COMPLICATIONS OF ANTITUMOR TREATMENT

The Effect of Anticoagulant Therapy on Survival and Outcome of Venous Thrombosis in Children, Teenagers, and Young Adults with Acute Lymphoblastic Leukemia Treated According to ALL-MB-2008 and ALL-MB-2015 Protocols

COMPLICATIONS OF ANTITUMOR TREATMENT , , , , , , ,

VV Dmitriev, NV Migal, OI Bydanov, NV Lipai, EV Dmitriev

Republican National Applied Research Center of Pediatric Oncology, Hematology and Immunology, 43 Frunzenskaya, Borovlyany, Minskii district, Republic of Belarus, 223053

For correspondence: Vyacheslav Vasil’evich Dmitriev, MD, PhD, 43 Frunzenskaya str., Borovlyany, Minskii district, Republic of Belarus, 223053; Tel.: +375(17)265-42-22; e-mail: dmitrievhaematol@mail.ru

For citation: Dmitriev VV, Migal NV, Bydanov OI, et al. The Effect of Anticoagulant Therapy on Survival and Outcome of Venous Thrombosis in Children, Teenagers, and Young Adults with Acute Lymphoblastic Leukemia Treated According to ALL-MB-2008 and ALL-MB-2015 Protocols. Clinical oncohematology. 2019;12(3):338–43 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-338-343

ABSTRACT

Aim. To assess the effect of anticoagulant therapy on survival and outcome of venous thrombosis in children, teenagers, and young adults with acute lymphoblastic leukemia (ALL).

Materials & Methods. Venous thrombosis was diagnosed in 42 out of 592 ALL patients treated according to ALL-MB-2008 and ALL-MB-2015 protocols from 2008 to 2017.

Results. A daily dose of 150–200 IU/kg low molecular weight heparin (LMWH) was administered to 30 patients. Duration of anticoagulant treatment was up to 1 month in 4 patients, 2–3 months in 8 patients, 4–6 months in 12 patients, and 7–12 months in 4 patients. To 2 patients anticoagulants were administered for more than 24 months. Complete recanalization of thrombosed vessel was achieved in 19 patients, partial recanalization was achieved in 6 patients, obliteration of predominantly internal jugular vein was found in 5 patients. During thrombocytopenia (100 to 35 × 109/L) 12 patients received reduced doses of LMWH for 1–4 weeks. In the period of chemotherapy-induced thrombocytopenia the daily LMWH dose was reduced in proportion to thrombocyte level. After thrombocyte recovery up to more than 100 × 109/L antithrombotic treatment was continued with LMWH daily dose of 150–200 anti-Xa IU/kg. The duration of anticoagulant treatment among 12 patients who received reduced doses of LMWH was up to 1 month in 3 patients, 2–3 months in 4 patients, 4–6 months in 3 patients, and 7–12 months in 2 patients. Complete recanalization of thrombosed vessel was achieved in 8 patients, partial recanalization was achieved in 2 patients, vein obliteration was found in 2 patients. No correlation between LMWH dosage and thrombosis outcome was observed (χ2 = 0.494; p = 0.78). Maintenance (accompanying) therapy was completed in 38 out of 42 ALL patients with venous thrombosis. Event-free survival was 83 ± 8 %, that was similar to the one (81 ± 2 %) in patients without thrombosis (p = 0.654).

Conclusion. Anticoagulant treatment of venous thrombosis complicating ALL in children, teenagers, and young adults did not yield a decrease of either overall or event-free survival. Reduction of LMWH doses in the period of chemotherapy-induced thrombocytopenia did not affect the outcome of venous thrombosis.

Keywords: venous thrombosis, coagulation, acute lymphoblastic leukemia, children, teenagers, young adults, anticoagulant therapy, low molecular weight heparin.

Received: October 30, 2018

Accepted: June 5, 2019

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REFERENCES

  1. Жарков П.А., Румянцев А.Г., Новичкова Г.А. Венозные тромбозы у детей со злокачественными новообразованиями (обзор литературы). Российский журнал детской гематологии и онкологии. 2015;2(1):66–74. doi: 10.17650/2311-1267-2015-1-66-74.

    [Zharkov PA, Rumyantsev AG, Novichkova GA. Venous thromboembolism in children with cancer. Russian Journal of Pediatric Hematology and Oncology. 2015;2(1):66–74. doi: 10.17650/2311-1267-2015-1-66-74. (In Russ)]

  2. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32(7):554–63. doi: 10.1097/mph.0b013e3181e6f003.

  3. Payne JH, Vora AJ. Thrombosis and acute lymphoblastic leukemia. Br J Haematol. 2007;138(4):430–45. doi: 10.1111/j.1365-2141.2007.06677.x.

  4. Athale UH, Laverdiere C, Nayiager T, et al. Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer. 2017;17(1):313. doi: 10.1186/s12885-017-3306-5.

  5. Tuckuviene R, Ranta S, Albertsen BK, et al. Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study. J Thromb Haemost. 2016;14(3):485–94. doi: 10.1111/jth.13236.

  6. Caruso V, Iacoviello L, Di Castelnuovo A, et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood, 2006;108(7):2216–22. doi: 10.1182/blood-2006-04-015511.

  7. Mitchell L, Lambers M, Flege S, et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. 2010;115(24):4999–5004. doi: 10.1182/blood-2010-01-263012.

  8. Appel IM, Hop WCJ, van Kessel-Bakvis C, et al. L-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia. Thromb Haemost. 2008;100(08):330–7. doi: 10.1160/th07-10-0620.

  9. Kearon С, Akl E, Ornelas J, et al. Antithrombotic Therapy for VTE Disease. CHEST Guideline and Expert Panel Report. CHEST. 2016;149 (2):315–52. doi: 10.1016/j.chest.2015.11.026.

  10. Carrier M, Khorana AA, Zwicker JI, et al. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost. 2013;11(9):1760–5. doi: 10.1111/jth.12338.

  11. Saccullo G, Malato A, Raso S, et al. Cancer patients requiring interruption of long-term warfarin because of surgery or chemotherapy induced thrombocytopenia: the use of fixed subtherapeutic doses of low molecular weight heparin. Am J Hematol. 2012;87(4):388–91. doi: 10.1002/ajh.23122.

  12. Kerlin B, Stephens J, Hogan M, et al. Development of a Pediatric-Specific Clinical Probability Tool for Diagnosis of Venous Thromboembolism: A Feasibility Study. Pediatr Res. 2014;77(3):463–71. doi: 10.1038/pr.2014.198.

  13. Babilonia KM, Golightly LK, Gutman JA, et al. Antithrombotic Therapy in Patients With Thrombocytopenic Cancer: Outcomes Associated With Reduced-Dose, Low-Molecular-Weight Heparin During Hospitalization. Clin Appl Thromb Hemost. 2014;20(8):799–806. doi: 10.1177/1076029614543140.

  14. Dmitriev Nadroparin and dalteparin pharmacokinetics in thromboses complicated the treatment of children with oncological diseases. The Book of Abstracts The Congress on Open Issues in Thrombosis and Hemostasis 2018 jointly with the 9th Russian Conference on Clinical Hemostasiology and Hemorheology, Saint Petersburg, Russia October 4–6, 2018. pp 60.

Clinical and Laboratory Characteristics and Differential Diagnosis between Secondary Hemophagocytic Syndrome and Sepsis

COMPLICATIONS OF ANTITUMOR TREATMENT , , , ,

VG Potapenko1,2, MYu Pervakova2, AV Titov1, OV Goloshchapov2, SV Lapin2, EA Surkova2, AV Klimovich1, OP Mironova1, NN Petrova1, NYu Chernookaya1, EV Karyagina3, NV Skorobogatova1, ES Pavlyuchenko4, EA Karev4, NA Potikhonova5, VA Dubkova6, AYu Kaskov7, AV Rysev7, TG Kulibaba6, NV Medvedeva1

1 Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

2 IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

3 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

4 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

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

6 Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

7 II Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine, 3 Budapeshtskaya str., Saint Petersburg, Russian Federation, 192242

For correspondence: Vsevolod Gennad’evich Potapenko, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110; Tel.: +7(905)284-51-38; e-mail: potapenko.vsevolod@mail.ru

For citation: Potapenko VG, Pervakova MYu, Titov AV, et al. Clinical and Laboratory Characteristics and Differential Diagnosis between Secondary Hemophagocytic Syndrome and Sepsis. Clinical oncohematology. 2019;12(3):329–37 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-329-337

ABSTRACT

Background. Secondary hemophagocytic syndrome (SHPS) and sepsis, although very similar in their clinical manifestations and laboratory parameters, essentially differ in terms of methods of their treatment. SHPS therapy is aimed at immunosuppression, whereas in sepsis anti-infectious treatment is required. To choose the correct therapy a rapid differential diagnosis is necessary.

Aim. Search and analysis of criteria of differential diagnosis between SHPS and sepsis.

Materials & Methods. The data of 102 patients were analyzed: 55 SHPS patients (median age 60 and range 18–81 years) and 47 sepsis patients (median age 60 and range 18–89 years). SHPS was diagnosed on the basis of HLH-2004 and H-Score criteria. Sepsis was confirmed by documented inflammatory lesions and systemic inflammatory reactions. Microbiologically confirmed sepsis was reported in 10 (21 %) patients. In all sepsis patients multiple organ failure was identified.

Results. The study of SHPS and sepsis groups revealed significant differences (p < 0.05) in the levels of C-reactive protein, procalcitonin, creatinine, albumin, and sodium. It was also found out that splenomegaly rate and the levels of triglycerides, ferritin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in SHPS were significantly higher than in sepsis, but the levels of glycosylated ferritin (%GF), fibrinogen, leukocytes, neutrophils, and thrombocytes were lower. The following medians (quartiles 1–3) were reported in SHPS and sepsis, respectively: triglycerides (mmol/L) were 3.1 (2.3–3.8) and 1.5 (0.8–2.7), total ferritin (ng/mL) was 7,170 (3,159.2–12,551.0) and 1,274 (559.0–3,041.5), %GF was 26.5 (16.7–37.3) and 54.5 (37.7–71.8), fibrinogen (g/L) was 2.8 (1.4–4.4) and 5.3 (2.8–6.8), ALT (IU/L) was 50 (20–102) and 30 (15.3–55.5), AST (IU/L) was 66 (40.0–105.6) and 36 (24.6–78.0), leukocytes (×109/L) were 3.7 (2.1–5.5) and 8.9 (6.5–14.5), thrombocytes (×109/L) were 56 (25.2–93.5) and 157 (97–308). According to ROC analysis the areas under the curve were as follows: 0.88 for neutrophil level, 0.85 for total ferritin, %GF, leukocytes, and thrombocytes, 0.74 for triglycerides, 0.71 for fibrinogen, 0.65 for sodium, and 0.61 for ALT and AST.

