Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

1 1586 Military Clinical Hospital, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Central Military Clinical Hospital, 3 Gospital’naya sq., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, MD, PhD, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches. Clinical oncohematology. 2019;12(3):344–9 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-344-349


ABSTRACT

Aim. To study the effect of hepcidin, soluble transferrin receptor (sTfR), and cytokines on iron metabolism and occurrence of anemia in patients with malignancies and to propose, on this basis, a draft classification of anemia of chronic disease (ACD) based on the major pathogenic factor.

Materials & Methods. The trial included 63 patients with malignancies of stage II/IV: 41 patients with anemia (34 men, 7 women, mean age 67.1 ± 9.9 years), 22 patients without anemia (17 men, 5 women, mean age 60.2 ± 14.9 years). Comparative analysis was based on the values of iron metabolism, C-reactive protein (CRP), hepcidin, sTfR, as well as pro-inflammatory (interleukin-6 [IL-6], tumour necrosis factor α [TNF-α]) and anti-inflammatory (IL-10) cytokines in solid malignancy patients with and without anemia. The correlation analysis between IL-6, IL-10, TNF-α, hepcidin, sTfR, and blood count was performed.

Results. Compared with the control group patients with anemia show lower levels of iron concentration, total iron-binding capacity (TIBC), and percent transferrin saturation (TSAT), as well as higher level of CRP, hepcidin, sTfR, IL-6, IL-10, and TNF-α (< 0.05). IL-6 (r = –0.58), TNF-α (r = –0.32), and hepcidin (r = –0.57) proved to negatively affect erythrocyte level. A negative correlation was established between hemoglobin concentration and IL-6 (r = –0.57), IL-10 (r = –0.64), TNF-α (r = –0.65), hepcidin (r = –0.3), and sTfR (r = –0.57). A correlation was identified between concentrations of hepcidin and IL-6 (r = 0.58), IL-10 (r = 0.33), TNF-α (r = –0.4), as well as between concentrations of sTfR and IL-10 (r = 0.58), TNF-α (r = –0.53). A relationship was identified between IL-6 concentration and iron status (r = –0.38), TIBC (r = –0.56), TSAT (r = –0.31), ferritin (r = 0.56), transferrin (r = –0.72), CRP (r = 0.86) as well as between concentrations of IL-10 and iron (r = –0.63), TSAT (r = –0.67), transferrin (r = –0.7), ferritin (r = 0.55), CRP (r = 0.65), TIBC (r = –0.71). A correlation between the levels of TNF-α and TIBC (r = –0.36), transferrin (r = –0.5) was confirmed.

Conclusion. The paper deals with multi-factorial pathogenesis of anemia in patients with malignancies. Most important factors are iron deficiency and erythropoietic disorder. A draft ACD classification based on the major pathogenic factor of anemia (ACD with dominating iron deficiency, ACD with impaired regulatory mechanism of erythropoiesis, and ACD with insufficient erythropoietin production) is proposed.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10, tumor necrosis factor alpha, hepcidin, soluble transferrin receptor.

Received: January 21, 2019

Accepted: June 18, 2019

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Pure Red Cell Aplasia with M-Gradient: A Literature Review and Clinical Experience

AV Pivnik1,2, AA Petrenko1, SV Kozhurin3, SA Mar’ina3

1 RUDN University, 6 Miklukho-Maklaya str., Moscow, Russian Federation, 117198

2 AS Loginov Moscow Clinical Scientific Center, 89 Entuziastov sh., Moscow, Russian Federation, 111123

3 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Prof. Aleksandr Vasil’evich Pivnik, MD, PhD, 89 Entuziastov sh., Moscow, Russian Federation, 111123; Tel.: 8(495)304-30-39; e-mail: pivnikav@gmail.com

For citation: Pivnik AV, Petrenko AA, Kozhurin SV, Mar’ina SA. Pure Red Cell Aplasia with M-Gradient: A Literature Review and Clinical Experience. Clinical oncohematology. 2018;11(3):273–80.

DOI: 10.21320/2500-2139-2018-11-3-273-280


ABSTRACT

Background. Pure red cell aplasia (PRCA) is a rare syndrome characterized by a decrease of erythroid progenitor cell count in the bone marrow. M-gradient with both a light and a heavy chain types in PRCA patients is a rare phenomenon which is considered to be a specific form of the disease.

