load for parvovirus B19 was down to 720 IU/ml. A typical feature of the case was the lack of pure red cell aplasia of the bone marrow with the existing viral load of parvovirus B19. HIV infection progressed: 44 cells/μl, viral load – not determined. The case ended lethally.

Terapevticheskii arkhiv. 2020;92(7):100-103
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POEMS-syndrome: diagnostic difficulties
Lebedev P.A., Paranina E.V., Rossiyev V.A., Fedorova E.Y., Nikolaeva A.S.
Abstract

POEMS – syndrome is a rare paraneoplastic syndrome whose name is an acronym formed from the initial letters of the names of the symptoms originally used to determine it: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes. Due to the rarity of the disease and the small number of cases described in the literature, its diagnosis is difficult. The average time from onset of symptoms to diagnosis is 18 months. Moreover, the prognosis of the disease depends on the early onset of specific treatment. The article describes a clinical case of POEMS-syndrome in a 53-year-old man, which illustrates the difficulties associated with the timely recognition of this unusual disease.

Terapevticheskii arkhiv. 2020;92(7):104-108
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