Conclusion. In differential diagnosis between SHPS and sepsis most important are the levels of total ferritin, its glycosylated fraction, and triglycerides; less important are fibrinogen, neutrophils, thrombocytes and spleen size. As diagnosis and differential diagnosis between SHPS and sepsis are based on the sum total of clinical and laboratory markers, none of the specified characteristics can serve as a reliable parameter if taken separately.

Keywords: secondary hemophagocytic syndrome, sepsis, ferritin, glycosylated ferritin, triglycerides, hyperferritinemia.

Received: November 20, 2018

Accepted: May 15, 2019

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REFERENCES

  1. Масчан М.А., Полтавец Н.В., Скворцова Ю.В. и др. Результаты трансплантации гемопоэтических стволовых клеток при первичном гемофагоцитарном лимфотистиоцитозе у детей. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2011;10(1):6–14.

    [Maschan MA, Poltavets NV, Skvortsova YuV, et al. Results of hematopoietic stem cell transplantation in children with primary hemophagocytic lymphohistiocytosis. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2011;10(1):6–14. (In Russ)]

  2. Li J, Wang Q, Zheng W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine. 2014;93(2):100–5. doi: 1097/md.0000000000000022.

  3. Костик М.М., Дубко М.Ф., Масалова В.В. и др. Современные подходы к диагностике и лечению синдрома активации макрофагов у детей с ревматическими заболеваниями. Современная ревматология. 2015;9(1):55–9. doi: 10.14412/1996-7012-2015-1-55-59.

    [Kostik MM, Dubko MF, Masalova VV, et al. Current approaches to diagnosing and treating macrophage activation syndrome in children with rheumatic diseases. Sovremennaya revmatologiya. 2015;9(1):55–9. doi: 10.14412/1996-7012-2015-1-55-59. (In Russ)]

  4. Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med. 2009;10(3):387–92. doi: 10.1097/PCC.0b013e3181a1ae08.

  5. Halacli B, Unver N, Halacli SO, et al. Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care. 2016;35:185–90. doi: 10.1016/j.jcrc.2016.04.034.

  6. Lachmann G, Spies C, Schenk T, et al. Hemophagocytic Lymphohistiocytosis. 2018;50(2):149–55. doi: 10.1097/shk.0000000000001048.

  7. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a Score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–20. doi: 10.1002/art.38690.

  8. Румянцев А.Г., Масчан А.А. Федеральные клинические рекомендации по диагностике и лечению гемофагоцитарного лимфогистиоцитоза. М., 2014. 19 с.

    [Rumyantsev AG, Maschan AA. Federal’nye klinicheskie rekomendatsii po diagnostike i lecheniyu gemofagotsitarnogo limfogistiotsitoza. (Federal guidelines for the diagnosis and treatment of hemophagocytic lymphohistiocytosis.) Moscow; 2014. 19 р. (In Russ)]

  9. Lehmberg K, Nichols KE, Henter JI, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004. doi: 10.3324/haematol.2015.123562.

  10. La Rosee P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology. 2015;2015(1):190–6. doi: 10.1182/asheducation-2015.1.190.

  11. Tsuji T, Hirano T, Yamasaki H, et al. A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol. 2014;93(5):821–6. doi: 10.1007/s00277-013-1925-8.

  12. Trottestam H, Horne A, Arico M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84. doi: 10.1182/blood-2011-06-356261.

  13. Buda P, Gietka P, Wieteska-Klimczak A, et al. Secondary hemophagocytic syndromes. Wiad Lek. 2013;66(2 Pt 2):153–63.

  14. Piagnerelli M, Cotton F, Herpain A, et al. Time course of iron metabolism in critically ill patients. Acta Clin Belg. 2013;68(1):22–7. doi: 10.2143/acb.68.1.2062715.

  15. Colafrancesco S, Priori R, Alessandri C, et al. sCD163 in AOSD: a biomarker for macrophage activation related to hyperferritinemia. Immunol Res. 2014;60(2–3):177–83. doi: 10.1007/s12026-014-8563-7.

  16. Rosario C, Zandman-Goddard G, Meyron-Holtz EG, et al. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013;11(1):185. doi: 10.1186/1741-7015-11-185.

  17. Fardet L, Coppo P, Kettaneh A, et al. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum. 2008;58(5):1521–7. doi: 10.1002/art.23415.

  18. Клинические рекомендации по диагностике и лечению тяжелого сепсиса и септического шока в лечебно-профилактических организациях Санкт-Петербурга [электронный документ]. Доступно по: http://www.spbsepsis.ru/wp-content/uploads/Protocols_24_11_2016.pdf (ссылка активна на 30.08.2018).

    [Klinicheskie rekomendatsii po diagnostike i lecheniyu tyazhelogo sepsisa i septicheskogo shoka v lechebno-profilakticheskikh organizatsiyakh Sankt-Peterburga. (Clinical guidelines for the diagnosis and treatment of severe sepsis and septic shock in medical and preventive care institutions of Saint Petersburg.) [Internet] Available from: http://www.spbsepsis.ru/wp-content/uploads/Protocols_24_11_2016.pdf. (accessed 30.08.2018) (In Russ)]

  19. Worwood M, Cragg SJ, Williams AM, et al. The clearance of 131I-human plasma ferritin in man. Blood. 1982;60(4):827–33.

  20. Потапенко В.Г., Первакова М.Ю., Лапин С.В. и др. Роль фракционного анализа ферритина в диагностике вторичного гемофагоцитарного синдрома. Клиническая лабораторная диагностика. 2018;63(1):21–7.

    [Potapenko VG, Pervakova MYu, Lapin SV, et al. The role of fraction analysis of ferritin in diagnosis of secondary hemophagocytic syndrome. Klinicheskaya laboratornaya diagnostika. 2018;63(1):21–7. (In Russ)]

  21. Тиц Н.У. Клиническая оценка лабораторных тестов. Пер. с англ. М.: Медицина, 1986. 480 с.

    [Tits NU. Clinical evaluation of laboratory tests. (Russ. ed.: Tits Klinicheskaya otsenka laboratornykh testov. Moscow: Meditsina Publ.; 1986. 480 p.)]

  22. Schram AM, Comstock P, Campo M, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412–9. doi: 10.1111/bjh.13837.

  23. Strauss R, Neureiter D, Westenburger B, et al. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients-a postmortem clinicopathologic analysis. Crit Care Med. 2004;32(6):1316–21. doi: 10.1097/01.ccm.0000127779.24232.15.

  24. Gupta A, Weitzman S, Abdelhaleem M. The role of hemophagocytosis in bone marrow aspirates in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(2):192–4. doi: 10.1002/pbc.21441.

  25. Милютина Л.Н., Гринцевич М.Н., Инюшкина Е.В. Вторичный гемофагоцитарный синдром у детей. Инфекционные болезни. 2017;15(1):67–73.

    [Milyutina LN, Grintsevich MN, Inyushkina EV. Secondary hemophagocytic syndrome in children. Infektsionnye bolezni. 2017;15(1):67–73. (In Russ)]

  26. Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15(1):172. doi: 10.1186/s12916-017-0930-5.

  27. Santambrogio P, Cozzi A, Levi S, et al. Human serum ferritin G‐peptide is recognized by anti-L ferritin subunit antibodies and concanavalin-A. Br J Haematol. 1987;65(2):235–7. doi: 10.1111/j.1365-2141.1987.00231.x-i1.

  28. Wang Z, Wang Y, Wang J, et al. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol. 2009;90(4):501–5. doi: 10.1007/s12185-009-0391-5.

  29. Nabergoj M, Marinova M, Binotto G, et al. Diagnostic and prognostic value of low percentage of glycosylated ferritin in acquired hemophagocytic lymphohistiocytosis: A single-center study. Int J Lab Hematol. 2017;39(6):620–4. doi: 10.1111/ijlh.12713.

  30. Creput C, Galicier L, Buyse S, et al. Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intens Care Med. 2008;34(7):1177–87. doi: 10.1007/s00134-008-1111-y.

  31. Li F, Li P, Zhang R, et al. Identification of clinical features of lymphoma-associated hemophagocytic syndrome (LAHS): an analysis of 69 patients with hemophagocytic syndrome from a single-center in central region of China. Med Oncol. 2014;31(4):902. doi: 10.1007/s12032-014-0902-y.

  32. Tseng YT, Sheng WH, Lin BH, et al. Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults. J Microbiol Immunol Infect. 2011;44(3):191–7. doi: 10.1016/j.jmii.2011.01.027.

  33. Grion CM, Cardoso LT, Perazolo TF, et al. Lipoproteins and CETP levels as risk factors for severe sepsis in hospitalized patients. Eur J Clin Invest. 2010;40(4):330–8. doi: 10.1111/j.1365-2362.2010.02269.x.

  34. Lekkou A, Mouzaki A, Siagris D, et al. Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis. J Crit Care. 2014;29(5):723–7. doi: 10.1016/j.jcrc.2014.04.018.

  35. Soker M, Colpan L, Ece A, et al. Serum levels of IL-1 beta, sIL-2R, IL-6, IL-8, and TNF-alpha in febrile children with cancer and neutropenia. Med Oncol. 2001;18(1):51–8. doi: 10.1385/mo:18:1:51.

  36. Ambrosetti A, Nadali G, Vinante F, et al. Serum levels of soluble interleukin-2 receptor in Hodgkin disease. Relationship with clinical stage, tumor burden, and treatment outcome. Cancer. 1993;72(1):201–6. doi: 10.1002/1097-0142(19930701)72:1<201::aid-cncr2820720136>3.0.co;2-v.

  37. Goto H, Tsurumi H, Takemura M, et al. Serum-soluble interleukin-2 receptor (sIL-2R) level determines clinical outcome in patients with aggressive non-Hodgkin’s lymphoma: in combination with the International Prognostic Index. J Cancer Res Clin Oncol. 2005;131(2):73–9. doi: 10.1007/s00432-004-0600-9.