Aim. To review a clinical presentation, diagnostic capabilities, and treatment outcomes of PRCA with M-gradient.

Materials & Methods. The analysis included 10 patients. The most effective empirically established treatment program was 200–400 g of cyclophosphamide 2–3 times a week to a total dose of 6–10 g and loading courses of 100–120 mg of oral and 180–240 mg of intravenous prednisone daily within 5 days. On the 6th day prednisone injections were discontinued, and from the 7th day the oral dose of prednisone was gradually reduced to permanent discontinuation in 2–3 days. This treatment course was repeated 1–3 times at intervals of a week. Targeted enzyme immunoassay of M-gradient was performed in 4 patients in order to determine whether M-gradient is the sum of two antibody types, i.e. erythrokaryocyte antibodies and secondary anti-idiotype antibodies against primary antibodies.

Results. The total of 6 out of 10 PRCA patients reached complete remission within the period from 9 months to 22 years of follow-up, in 4 patients no remission was achieved. M-gradient contained IgG (n = 9) and IgA (n = 1) oligoclones. In typing it consisted of IgGλ (n = 4), IgGκ (n = 5) and IgAκ (n = 1). M-gradient enzyme immunoassay showed no primary and secondary anti-idiotype antibodies.

Conclusion. The obtained results allow to regard gammopathy in PRCA as an effect of oligoclonal hyper-immunoglobulin without any pathogenetic connection between M-gradient and PRCA.

Keywords: partial red cell aplasia of the bone marrow, PRCA, anemia, M-gradient, monoclonal gammopathy.

Received: February 5, 2018

Accepted: May 11, 2018

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Correction of Anemia and Evaluation of Efficacy of Red Blood Cell Transfusion in Patients with Oncohematological Diseases

NA Romanenko1, AV Chechetkin1, LYu Zhiguleva1, GV Grishina1, SV Bondarchuk2, SS Bessmel’tsev1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

For correspondence: Nikolai Aleksandrovich Romanenko, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: 8(812)717-58-57; Fax: 8(812)717-67-80; е-mail: rom-nik@yandex.ru

For citation: Romanenko NA, Chechetkin AV, Zhiguleva LYu, et al. Correction of Anemia and Evaluation of Efficacy of Red Blood Cell Transfusion in Patients with Oncohematological Diseases. Clinical oncohematology. 2018;11(3):265–72.

DOI: 10.21320/2500-2139-2018-11-3-265-272


ABSTRACT

Aim. To study the quality of life (QL) of patients with oncohematological diseases and anemia with respect to hemoglobin level and to evaluate the efficacy of red blood cell transfusion (RBCT).

Materials & Methods. QL of patients (n = 326) was studied using FACT-An questionnaire. RBCT efficacy was evaluated in two groups. The first group included patients (n = 28; 13 men and 15 women) with oncohematological diseases and chronic anemia aged 23–80 (median 65) years, the second (control) group included patients (n = 12; 11 men and 1 woman) after severe blood loss after injury (acute anemia) aged 25–43 (median 36) years. The baseline levels of hemoglobin (Hb) and hematocrit (Ht) were < 80 g/L and < 25 % in all patients, respectively. The target levels of Hb and Ht were > 80 g/L and > 25 %, respectively.

Results. The association between the severity of anemia and QL was shown. The lowest QL was observed in patients with grade III–IV anemia (Hb < 80 g/L). Each patient in both groups received 1–8 units of blood cells (median 2) during the hospital stay. After RBCT the levels of Hb and Ht increased from 64.1 ± 2.7 g/L to 90.2 ± 1.7 g/L and from 20.1 ± 0.8 % to 28.9 ± 0.7 %, respectively. The levels of Hb and Ht in the second (control) group increased from 65.9 ± 3.0 g/L to 88.3 ± 3.2 g/L and from 19.6 ± 0.9 % to 26.7 ± 1.4 %, respectively. Venous blood oxygen saturation (SvO2) increased in the first group from 42.0 ± 3.3 % to 57.6 ± 4.1 %, and in the second group from 51.3 ± 1.9 % to 69.0 ± 1.3 %. However, after RBCT the SvO2 level reached > 60 % only in 67.9 % of patients in the first group and in all the patients (100 %) in the second group. In 32.1 % of patients with various forms of hematologic cancer and chronic anemia tissue hypoxia was still observed after RBCT despite increased Hb > 80 g/L and Ht > 25 %. Therefore, it was proposed to raise the target Hb and Ht threshold levels for patients with low SvO2.