  38. Da Silva PB, Perini GF, Pereira Lde A, et al. Imbalance of Pro- and Anti-Inflammatory Cytokines in Patients With cHL Persists Despite Treatment Compared With Control Subjects. Clin Lymph Myel Leuk. 2015;15:S151–7. doi: 10.1016/j.clml.2015.02.002.

  39. Perez EM, Bello JL, Bendana A, et al. Detection of soluble interleukin-2 receptor in the serum of patients with non-Hodgkin’s lymphoma. Med Clin (Barc). 1998;111(5):161–7.

  40. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007;166(2):95–109. doi: 10.1007/s00431-006-0258-1.

  41. Kinasewitz GT, Zein JG, Lee GL, et al. Prognostic value of a simple evolving disseminated intravascular coagulation Score in patients with severe sepsis. Crit Care Med. 2005;33(10):2214–21. doi: 10.1097/01.CCM.0000181296.53204.DE.

  42. Rigaud D, Hassid J, Meulemans A, et al. A paradoxical increase in resting energy expenditure in malnourished patients near death: the king penguin syndrome. Am J Clin Nutr. 2000;72(2):355–60. doi: 10.1093/ajcn/72.2.355.

  43. Luo X, Yang X, Li J, et al. The procalcitonin/albumin ratio as an early diagnostic predictor in discriminating urosepsis from patients with febrile urinary tract infection. 2018;97(28):e11078. doi: 10.1097/MD.0000000000011078.

  44. Smolar M, Dedinska I, Hosala M, et al. Importance of Markers of Sepsis in Surgical Patients. Am Surg. 2018;84(6):1058–63.

  45. Karamnov S, Brovman EY, Greco KJ, et al. Risk Factors and Outcomes Associated With Sepsis After Coronary Artery Bypass and Open Heart Valve Surgeries. Semin Cardiothorac Vasc Anesth. 2018;22(4):359–68. doi: 10.1177/1089253218785362.

  46. Lee JY, Kim JH, Lee JS, et al. Initial Characteristics and Clinical Severity of Hemophagocytic Lymphohistiocytosis in Pediatric Patients Admitted in the Emergency Department. Pediatr Emerg Care. 2018. Published ahead of print. doi: 10.1097/PEC.0000000000001518.

  47. Gao X, Qiu HX, Wang JJ, et al. Clinical significance of serum calcium and albumin in patients with secondary hemophagocytic lymphohistiocytosis. Zhonghua Xue Ye Xue Za Zhi. 2017;38(12):1031–5. doi: 10.3760/cma.j.issn.0253-2727.2017.12.005.

  48. Huang W, Wang Y, Wang J, et al. [Clinical characteristics of 192 adult hemophagocytic lymphohistiocytosis]. Zhonghua Xue Ye Xue Za Zhi. 2014;35(9):796–801. doi: 10.3760/cma.j.issn.0253-2727.2014.09.003.

  49. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103(6):1103–13. doi: 1002/cncr.20890.

  50. Hansson LO, Lindquist L. C-reactive protein. Curr Opin Infect Dis. 1997;10(3):196–201. doi: 1097/00001432-199706000-00007.

  51. Arismendi-Morillo GJ, Briceno-Garcia AE, Romero-Amaro ZR, et al. Acute non-specific splenitis as indicator of systemic infection. Assessment of 71 autopsy cases. Invest Clin. 2004;45(2):131–5.

  52. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633–9. doi: 10.1002/art.11368.

  53. Artero EA, Nunez AC, Severo BA, et al. Severe liver disease as first sign of a haemophagocytic syndrome. Gastroenterologia y Hepatologia. 2017;40(5):348–9. doi: 10.1016/j.gastre.2016.04.015.

Cardiovascular Toxicity of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia

COMPLICATIONS OF ANTITUMOR TREATMENT , , , ,

IL Davydkin1,2, KV Naumova1, AM Osadchuk1, IA Zolotovskaya1, OE Danilova1, TYu Stepanova1, OV Tereshina1, LV Limareva3, AS Shpigel’1, TP Kuz’mina1

1 Samara State Medical University, 89 Chapaevskaya str., Samara, Russian Federation, 443099

2 SamGMU Research Institute of Hematology, Transfusiology and Intensive Care, 89 Chapaevskaya str., Samara, Russian Federation, 443099

3 SamGMU Institute of Experimental Medicine and Biotechnology, 89 Chapaevskaya str., Samara, Russian Federation, 443099

For correspondence: Kseniya Viktorovna Naumova, 89 Chapaevskaya str., Samara, Russian Federation, 443099; Tel.: +7(905)303-12-08; e-mail: senechka.naumova@rambler.ru

For citation: Davydkin IL, Naumova KV, Osadchuk AM, et al. Cardiovascular Toxicity of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia. Clinical oncohematology. 2018;11(4):378–87.

DOI: 10.21320/2500-2139-2018-11-4-378-387

ABSTRACT

In the present review the cardiovascular complications in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKI) are discussed. It covers current views on pathogenesis of TKI cardiovascular toxicity. The pathophysiology of cardiovascular diseases (CVD) is considered as a part of the so-called pathophysiological continuum, i.e. a complex of processes developing at the molecular and cellular levels before clinical symptoms of the above diseases occur. Cardiovascular toxicity of certain TKIs can contribute to progression of pathophysiological processes in CML patients. The study of mechanisms underlying cardiovascular complications of TKI-based therapy is essential for evaluating the risks of their development in each patient. Identification of CVD predictors during TKI-based therapy can allow to elaborate a scheme for cardiovascular monitoring and safe patient management under consideration of individual risks and to avoid severe life-threatening complications.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, adverse effects, cardiotoxicity, cardiovascular events.

Received: May 14, 2018

Accepted: August 29, 2018

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REFERENCES

  1. Elliott P. Pathogenesis of cardiotoxicity induced by anthracyclines. Sem Oncol. 2006;33:2–7. doi: 10.1053/j.seminoncol.2006.04.020.

  2. Tokarska-Schlattner M, Zaugg M, Zuppinger C, et al. New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. J Mol Cell Cardiol. 2006;41(3):389–405. doi: 10.1016/j.yjmcc.2006.06.009.

  3. Mellor HR, Bell AR, Valentin JP, Roberts RRA. Cardiotoxicity associated with targeting kinase pathways in cancer. Toxicol Sci. 2011;120(1):14–32. doi: 10.1093/toxsci/kfq378.

  4. Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta 2009;48(7):964–70. doi: 10.1080/02841860903229124.

  5. Baccarani M, Deininger MW, Rosti G, et European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84. doi: 10.1182/blood-2013-05-501569.

  6. Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33(35):4210–8. doi: 10.1200/jco.2015.62.4718.

  7. Anhel N, Delgado DH, Lipton JH. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. Vasc Health Risk Manage. 2017;13:293–303. doi: 10.2147/vhrm.s108874.

  8. Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110(12):4055–63. doi: 10.1182/blood-2007-07-102061.

  9. Туркина А.Г., Челышева Е.Ю. Стратегия терапии хронического миелолейкоза: возможности и перспективы. Терапевтический архив. 2013;85(7):4–9.

    [Turkina AG, Chelysheva EYu. Therapeutic strategy for chronic myeloid leukemia: possibilities and prospects. Terapevticheskii arkhiv. 2013;85(7):4–9. (In Russ)]

  10. Laneuville P. When to Stop Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Curr Treat Opt 2018;19(3):15. doi: 10.1007/s11864-018-0532-2.

  11. Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128(1):17–23. doi: 10.1182/blood-2016-01-694265.

  12. Etienne G, Guilhot J, Rea D, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017;35(3):298–305. doi: 10.1200/JCO.2016.68.2914.

  13. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2016;129(7):846–54. doi: 10.1182/blood-2016-09-742205.

  14. Hehlmann R. Research in the heart of hematology: chronic myeloid leukemia 2017. Haematologica. 2017;102(3):418–21. doi: 10.3324/haematol.2016.159848.

  15. Куликов С.М., Виноградова О.Ю., Челышева Е.Ю. и др. Заболеваемость хроническим миелолейкозом в 6регионах России по данным популяционного исследования 2009–2012 гг. Терапевтический архив. 2014;86(7):24–30.

    [Kulikov SM, Vinogradova OYu, Chelysheva EYu, et al. Incidence of chronic myeloid leukemia in 6 regions of Russia according to the data of the 2009–2012 population-based study. Terapevticheskii arkhiv. 2014;86(7):24–30. (In Russ)]

  16. Рабочая группа по онкологическим заболеваниям и сердечно-сосудистой токсичности Европейского общества кардиологов (ЕОК). Меморандум ESC по лечению онкологических заболеваний и сердечно-сосудистой токсичности, разработанный под эгидой комитета по практике ESC Российский кардиологический журнал. 2017;3(143):105–39. doi: 10.15829/1560-4071-2017-3-105-139.

    [The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines. Russian Journal of Cardiology. 2017;3(143):105–39. doi: 10.15829/1560-4071-2017-3-105-139. (In Russ)]

  17. Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30(8):1648–71. doi: 10.1038/leu.2016.104.

  18. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12(8):908–16. doi: 10.1038/nm1446.

  19. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–27. doi: 10.1056/nejmoa1609324.

  20. Gambacorti-Passerini С, Cortes JE, Lipton JH, et al. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014;89(10):947–53. doi: 1002/ajh.23788.

  21. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018;36(3):231–9. doi: 10.1200/jco.2017.74.7162.

  22. Cortes JE, Khoury HJ, Kantarjian H, et al. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib. Am J Hematol. 2016;91(6): 606–16. doi: 10.1002/ajh.24360.

  23. Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128–37. doi: 10.1161/circulationaha.111.079921.

  24. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333–40. doi: 10.1200/jco.2015.64.8899.

  25. Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91(9):869–74. doi: 10.1002/ajh.24423.

  26. Jeon Y-W, Lee S-E, Kim S-H, et al. Six-Year Follow-Up Of Dasatinib-Related Pulmonary Arterial Hypertension (PAH) For Chronic Myeloid Leukemia In Single Center. Blood. 2013;122(21):4017.

  27. Kong JH, Jeon Y-W, Lee S-E, et al. Long-Term Assessment of Dasatinib-Induced Pulmonary Arterial Hypertension in Chronic Myeloid Leukemia. Blood. 2014;124(21):5535.

  28. Рабочая группа по диагностике и лечению легочной гипертензии Европейского общества кардиологов (ESC) и Европейского общества пульмонологов (ERS). Рекомендации ESC/ERS по диагностике и лечению легочной гипертензии 2015. Российский кардиологический журнал. 2016;5(133):5–64. doi: 10.15829/1560-4071-2016-5-5-64.

    [The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Russian Journal of Cardiology. 2016;5(133):5–64. doi: 10.15829/1560-4071-2016-5-5-64. (In Russ)]

  29. Aichberger KJ, Herndlhofer S, Schernthaner G-H, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037.

  30. Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Nat Cancer Inst. 2011;103(17):1347–8. doi: 10.1093/jnci/djr292.

  31. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. doi: 10.1038/leu.2016.5.

  32. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88. doi: 10.1056/nejmoa1205127.

  33. Cortes JE, Kim D-W, Pinilla-Ibarz J. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: Final 5-year results of the phase 2 PACE trial. Blood. 2018:blood-2016-09-739086. doi: 10.1182/blood-2016-09-739086.

  34. Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(5):612–21. doi: 10.1016/s1470-2045(16)00080-2.

  35. Иклусиг® (инструкция по медицинскому применению). Австралия: Ariad Pharmaceuticals. Доступно по: http://lechimvizraile.ru/articles/iklusig_instruktsiya_po_primeneniyu/ Ссылка активна на 7.06.2018.

    [Iclusig® (package insert). Australia: Ariad Pharmaceuticals. Available from: http://lechimvizraile.ru/articles/iklusig_instruktsiya_po_primeneniyu/ (accessed 7.06.2018) (In Russ)]

  36. Dorer DJ, Knickerbocker RK, Baccarani M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91. doi: 10.1016/j.leukres.2016.07.007.

  37. Dahlen T, Edgren G, Lambe M, et al. Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study. Ann Int Med. 2016;165(3):161–6. doi: 10.7326/m15-2306.

  38. Ross DM, Arthur C, Burbury K, et al. Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors. Int Med J. 2018;48(Suppl 2):5–13. doi: 10.1111/imj.13716.

  39. Douxfils J, Haguet H, Mullier F, et al. Association Between BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia and Cardiovascular Events, Major Molecular Response, and Overall Survival A Systematic Review and Meta-analysis. JAMA Oncol. 2016;2(5):625–32. doi: 10.1001/jamaoncol.2015.5932.

  40. Haguet H, Douxfils J, Mullier F, et al. Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis. Exp Opin Drug Safety. 2017;16(1):5–12. doi: 10.1080/14740338.2017.1261824.

  41. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39. doi: 10.1038/nrc2559.

  42. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004;4(5):361–70. doi: 10.1038/nrc1360.

  43. Zuppinger C, Suter TM. Cancer therapy-associated cardiotoxicity and signaling in the myocardium. J Cardiovasc Pharmacol. 2010;56(2):141–6. doi: 10.1097/fjc.0b013e3181e0f89a.

  44. Зейфман А.А., Челышева Е.Ю., Туркина А.Г., Чилов Г.Г. Роль селективности ингибиторов тирозинкиназ в развитии побочных эффектов при терапии хронического миелолейкоза. Клиническая онкогематология. 2014;7(1):16–27.

    [Zeyfman AA, Chelysheva YeYu, Turkina AG, Chilov GG. Role of tyrosine-kinase inhibitor selectivity in development of adverse effects during treatment of chronic myeloid leukemia. Klinicheskaya onkogematologiya. 2014;7(1):16–27 (In Russ)]

  45. Bellinger AM, Arteaga CL, Force T, et al. Cardio-oncology. 2015;132(23):2248–58. doi: 10.1161/circulationaha.115.010484.

  46. Han MS, Chung KW, Cheon HG, et al. Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice. 2009;58(2):329–36. doi: 10.2337/db08-0080.

  47. Iurlo A, Orsi E, Cattaneo D, et al. Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem? Oncotarget. 2015;6(32):33944–51. doi: 10.18632/oncotarget.5580.

  48. Alhawiti N, Burbury KL, Kwa FA, et al. The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Thromb Res. 2016;145:54–64. doi: 10.1016/j.thromres.2016.07.019.

  49. Albrecht-Schgoer K, Huber K, Grebien F, et al. Nilotinib exerts direct proatherogenic and anti-angiogenic effects on vascular endothelial cells: a potential explanation for drug-induced vasculopathy in CML. Blood. 2013;122(21):257.

  50. Bair SM, Choueiri TK, Moslehi J. Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med. 2013;23(4):104–13. doi: 1016/j.tcm.2012.09.008.

  51. Садыкова Д.И. Современные подходы к диагностике и лечению легочной гипертензии. Практическая медицина. 2012;7(62):21–6.

    [Sadykova DI. Modern approaches to diagnostic and treatment of pulmonary hypertension. Prakticheskaya meditsina. 2012;7(62):21–6. (In Russ)]

  52. Godinas L, Guingabert C, Seferian A, et al. Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword? Semin Respir Crit Care Med. 2013;34(5):714–24. doi: 10.1055/s-0033-1356494.

  53. Morello F, Perino A, Hirsch E. Phosphoinositide 3-kinase signaling in the vascular system. Cardiovasc Res. 2009;82(2):261–71. doi: 10.1093/cvr/cvn325.

  54. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34. doi: 10.1056/nejmoa021491.

  55. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7(6):475–85. doi: 10.1038/nrc2152.

  56. Dhaun N, Goddard J, Webb DJ. The endothelin system and its antagonism in chronic kidney disease. J Am Soc Nephrol. 2006;17(4):943–55. doi: 10.1681/asn.2005121256.

  57. Amiri F, Virdis A, Neves MF, et al. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation. 2004;110(15):2233–40. doi: 10.1161/01.cir.0000144462.08345.b9.

  58. Lankhorst S, Baelde HJ, Kappers MH, et al. Greater sensitivity of blood pressure than renal toxicity to tyrosine kinase receptor inhibition with sunitinib. Hypertension. 2015;66(3):543–9. doi: 10.1161/hypertensionaha.115.05435.

  59. Kostos L, Burbury K, Srivastava G, Prince HM. Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: case report. Platelets. 2015;26(8):809–11. doi: 10.3109/09537104.2015.1049138.

  60. Quintas-Cardama A, Kantarjian H, Ravandi F, et al. Bleeding diasthesis in patients with chronic myelogenous leukaemia receiving dasatinib therapy. Cancer. 2009;115(11):2482–90. doi: 10.1002/cncr.24257.

  61. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908–14. doi: 10.1200/jco.2007.12.0329.

  62. Poredos P, Jug B. The prevalence of peripheral arterial disease in high risk subject sand coronary or cerebrovascular patients. Angiology. 2007;58(3):309–15. doi: 10.1177/0003319707302494.

  63. Steg Ph, Bhatt DL, Wilson PWF, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297(11):1197. doi: 10.1001/jama.297.11.1197.

  64. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27(1):107–12. doi: 10.1038/leu.2012.181.

  65. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabeticpatients in general clinical practice. J Oncol Pharm Pract. 2010;17(3):197–202. doi: 10.1177/1078155210378913.

  66. Lassila M, Allen TJ, Cao Z, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24(5):935–42. doi: 10.1161/01.atv.0000124105.39900.db.

  67. Hoffmann VS, Baccarani M, Hasford J, et al. The EUTOS population based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. 2015;29(6):1336–43. doi: 10.1038/leu.2015.73.

  68. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum: validated clinical evidence of improved patient outcomes. Part I: pathophysiology and clinical trial evidence risk factors through stable coronary artery disease. Circulation. 2006;114(25):2850–70. doi: 10.1161/circulationaha.106.655688.

  69. Daher IN, Daigle TR, Bhatia N, Durand J-B. The Prevention of Cardiovascular Disease In Cancer Survivors. Tex Heart Inst J. 2012;39(2):190–8.

  70. Brown S-A, Nhola L, Herrmann J. Cardiovascular toxicities of small molecule tyrosine kinase inhibitors: an opportunity for systems-based approaches. Clin Pharmacol Ther. 2016;101(1):65–80. doi: 10.1002/cpt.552.

  71. Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. 2013;27(6):1316–21. doi: 10.1038/leu.2013.70.

  72. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96. doi: 10.1056/nejmoa1306494.

  73. Гусарова Г.А., Туркина А.Г. Артериальные события у больных хроническим миелолейкозом, получающих терапию ингибиторами тирозинкиназ 2-го поколения. Клиническая онкогематология. 2016;9(4):474–84. doi: 10.21320/2500-2139-2016-9-4-474-484.

    [Gusarova GA, Turkina AG. Arterial Events in Patients with Chronic Myeloid Leukemia Receiving Treatment with Second Generation Tyrosine Kinase Inhibitors. Clinical oncohematology. 2016;9(4):474–84. doi: 10.21320/2500-2139-2016-9-4-474-484. (In Russ)]

  74. Li W, Croce K, Steensma DP, et al. Vascular and metabolic implications of novel targeted cancer therapies. J Am Coll Cardiol. 2015;66(10):1160–78. doi: 10.1016/j.jacc.2015.07.025.

  75. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24(11):987–1003. doi: 10.1016/s0195-668x(03)00114-3.

  76. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2017;69(11):e71–e126. doi: 10.1016/j.jacc.2016.11.007.

  77. Овсянникова Е.Г., Попов Е.А., Давыдкин И.Л. и др. Современные аспекты диагностики, прогнозирования и лечения хронического миелолейкоза. Астраханский медицинский журнал. 2015;10(3):27–44.

    [Ovsyannikova EG, Popov EA, Davydkin IL, et al. Modern aspects of diagnosis, prognosis and treatment of chronic myeloid leukemia. Astrakhanskii meditsinskii zhurnal. 2015;10(3):27–44. (In Russ)]

  78. Jessup M, Abraham WT, Casey DE, et al. 2009 ACCF/AHA Guidelines for the Diagnosis and Management of heart failure in adults: a report of the American College of cardiology foundation/American heart association task force on practice guidelines: developed in collaboration with the International Society for heart and lung transplantation. Circulation. 2009;119(14):1977–2016. doi: 10.1161/circulationaha.109.192064.

  79. Granados-Principal S, Quiles JL, Ramirez-Tortosa CL, et al. New advances in molecular mechanisms and the prevention of adriamycin toxicity by antioxidant nutrients. Food Chem Toxicol. 2010;48(6):1425–38. doi: 10.1016/j.fct.2010.04.007.

  80. Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005;131(5):561–78. doi: 10.1111/j.1365-2141.2005.05759.x.