Conclusion. The effect of the severity of anemia on QL was demonstrated. The patients with Hb < 80 g/L were shown to have low quality of life. SvO2 determination in anemia patients proved to be of great importance for RBCT efficacy evaluation. In patients with low SvO2 (< 60 %) RBCT should be continued until the target levels of Hb 100 g/L and Ht 33 % are reached.

Keywords: anemia, chronic anemia, red blood cell transfusions, hemoglobin concentration, hematocrit, venous blood oxygen saturation, quality of life, FACT-An questionnaire.

Received: March 10, 2018

Accepted: May 30, 2018

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Pathogenetic Characteristics of Anemia in Patients with Solid Tumors

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

11586 Military Clinical Hospital, 4 Mashtakova str., Podolsk, Russian Federation, 142110

2SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3NN Burdenko Main Military Clinical Hospital, 3 Gospitalnaya sq., Moscow, Russian Federation, 105229

For correspondence: Valery Timofeevich Sakhin, PhD, 4 Mashtakova str., Podolsk, Russia, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-514-518


ABSTRACT

Aim. To study the impact iron metabolism disturbances and cytokine levels on the development of anemia in patients with solid tumors.

Materials & Methods. The research included 42 patients with malignant neoplasms, including 24 patients with anemia (19 men and 5 women, median age 67.7 ± 10 years) and 18 patients without anemia (15 men, 3 women, median age 65.7 ± 14 years). Anemia was diagnosed according to the WHO criteria (in men: erythrocytes < 4.0 × 1012/L, hemoglobin < 130 g/L, hematocrit < 39 %; in women: erythrocytes < 3.8 × 1012/L, hemoglobin < 120 g/L, hematocrit < 36 %).

Results. A comparative analysis of iron metabolism in patients with and without anemia was performed. The lower values of serum iron and transferrin saturation in patients with anemia were shown (< 0.05). The total iron-binding capacity, the levels of ferritin, transferrin, C-reactive protein, indirect bilirubin were similar between groups (> 0,05). Higher levels of interleukins 6 and 10 (IL-6 and IL-10) were observed in patients with anemia (< 0.05). For IL-6, correlations were observed with levels of erythrocytes (r = –0,58), hemoglobin (r = –0,57), hematocrit (r = –0,52), and leukocytes (r = 0,42). The levels of IL-10 slightly correlated with the levels of erythrocytes, leukocytes, platelets, MCV, and MCH (r < 0.3). For IL-10, correlations were established with levels of MCHC (r = –0,71), hemoglobin (r = –0,64) and hematocrit (r = –0,32). Correlations between the levels IL-6, IL-6 and hemoglobin, erythrocytes and several color indices may indicate their influence on the development of anemia in patients with malignant neoplasms.

Conclusion. A functional iron deficiency in patients with anemia was found. Several causes of anemia development and significant role of interleukins in anemia pathogenesis were also discovered.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10.

Received: March 21, 2017

Accepted: June 22, 2017

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Anemias in Oncology: Potential of Maintenance Therapy

AV Snegovoi, VB Larionova, LV Manzyuk, IB Kononenko

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Anton Vladimirovich Snegovoi, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-41-09; e-mail: anvs2012@gmail.com

For citation: Snegovoi AV, Larionova VB, Manzyuk LV, Kononenko IB. Anemias in Oncology: Potential of Maintenance Therapy. Clinical oncohematology. 2016;9(3):326-35 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-326-35


ABSTRACT

Development of anemia during chemotherapy or chemoradiotherapy of malignancies is a serious adverse event negatively affecting the quality of life and effectiveness of the treatment. In this regard, the leading consensus committees of NCCN, ESMO, ASCO, and RUSSCO have prepared and are regularly updating recommendations for diagnosing and treatment of anemia in cancer patients. The article presents recent data on the pathogenesis and methods of treatment of anemia in cancer patients, including administration of erythropoiesis stimulating agents: recombinant erythropoietins, intravenous iron products, vitamins, and red blood cell transfusions.