  81. Mohamed HE, El-Swefy SE, Hagar HH. The protective effect of glutathione administration on Adriamycin-induced acute cardiac toxicity in rats. Pharmacol Res. 2000;42(2):115–21. doi: 10.1006/phrs.1999.0630.

  82. van Leeuwen RWF, van Gelder T, Mathijssen RHJ, Jansman FGA. Drug–drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol. 2014;15(8):e315–e26. doi: 10.1016/s1470-2045(13)70579-5.

  83. Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117(8):e75–e87. doi: 10.1182/blood-2010-07-294330.

  84. Туркина А.Г., Зарицкий А.Ю., Шуваев В.А. и др. Клинические рекомендации по диагностике и лечению хронического миелолейкоза. Клиническая онкогематология. 2017;10(3):294–316. doi: 10.21320/2500-2139-2017-10-3-294-316.

    [Turkina AG, Zaritskii AYu, Shuvaev VA, et al. Clinical Recommendations for the Diagnosis and Treatment of Chronic Myeloid Leukemia. Clinical oncohematology. 2017;10(3):294–316. doi: 10.21320/2500-2139-2017-10-3-294-316. (In Russ)]

  85. Poch MM, Sibai H, Deotare U, Lipton JH. Ponatinib in the therapy of chronic myeloid leukemia. Exp Rev Hematol. 2016;9(10):923–32. doi: 10.1080/17474086.2016.1232163.

  86. Breccia M, Pregno P, Spallarossa P, et al. Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. Ann Hematol. 2016;96(4):549–58. doi: 10.1007/s00277-016-2820-x.

Dermatological Toxicity of Hydroxycarbamide

COMPLICATIONS OF ANTITUMOR TREATMENT ,

IN Subortseva, AL Melikyan, EA Gilyazitdinova, TI Kolosheinova, EI Pustovaya, EK Egorova, AM Kovrigina, AB Sudarikov, AO Abdullaev

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

For correspondence: Irina Nikolaevna Subortseva, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: soubortseva@yandex.ru.

For citation: Subortseva IN, Melikyan AL, Gilyazitdinova EA, et al. Dermatological Toxicity of Hydroxycarbamide. Clinical oncohematology. 2018;11(3):252–58.

DOI: 10.21320/2500-2139-2018-11-3-252-258

ABSTRACT

Hydroxycarbamide is an antitumor agent mainly used for treatment of Ph-negative myeloproliferative disorders and sickle cell disease. The development of skin ulcers is a rare but serious adverse event in long-term antitumor therapy. Hydroxycarbamide-induced ulcers are often multiple and bilateral, and usually occur in the lower legs, although they can occur in other regions of the body. The ulcers are small-sized and shallow with sharp margins and yellow fibrine-covered base. They cause constant severe, difficult to treat pain which is a characteristic sign. The drug withdrawal usually leads to spontaneous healing of ulcers. Regular dermatologic screening must be obligatory for all the patients receiving hydroxycarbamide. The present paper provides a literature review on dermatological toxicity of hydroxycarbamide and a clinical case description.

Keywords: hydroxycarbamide, adverse events, dermatologic screening, Ph-negative chronic myeloproliferative disorders.

Received: February 7, 2018

Accepted: May 4, 2018

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REFERENCES

  1. Mathews CK. DNA synthesis as a therapeutic target: the first 65 years. FASEB J. 2012;26(6):2231–7. doi: 10.1096/fj.12-0602ufm.
  2. Yarbro JW, Leavell UW. Hydroxyurea: a new agent for the management of refractory psoriasis. J Ky Med Assoc. 1969;67:899–901.
  3. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science. 1994;266(5186):801–5. doi: 10.1126/science.7973634.
  4. Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders. Expert Rev Anticancer Ther. 2011;11(3):403–14. doi: 10.1586/era.11.10.
  5. Adunyah SE, Chander R, Barner VK, Cooper RS. Regulation of c-jun mRNA expression by hydroxyurea in human K562 cells during erythroid differentiation. Biochim Biophys Acta. 1995;1263(2):123–32. doi: 10.1016/0167-4781(95)00079-v.
  6. Paleri V, Lindsey L. Oral ulcers caused by hydroxyurea. J Laryngol Otol. 2000;114(12):976–7. doi: 10.1258/0022215001904518.
  7. Lannemyr O, Kutti J. Hydroxyurea as a cause of drug fever in essential thrombocythaemia. Eur J Haematol. 1999;62(5):354–5. doi: 10.1111/j.1600-0609.1999.tb01917.x.
  8. Kalambokis G, Stefanou D, Arkoumani E, et al. Fulminant bronchiolitis obliterans organizing pneumonia following 2 d of treatment with hydroxyurea, interferon-alpha and oral cytarabine ocfosfate for chronic myelogenous leukemia. Eur J Haematol. 2004;73(1):67–70. doi: 10.1111/j.1600-0609.2004.00252.x.
  9. Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch Dermatol. 1975;111(2):183–7. doi: 10.1001/archderm.1975.01630140041002.
  10. Bohn J, Hansen JP, Menne T. Ulcerative lichen planus-like dermatitis due to long-term hydroxyurea therapy. J Eur Acad Dermatol Venereol 1998;10(2):187–9. doi: 10.1111/j.1468-3083.1998.tb00726.x.
  11. Senet P, Aractingi S, Pornkuf M, et al. Hydroxyurea-induced dermatomyositis-like eruption. Br J Dermatol. 1995;133(3):455–9. doi: 10.1111/j.1365-2133.1995.tb02677.x.
  12. Vassallo C, Passamonti F, Merante S, et al. Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukaemia. Clin Exp Dermatol. 2001;26(2):141–8. doi: 10.1046/j.1365-2230.2001.00782.x.
  13. Bahadoran P, Castanet J, Lacour JP, et al. Pseudo-dermatomyositis induced by long-term hydroxyurea therapy: report of two cases. Br J Dermatol. 1996;134(6):1161–2. doi: 10.1111/j.1365-2133.1996.tb07975.x.
  14. Marie I, Joly P, Levesque H, et al. Pseudo-dermatomyositis as a complication of hydroxyurea therapy. Clin Exp Rheumatol. 2000;18(4):536–7.
  15. Quattrone F, Dini V, Barbanera S, et al. Cutaneous ulcers associated with hydroxyurea therapy. J Tissue Viabil. 2013;22(4):112–21. doi: 10.1016/j.jtv.2013.08.002.
  16. Daoud MS, Gibson LE, Pittelkow MR. Hydroxyurea dermopathy: a unique lichenoid eruption complicating long-term therapy with hydroxyurea. J Am Acad Dermatol. 1997;36(2):178–82. doi: 10.1016/s0190-9622(97)70276-7.
  17. Aste N, Fumo G, Contu F, et al. Nail pigmentation caused by hydroxyurea: report of 9 cases. J Am Acad Dermatol. 2002;47(1):146–7. doi: 10.1067/mjd.2002.120910.
  18. Ruzzon E, Randi ML, Tezza F, et al. Leg ulcers in elderly on hydroxyurea: a single center experience in Ph-myeloproliferative disorders and review of literature. Aging Clin Exp Res. 2006;18(3):187–90. doi: 10.1007/bf03324647.
  19. Latagliata R, Spadea A, Cedrone M, et al. Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012;118(2):404–9. doi: 10.1002/cncr.26194.
  20. Antonioli E, Guglielmelli P, Pieri L, et al. Hydroxyurea related toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol. 2012;87(5):552–4. doi: 10.1002/ajh.23160.
  21. Salmon-Ehr V, Leborgne G, Vilque JP, et al. Secondary cutaneous effects of hydroxyurea: prospective study of 26 patients from a dermatologic consultation. Rev Med Intern. 2000;21(1):30–4.
  22. Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010;148(6):961–3. doi: 10.1111/j.1365-2141.2009.08019.x.
  23. Kikuchi K, Arita K, Tateishi Y, et al. Recurrence of hydroxyurea-induced leg ulcer after discontinuation of treatment. Acta Derm Venereol. 2011;91(3):373–4. doi: 10.2340/00015555-1048.
  24. Sanchez-Palacios C, Guitart J. Hydroxyurea-associated squamous dysplasia. J Am Acad Dermatol. 2004;51(2):293–300. doi: 10.1016/j.jaad.2003.11.059.
  25. Young HS, Khan AS, Kendra JR, Coulson IH. The cutaneous side-effects of hydroxyurea. Clin Lab Haematol. 2000;22(4):229–32. doi: 10.1046/j.1365-2257.2000.00311.x.
  26. Dacey MJ, Callen JP. Hydroxyurea-induced dermatomyositis-like eruption. J Am Acad Dermatol. 2003;48(3):439–41. doi: 10.1067/mjd.2003.74.
  27. Velez A, Garcia-Aranda J-M, Moreno J-C. Hydroxyurea-induced leg ulcers: is macroerythrocytosis a pathogenic factor? J Eur Acad Dermatol Venereol. 1999;12(3):243–4. doi: 10.1111/j.1468-3083.1999.tb01037.x.
  28. Engstrom KG, Lofvenberg E. Treatment of myeloproliferative disorders with hydroxyurea: effects on red blood cell geometry and deformability. Blood. 1998;91(10):3986–91.
  29. Bader U, Banyai M, Boni R, et al. Leg ulcers in patients with myeloproliferative disorders: disease or treatment-related? Dermatology. 2000;200(1):45–8. doi: 10.1159/000018315.
  30. Hartmann K, Nagel S, Erichsen T, et al. Cutaneous ulcers following hydroxyurea therapy. Phlebologie. 2004;33(6):202–5.
  31. Kennedy BJ. Hydroxyurea-associated leg ulceration. Ann Intern Med. 1998;129(3):252. doi: 10.7326/0003-4819-129-3-199808010-00017.
  32. Nguyen TV, Margolis DJ. Hydroxyurea and lower leg ulcers. Cutis. 1993;52(4):217–9.
  33. Stahl RL, Silber R. Vasculitic leg ulcers in chronic myelogenous leukemia. Am J Med. 1985;78(5):869–72. doi: 10.1016/0002-9343(85)90297-9.
  34. Burns DA, Sarkany I, Gaylarde P. Effects of hydroxyurea therapy on normal skin: a case report. Clin Exp Dermatol. 1980;5(4):447–9. doi: 10.1111/j.1365-2230.1980.tb01731.x.
  35. Stagno F, Guglielmo P, Consoli U, et al. Successful healing of hydroxyurea-related leg ulcers with topical granulocyte-macrophage colony-stimulating factor. Blood. 1999;94(4):1479–80.
  36. Stone T, Berger A, Blumberg S, et al. A multidisciplinary team approach to hydroxyurea-associated chronic wound with squamous cell carcinoma. Int Wound J. 2012;9(3):324–9.
  37. Natarajan S, Williamson D, Grey J, et al. Healing of an MRSA-colonized, hydroxyurea-induced leg ulcer with honey. J Dermatol Treat. 2001;12(1):33–6. doi: 10.1080/095466301750163563.
  38. Tsuchiya S, Ichioka S, Sekiya N. Hydroxyurea-induced foot ulcer in a case of essential thrombocythaemia. J Wound Care. 2010;19(8):361–4. doi: 10.12968/jowc.2010.19.8.77715.
  39. Fioramonti P, Fino P, Parisi P, et al. A case of hydroxyurea-induced leg ulcer after definitive treatment suspension in a patient affected by thrombocythemia: effectiveness of a new collagenase. In Vivo. 2012;26(6):1053–6.
  40. Martorell-Calatayud A, Requena С, Nagore-Enguidanos E, Guillen-Barona C. Multiple, painful, treatment-resistant leg ulcers associated with dermatomyositis-like lesions over the interphalangeal joints induced by hydroxyurea. Actas Dermo-Sifiliograficas. 2009;100(9):804–7. doi: 10.1016/s1578-2190(09)70176-3.
  41. Varma S, Lanigan SW. Dermatomyositis-like eruption and leg ulceration caused by hydroxyurea in a patient with psoriasis. Clin Exp Dermatol. 1999;24(3):164–6. doi: 10.1046/j.1365-2230.1999.00443.x.
  42. Суборцева И.Н., Гилязитдинова Е.А., Колошейнова Т.И. и др. Предварительные результаты исследования по оценке эффективности и безопасности лечения пациентов с истинной полицитемией и эссенциальной тромбоцитемией цепэгинтерфероном α-2b. Клиническая онкогематология. 2017;10(4):581–2.[Subortseva IN, Gilyazitdinova EA, Kolosheinova TI, et al. Preliminary results of a study evaluating the efficacy and safety of cepeginterferon α-2b therapy of patients with polycythemia vera and essential thrombocythemia. Clinical oncohematology. 2017;10(4):581–2, abstract. (In Russ)]
  43. Меликян А.Л., Туркина А.Г., Абдулкадыров К.М. и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз). Гематология и трансфузиология. 2014;59(4):31–56.[Melikyan AL, Turkina AG, Abdulkadyrov KM, et al. Clinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis). Gematologiya i transfuziologiya. 2014;59(4):31–56. (In Russ)]
  44. Меликян А.Л., Туркина А.Г., Ковригина А.М. и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз). Гематология и трансфузиология. 2017;62(1):25–60.[Melikyan AL, Turkina AG, Kovrigina AM, et al. Clinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis). Gematologiya i transfuziologiya. 2017;62(1):25–60. (In Russ)]
  45. Меликян А.Л., Суборцева И.Н. Биология миелопролиферативных новообразований. Клиническая онкогематология. 2016;9(3):314–25. doi: 10.21320/2500-2139-2016-9-314-325.[Melikyan AL, Subortseva IN. Biology of Myeloproliferative Malignancies. Clinical oncohematology. 2016;9(3):314–25. doi: 10.21320/2500-2139-2016-9-314-325. (In Russ)]
  46. Franca ER, Teixeira MA, Matias Kde F, et al. Cutaneous effects after prolongaded use of hydroxyurea in polycythemia vera. Bras Dermatol. 2011;86(4):751–4.
  47. Poros A, Nadasdy K. Leg ulcer in hydroxyurea-treated patients. Haematologia. 2000;30:313–8. doi: 10.1163/156855900300109558.
  48. Yokota K, Tasaka T, Iwata K, et al. Huge postoperative ulcer following hydroxyurea therapy in a patient with polycythemia vera. Haematologica. 2003;88:ECR36.

Stevens-Johnson Syndrome after Treatment of Female Patient with Small Lymphocytic B-Cell Lymphoma, Autoimmune Hemolytic Anemia and Antiphospholipid Antibody Syndrome with Rituximab

COMPLICATIONS OF ANTITUMOR TREATMENT , , , , ,

AL Melikyan, IN Subortseva, AM Kovrigina, TI Kolosheinova, EK Egorova, EI Pustovaya

Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

For citation: Melikyan AL, Subortseva IN, Kovrigina AM, et al. Stevens-Johnson Syndrome after Treatment of Female Patient with Small Lymphocytic B-Cell Lymphoma, Autoimmune Hemolytic Anemia and Antiphospholipid Antibody Syndrome with Rituximab Clinical oncohematology. 2017;10(1): 120–7 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-120-127

ABSTRACT

Stevens-Johnson syndrome is a severe delayed type systemic allergic reaction which affects the skin and mucous membranes. In adults, Stevens-Johnson syndrome is usually caused by the administration of drugs or a malignant process. The paper presents a case of Stevens-Johnson syndrome after the treatment of a female patient with small lymphocytic B-cell lymphoma, autoimmune hemolytic anemia and antiphospholipid antibody syndrome with rituximab. A rare combination of Stevens-Johnson syndrome and small lymphocytic B-cell lymphoma of small lymphocytes, as well as the development of severe delayed type systemic allergic reaction to introduction of rituximab are of special interest. A detailed medical history and the clinical manifestations of the disease allowed to diagnose Stevens-Johnson syndrome at early stages and prescribe an adequate therapy. As a result of the treatment, the patient’s condition has improved considerably. Symptoms of general toxicity were arrested completely; there was a complete epithelization of erosive defects. Therefore, the presented clinical observation shows that timely diagnosis, complex drug therapy, and comprehensive care can cure the diseases as soon as possible and prevent complications.

Keywords: Stevens-Johnson syndrome, pathogenesis, clinical manifestations, diagnosis, treatment, rituximab.

Received: July 28, 2016

Accepted: December 6, 2016

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REFERENCES

  1. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803–13. doi: 10.1586/eci.11.66.
  2. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: A review. Crit Care Med. 2011;39(6):1521–32. doi: 10.1097/CCM.0b013e31821201ed.
  3. Yamane Y, Matsukura S, Watanabe Y, et al. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients—Treatment and outcome. Allergol Int. 2016;65(1):74–81. doi: 10.1016/j.alit.2015.09.001.
  4. Teh LK, Selvaraj M, Bannur Z, et al. Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02. J Pharm Pharm Sci. 2016;19(1):147–60. doi: 10.18433/J38G7X.
  5. Chung W-H, Hung S-I. Genetic Markers and Danger Signals in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Allergol Int. 2010;59(4):325–332 doi: 10.2332/allergolint.10-rai-0261.
  6. Chantaphakul H, Sanon T, Klaewsongkram J. Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Ther Med. 2015;10(2):519–24. doi: 10.3892/etm.2015.2549.
  7. Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. J Clin Epidemiol. 1996;49(7):769–73. doi: 10.1016/0895-4356(96)00035-2.
  8. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol. 2008;58(1):33–40. doi: 10.1016/j.jaad.2007.08.039.
  9. Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149–53. doi: 10.1046/j.1523-1747.2000.00061.x.
  10. Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. J Plast Reconstr Aesthet Surg. 2016;69(6):736–41. doi: 10.1016/j.bjps.2016.04.018.
  11. Tripathi A, Ditto AM, Grammer LC, et al. Corticosteroid therapy in an additional 13 cases of Stevens–Johnson syndrome: a total series of 67 cases. Allergy Asthma Proc. 2000;21(2):101–5. doi: 10.2500/108854100778250914.
  12. Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens–Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144–8. doi: 10.2340/00015555-0214.
  13. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282(5388):490–3. doi: 10.1126/science.282.5388.490.
  14. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens–Johnson syndrome: our current understanding. Int Immunopharmacol. 2006;6(4):543–9. doi: 10.1016/j.intimp.2005.11.012.
  15. Prins C, Kerdel FA, Padilla RS, et al. TEN-IVIG Study Group. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139(1):26–32. doi: 10.1001/archderm.139.1.26.
  16. Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis: analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean patients. Acta Derm Venereol. 2005;85:497–502.
  17. Bamichas G, Natse T, Christidou F, et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher. 2002;6(3):225–8. doi: 10.1046/j.1526-0968.2002.00409.x.
  18. Egan CA, Grant WJ, Morris SE, et al. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol. 1999;40(3):458–61. doi: 10.1016/S0190-9622(99)70497-4.
  19. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol. 1985;121(12):1548–9. doi: 10.1001/archderm.1985.01660120074023.
  20. Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS. Clinical review: Serious adverse events associated with the use of rituximab – a critical care perspective. Crit Care. 2012;16(4):231. doi: 10.1186/cc11304.
  21. Lowndes S, Darby A, Mead G, Lister A. Stevens-Johnson syndrome after treatment with rituximab. Ann Oncol. 2002;13(12):1948–50. doi: 10.1093/annonc/mdf350.
  22. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer. 2001;85(11):1619–23. doi: 10.1054/bjoc.2001.2127.
  23. Суборцева И.Н. Клинико-биологические особенности первичной экстранодальной диффузной В-крупноклеточной лимфомы: Дис. ¼ канд. мед. наук. М., 2013. 138 с.
    [Subortseva IN. Kliniko-biologicheskie osobennosti pervichnoi ekstranodal’noi diffuznoi B-krupnokletochnoi limfomy. (Clinical and biological features of the primary extranodal diffuse large B-cell lymphoma.) [dissertation] Moscow; 2013. 138 р. (In Russ)]
  24. Foran JM, Gupta RK, Cunningham D, et al. A UK multicentre phase II study of rituximab in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol. 2000;109(1):81–8. doi: 10.1046/j.1365-2141.2000.01965.x.
  25. Davis TA, White CA, Grillo-Lopez AJ, et al. Single agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17(6):1851–7.
  26. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90(6):2188–95.
  27. Piro LD, White CA, Grillo-Lopez AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1999;10:655–61.
  28. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukaemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001;19(8):2153–64.
  29. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med. 2001;345(13):1000. doi: 10.1056/NEJM200109273451315.
  30. Walewski J, Kraszewska E, Mioduszewska O, et al. Rituximab (MabtheraTM, RituxanTM) in patients with recurrent indolent lymphoma. Med Oncol. 2001;18(2):141–8. doi: 10.1385/mo:18:2:141.
  31. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. Burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23(2):87–96. doi: 10.1097/00004630-200203000-00004.
  32. Cummins DL, Mimouni D, Tzu J, et al. Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies. J Am Acad Dermatol. 2007;56(1):153–9. doi: 10.1016/j.jaad.2006.06.007.