Keywords: cancer, anemia, erythropoietins, intravenous iron products, red blood cell transfusions.

Received: February 29, 2016

Accepted: March 31, 2016

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Malignant Lymphoproliferative Disorders with Anemia: Changes of Quality of Life in Patients Treated with Donor Red Blood Cell Transfusions and Recombinant Erythropoietin

S.S. Bessmeltsev1, N.A. Romanenko1, N.A. Potikhonova1, S.A. Tiranova1, M.N. Zenina1, A.E. Romanenko2, L.Yu. Zhiguleva1, K.M. Abdulkadyrov1

1 Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 St. Olga Children Hospital, 2 Zemledelcheskaya str., Saint Petersburg, Russian Federation, 194156

For correspondence: Stanislav Semenovich Bessmel’tsev, DSci, Professor, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-58-57; e-mail: RNIIHT@mail.ru

For citation: Bessmel’tsev SS, Romanenko NA, Potikhonova NA, et al. Malignant Lymphoproliferative Disorders with Anemia: Changes of Quality of Life in Patients Treated with Donor Red Blood Cell Transfusions and Recombinant Erythropoietin. Clinical oncohematology. 2015;8(4):368–378 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-368-378

ABSTRACT

Aim. To evaluate the quality of life of anemic patients with malignant lymphoproliferative disorders after red blood cells transfusion and administration of human recombinant erythropoietin agents.

Methods. The efficacy was assessed based on evaluation of clinical data, lab test findings and quality of life (QoL) parameters using the FACT-An questionnaire. Red blood cells transfusions (RBCsT) were prescribed to anemic patients with malignant lymphoproliferative disorders (LPD) (n = 54) with initial Hb levels of 7.0 ± 0.16 g/dl. After red blood cells transfusion (Me = 3 Units) the Hb level increased up to 9.31 ± 0.12 g/dl. Human recombinant erythropoietin agents (EPO) were prescribed to LPD patients (n = 77) with initial Hb levels of 8.84 ± 0.14 g/dl.

Results. A positive response with a ³ 2.0 g/dl increase of Hb levels was observed in 52 (67.5 %) of 77 patients. The Hb level in responsive patients increased up to 12.31 ± 0.24 g/dl. Statistically significant QoL changes were observe according to «Physical well-being», «Emotional well-being», «Functional well-being», and «Anemia» scales. After EPO-therapy, significant changes were found according to «Physical well-being» and «Anemia» scales. A comparative analysis of QoL in both groups of patients demonstrated maximum changes according to the «Physical well-being» scale (from 12.9 ± 0.7 to 11.0 ± 0.8 points after RBCsT, < 0.001; from 11.6 ± 0.7 to 9.6 ± 0.7 points on EPO, < 0.02) and the «Anemia» scale (from 41.1 ± 2.0 to 34.2 ± 2.2 points after RBCsT, < 0.001; from 34.5 ± 1.7 to 30.1 ± 1.6 points on EPO; < 0.001).

Conclusion. Therefore, RBCsT and EPO therapy may significantly increase the Hb levels and improve QoL. However, the QoL of LPD patients on EPO proved to be better than that after RBCsT, because it had been possible to achieve normal and stable Hb levels.


Keywords: anemia, malignant lymphoproliferative disorders, erythropoietin, recombinant erythropoietin, donor’s red blood cells, red blood cell transfusions, quality of life, FACT-An questionnaire, «Anemia» scale.

Received: May 13, 2015

Accepted: October 12, 2015

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Anemias and iron deficiency in cancer patients

V.V. Ptushkin

Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russian Federation


ABSTRACT

Anemia is frequent in cancer patients and its incidence increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin production. Erythropoiesis-stimulating agents improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic events with еrythropoiesis-stimulating agents use during chemotherapy, but not increased on-study mortality or reduced overall survival. Inflammatory cytokine production in patients with cancer, reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of iron deficiency, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents.


Keywords: Anemia, cancer, erythropoietin, iron propagates, ferric carboxymaltose, ferritin, transferrin

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