 

Diagnostic and Prognostic Value of Biochemical Markers of Infectious Complications of High-Dose Therapy with Autologous Hematopoietic Stem Cell Transplantation in Malignant Lymphoproliferative Diseases

COMPLICATIONS OF ANTITUMOR TREATMENT , , , ,

VO Sarzhevskii, YuN Dubinina, VYa Mel’nichenko

NI Pirogov National Medical and Surgical Center under the Ministry of Health of the Russian Federation, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Dubinina YuN, Mel’nichenko VYa. Diagnostic and Prognostic Value of Biochemical Markers of Infectious Complications of High-Dose Therapy with Autologous Hematopoietic Stem Cell Transplantation in Malignant Lymphoproliferative Diseases. Clinical oncohematology. 2017;10(1):113–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-113-119

ABSTRACT

Aim. To evaluate diagnostic and prognostic value of C-reactive protein (CRP), procalcitonin (PCT) and presepsin (PSP) in patients with malignant lymphoproliferative disorders after a high-dose chemotherapy and auto-HSCT.

Methods. 28 patients were included in the study (20 women and 8 men; 12 of them with Hodgkin’s lymphoma, 6 with non-Hodgkin’s lymphomas, and 10 with multiple myeloma). The median age was 40 years (23–66 years). The conditioning regimens were CBV, BEAM or melphalan 200 mg/m2. PSP, PCT and CRP levels were evaluated on the day of admission (DA), D+1, D+3, D+7 and on the day of discharge (DD). Depending on the presence of infectious complications, the patients were divided into 2 groups: group 1 — patients without complications (n = 12), group 2 — patients with complications (n = 16). In group 2 there were 15 patients with febrile neutropenia (FN) and 1 with sepsis.

Results. The median (range) of FN development was 5.5 days. Median CRP level on the DA and the DD in group 1 was 2.25 mg/l (0.6–20.4) and 14.85 mg/l (3.7–50), respectively (p = 0.001), while in group 2 it was 3.2 mg/l (0.2–53) and 19.7 mg/l (5.1–152.2), respectively (p = 0.025). However, CRP did not significantly differ between groups 1 and 2 at any point of analysis. The study also demonstrated a significant increase in the PCT levels in both groups after allo-HSCT. Median PCT level on the DA and the DD in group 1 was 0.023 ng/ml (0.02–0.112) and 0.07 ng/mL (0.02–0.356), respectively (p = 0.04), and in group 2 — 0.039 ng/ml (0.02–0.158) and 0.106 ng/mL (0.045–3.67), respectively (p = 0.001). Comparison of PCT levels on study days demonstrated no significant difference between groups. On the DA the median PSP level in group 1 was 166.5 pg/ml (77.2–476), on the DD it was 199 pg/ml (90–298) (p = 0.78). Median PSP levels in group 2 on the DA (129 pg/ml, range 84.2–501) and also on the DD (288.5 pg/ml, range 83.4–1345) were significantly different (p = 0.03). In the comparative analysis of PSP in groups 1 and 2, there were no significant differences on the DA and on the D+1. Significant difference in PSP levels between the analyzed groups was on the D+3, D+7 and on the DA.

Conclusion. The preliminary data showed that PSP is the most sensitive marker of infectious complications in patients with lymphoproliferative diseases after auto-HSCT.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, infection, presepsin, procalcitonin, C-reactive protein.

Received: July 28, 2016

Accepted: December 10, 2016

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REFERENCES

  1. Bhatt VR, Loberiza FR Jr, Jing H, et al. Mortality patterns among recipients of autologous hematopoietic stem cell transplantation for lymphoma and myeloma in the past three decades. Clin Lymph Myel Leuk. 2015;15(7):409–15.e1. doi: 10.1016/j.clml.2015.02.024.
  2. Zhang W, Zhao Q, Huang H. Febrile neutropenic infection occurred in cancer patients undergoing autologous peripheral blood stem cell transplantation. Transplant Proc. 2015;47(2):523–7. doi: 10.1016/j.transproceed.2015.01.013.
  3. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065-71. doi: 10.1016/s0140-6736(02)08938-9.
  4. Massaro K, Macedo R, de Castro B, et al. Risk factor for death in hematopoietic stem cell transplantation: are biomarkers useful to foresee the prognosis in this population of patients? Infection. 2014;42(6):1023–32. doi: 10.1007/s15010-014-0685-2.
  5. Saarinen U, Strandjord S, Warkentin P, et al. Differentiation of presumed sepsis from acute graft-versus-host disease by C-reactive protein and serum total IgE in bone marrow transplant recipients. Transplantation. 1987;44(4):540–6. doi: 10.1097/00007890-198710000-00017.
  6. Bonig H, Schneider DT, Sprock I, et al. ‘Sepsis’ and multi-organ failure: predictors of poor outcome after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2000;25(Suppl 2):S32–4. doi: 10.1038/sj.bmt.1702350.
  7. Yonemori K, Kanda Y, Yamamoto R, et al. Clinical value of serial measurement of serum C-reactive protein level in neutropenic patients. Leuk Lymphoma. 2001;41(5–6):607–14. doi: 10.3109/10428190109060351.
  8. Hamalainen S, Kuittinen T, Matinlauri I, et al. Severe sepsis in autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome. Scand J Infect Dis. 2009;41(1):14–20. doi: 10.1080/00365540802454706.
  9. Assicot M, Bohuon C, Gendrel D, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341(8844):515–8. doi: 10.1016/0140-6736(93)90277-n.
  10. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004;39(2):206–17. doi: 10.1086/421997.
  11. Sbrana A, Torchio M, Comolli G, et al. Use of procalcitonin in clinical oncology: a literature review. New Microbiol. 2016;39(3):174–80.
  12. Massaro KS, Costa SF, Leone C, et al. Procalcitonin (PCT) and C-reactive protein (CRP) as severe systemic infection markers in febrile neutropenic adults. BMC Infect Dis. 2007;7(1):137. doi: 10.1186/1471-2334-7-137.
  13. Giamarellou H, Giamarellos-Bourboulis E, Repoussis P, et al. Potential use of procalcitonin as a diagnostic criterion in febrile neutropenia: experience from a multicentre study. Clin Microbiol Infect. 2004;10(7):628–33. doi: 10.1111/j.1469-0691.2004.00883.x.
  14. Koivula I, Hamalainen S, Jantunen E, et al. Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia. Scand J Infect Dis. 2011;43(6–7):471–8. doi: 10.3109/00365548.2011.554855.
  15. Camussi G, Mariano F, Biancone L, et al. Lipopolysaccharide binding protein and CD14 modulate the synthesis of platelet-activating factor by human monocytes and mesangial and endothelial cells stimulated with lipopolysaccharide. J Immunol. 1995;155:316–24.
  16. Shozushima T, Takahashi G, Matsumoto N, et al. Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. J Infect Chemother. 2011;17(6):764–9. doi: 10.1007/s10156-011-0254-x.
  17. Olad E, Sedighi I, Mehrvar A, et al. Presepsin (scd14) as a marker of serious bacterial infections in chemotherapy induced severe neutropenia. Iran J Pediatr. 2014;24(6):715–22.
  18. Koh H, Aimoto M, Katayama T, et al. Diagnostic value of levels of presepsin (soluble CD14-subtype) in febrile neutropenia in patients with hematological disorders. J Infect Chemother. 2016;22(7):466–71. doi: 10.1016/j.jiac.2016.04.002.
  19. Urbonas V, Eidukaite A, Tamuliene I. The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy-induced febrile neutropenia. Cytokine. 2013;62(1):34–7. doi: 10.1016/j.cyto.2013.02.030.
  20. Freifeld GA, Bow JE, Sepkowitz AK, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52(4): e56–93. doi: 10.1093/cid/cir073.

 

Arterial Events in Patients with Chronic Myeloid Leukemia Receiving Treatment with Second Generation Tyrosine Kinase Inhibitors

COMPLICATIONS OF ANTITUMOR TREATMENT , , ,

GA Gusarova, AG Turkina

Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Galina Anatol’evna Gusarova, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel: +7(495)612-16-36; e-mail: galina1966@bk.ru

For citation: Gusarova GA, Turkina AG. Arterial Events in Patients with Chronic Myeloid Leukemia Receiving Treatment with Second Generation Tyrosine Kinase Inhibitors. Clinical oncohematology. 2016;9(4):474–84 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-474-484

ABSTRACT

Target therapy of chronic myeloid leukemia (CML) by tyrosine kinase inhibitors (TKI) allows to achieve high rates of the overall survival in CML. The choice of TKI treatment in every particular case should be based on individual CML patient’s characteristics, including comorbidities and the risk of adverse events (AE). Every TKI has a particular toxicity profile depending on off-target action spectrum. A probability of arterial AEs on TKI therapy is comparatively low but they may be life threatening. It is highly important to evaluate this kind of AEs during a long period of vascular TKI exposure. The age-specific increased incidence of cardiovascular and respiratory diseases is an additional factor in these patients with high overall survival on TKI therapy. The article is devoted to the analysis of frequency, mechanisms, particular features, methods of diagnostics and treatment of arterial AEs emerging on second generation TKI (nilotinib and dasatinib) therapy. The detailed characteristics of arterial occlusive events on nilotinib therapy and pulmonary arterial hypertension on dasatinib are presented. Special attention is paid to the analysis of risk factors of vascular AEs and the ways to correct modified risk factors. Timely assessment of clinical symptoms of cardiopulmonary, ischemic diseases/complications, and metabolic disorders helps to find specialized medical care (by a cardiologist, pulmonologist, endocrinologist), to prescribe an adequate therapy, provide prevention of complications and make decision about TKI dose adjustment/switching to alternative TKI being a true foundation of safe personalized treatment in CML patients.

Keywords: tyrosine kinase inhibitors, artery occlusion, atherosclerosis, pulmonary hypertension.

Received: May 24, 2016

Accepted: June 16, 2016

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REFERENCES

  1. Hochhaus A, O’Brien SC, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23(6):1054–61. doi: 10.1038/leu.2009.38.
  2. Martinelli G, Soverini S, Rosti G, et al. New tyrosine kinase inhibitors in chronic myeloid leukemia. Haematologica. 2005;90:534–41.
  3. Deiniger MW. Optimizing therapy of chronic myeloid leukemia. Exp Hematol. 2007;35(4):144–54. doi: 10.1016/j.exphem.2007.01.023.
  4. Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiling of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib reveal different interaction networks and novel kinase and non-kinase targets. Blood. 2007;110(12):4055–63. doi: 10.1182/blood-2007-07-102061.
  5. Drueckes P, Fendrich G, Furet P, et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804(3):445–53. doi: 10.1016/j.bbapap.2009.11.008.
  6. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. 2011;117(4):1141–5. doi: 10.1182/blood-2010-03-277152.
  7. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–70. doi: 10.1056/nejmoa0912614.
  8. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. doi: 10.1056/nejmoa055104.
  9. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037.
  10. Tefferi A, Letendre L. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am J Hematol. 2011;86(7):610–1. doi: 10.1002/ajh.22051.
  11. Quintas-Gardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymph Myel Leuk. 2012;12(5):337–40. doi: 1016/j.clml.2012.04.005.
  12. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004. doi: 10.1056/nejmoa022457.
  13. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly-diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28(3):424–30. doi: 10.1200/jco.2009.25.3724.
  14. Giles FG, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 2013;27(6):1310–5. doi: 10.1038/leu.2013.69.
  15. Le Coutre P, Rea D, Abruzzese H, et al. Severe peripheral artery disease during nilotinib therapy. J Natl Cancer Inst. 2011;103(17):1347–8. doi: 10.1093/jnci/djr292.
  16. Schwarz M, Kim TD, Mirault N, et al. Elevated risk of peripheral artery occlusive disease (PAOD) in nilotinib treated chronic phase chronic myeloid leukemia (CML) patients assessed by ankle-brachial-index (ABI) and duplex ultrasonography. 54 ASH Meeting and Exposition. 2012: abstract 914.
  17. Saglio G, Hochhaus, Huges TP, et al. ENESTnd Update: nilotinib (NIL) vs imatinib (IM) in patients (PTS) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and the impact of early molecular response (EMR) and Sokal risk at diagnosis on long-term outcomes. Blood. 2013;122(21): Abstract 92.
  18. Hadzijusufovic E, Albrect-Schgoer K, Huber K, et al. Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells: a potentional explanation for drug-induced vasculopathy in CML. Blood. 2013;122(12): Abstract 257.
  19. Rea D, Mirault T, Raffoux E, et al. Peripheral arterial occlusive disease (PAOD) in chronic phase chronic myeloid leukemia patients treated with nilotinib. Blood. 2013;122(21): Abstract 4018.
  20. Larson RA, Kim D-W, Jootar S, et al. ENESTnd 5 years (y) update: long-term outcomes of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib (NIL) versus imatinib (IM). J Clin Oncol. 2014;32(5s): Abstract 7073.
  21. Cortes JE, Saglio G, Baccarani M, et al. Final study results of the phase 3 Dasatinib versus Imatinib in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) trial (DASISION, CA 180-056). Blood. 2014;124(21):152.
  22. Hehlmann R, Lauseker M, Schreiber A, et al. Adverse events (AE) under imatinib treatment over 10 years: results from 1501 patients of the randomized CML-study IV. Blood. 2013;122(12): Abstract 4012.
  23. Lassila M. Imatinib attenuates diabetes-associates atherosclerosis. Atheroscler Tromb Vasc Biol. 2014;24(5):935–42. doi: 10.1161/01.atv.0000124105.39900.db.
  24. Rea D, Mirault T, Cluzeau T, et al. Early onset hypercholesterolemia induced by the 2nd generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Hematologica. 2014;99(7):1197–203. doi: 10.3324/haematol.2014.104075.
  25. Britto K, Wong E, Hou G, et al. Discoidin domain receptor 1 on bone marrow-derived cells promotes macrophage accumulation during atherogenesis. Circ Res. 2009;105(11):1141–8. doi: 10.1161/circresaha.109.207357.
  26. Franco C, Ahmad PJ, Hou G, et al. Increased cell and matrix accumulation during atherogenesis in mice with vessel wall-specific deletion of discoidin domain receptor 1. Circ Res. 2010;106(11):1775–83. doi: 10.1161/circresaha.109.213637.
  27. Breccia M, Muscaritoli M, Gentilini F, et al. Impaired fasting glucose level as metabolic effect of nilotinib in non-diabetic chronic myeloid leukemia patients resistant to imatinib. Leuk Res. 2007;31(12):1770–2. doi: 10.1016/j.leukres.2007.01.024.
  28. Крюков Н.Н., Николаевский Е.Н., Поляков В.П. Ишемическая болезнь сердца (Современные аспекты клиники, диагностики, лечения). Самара, 2010. 651 с.
    [Kryukov NN, Nikolaevskii EN, Polyakov VP. Ishemicheskaya bolezn’ serdtsa (Sovremennye aspekty kliniki, diagnostiki, lecheniya) (Coronary artery disease (Current aspects of clinical presentation, diagnosis, and treatment).) Samara; 2010. 651 p. (In Russ)]
  29. Pennywell DJ, Tan T-Z, Zhang WW. Optimal management of infrainguinal arterial occlusive disease. Vasc Health Risk Manag. 2014;10:599–608. doi: 10.2147/vhrm.s50779.
  30. Национальное общество по изучению атеросклероза (НОА), Российское кардиологическое общество (РКО), Российское общество кардиосоматической реабилитации и вторичной профилактики (РосОКР). Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, V пересмотр. М., 2012.
    [National Society of Atherosclerosis (NSA), Russian Cardiological Society (RCS), Russian Society of Cardiosomatic Rehabilitation and Secondary Prophylaxis (RSCR). Diagnosis and treatment of lipid metabolism impairment for prevention and treatment of atherosclerosis. National Guidelines, V edition. Moscow; 2012. (In Russ)]
  31. Мамедова Н.М., Чепурина Н.А. Суммарный сердечно-сосудистый риск: от теории к практике. Пособие для врачей. М., 2007.
    [Mamedova NM, Chepurina NA. Summarnyi serdechno-sosudistyi risk: ot teorii k praktike. Posobie dlya vrachei. (Overall cardiovascular risk: from theory to practice.) Moscow; 2007. (In Russ)]
  32. Valent P, Hadzijusufovich E, Schernthaner G-H, et al. Vascular safety issues in CML patients treated with BCR/ABL 1 kinase inhibitors. Blood. 2015;125(6):901–6. doi: 10.1182/blood-2014-09-594432.
  33. Valent P. Severe adverse events associated with the use of second-line BCR/ABL tyrosine kinase inhibitors: preferential occurrence in patients with comorbidities. Hematologica. 2011;96(10):1395–7.
  34. Всероссийское научное общество кардиологов. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, IV пересмотр. М., 2009.
    [Russian Scientific Cardiologists’ Society. Diagnosis and treatment of lipid metabolism impairment for prevention and treatment of atherosclerosis. National Guidelines, IV edition. Moscow; 2009. (In Russ)]
  35. Gardner AW, Poehlman ET. Exercise rehabilitation program for the treatment of claudication pain. A meta-analysis. 1995;274(12):975–80. doi: 10.1001/jama.1995.03530120067043.
  36. Tasigna [prescribing Information]. East Hanover, NJ: Novartis Pharmaceutical Corp.; 2015. [Internet] Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022068s0211bl.pdf (accessed 15.06.2016).
  37. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of а phase 3 study. Blood. 2014;123(15):2317–24. doi: 10.1182/blood-2013-10-532341.
  38. Shah NP, Cortes JE, Schiffer CA, et al. Four-year follow-up patients with chronic myeloid leukemia receiving 100 mg of dasatinib once daily. J Сlin Oncol. 2010;28(Suppl): Abstract
  39. Гусарова Г.А., Туркина А.Г., Воронцова А.В. и др. Отдаленные результаты терапии дазатинибом и анализ особенностей течения плеврального выпота у больных в поздней хронической фазе хронического миелолейкоза после неудачи лечения иматинибом. Бюллетень СО РАМН. 2014;34(6):27–35.
    [Gusarova GA, Turkina AG, Vorontsova AV, et al. Long-term results of therapy by dasatinib and features analysis of the pleural effusion course in patients at late chronic phase of chronic myeloid leukemia after imatinib treatment failure. Byulleten’ SO RAMN. 2014;34(6):27–35. (In Russ)]
  40. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908–14. doi: 1200/jco.2007.12.0329.
  41. Mattei D, Feola M, Orzan F, et al. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant. 2009;43(12):967–8. doi: 10.1038/bmt.2008.415.
  42. Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res. 2009;33(6):861–4. doi: 10.1016/j.leukres.2008.09.026.
  43. Dumitrescu D, Seck C, Ten Freyhaus H, et al. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J. 2011;38(1):218–20. doi: 10.1183/09031936.00154210.
  44. Hennigs JK, Keller G, Baumann HJ, et al. Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension? BMC Pulm Med. 2011;11(1):30. doi: 10.1186/1471-2466-11-30.
  45. Philibert L, Cazorla C, Peyriere H, et al. Pulmonary arterial hypertension induced by dasatinib: positive reintroduction with nilotinib. Fund Clin Pharmacol. 2011;25:95.
  46. Orlandi EM, Rocca B, Pazzano AS, Ghio S. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res. 2012;36(1):e4–e6. doi: 10.1016/j.leukres.2011.08.007.
  47. Sano M, Saotome M, Urushida T, et al. Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia: critical alert. Intern Med. 2012;51(17):2337–40. doi: 10.2169/internalmedicine.51.7472.
  48. Groeneveldt JA, Gans SJM, Bogaard HJ, Vonk-Noordegraaf A. Dasatinib-induced pulmonary arterial hypertension unresponsive to PDE-5 inhibition. Eur Respir J. 2013;42(3):869–70. doi: 10.1183/09031936.00035913.
  49. Kim JC, Shin SH, Yi HG, et al. Rapid-onset pulmonary arterial hypertension in a patient with acute lymphoblastic leukemia treated dasatinib. Herz. 2013;38(8):931–3. doi: 10.1007/s00059-013-3765-7.
  50. Patkowska E, Lech-Maranda E, Darocha S, et al. Reversible pulmonary arterial hypertension as a complication of dasatinib treatment, with efficacious and safe continuation of chronic myeloid leukaemia therapy with nilotinib. Hematologica. 2013;4(1):76–83.
  51. Buchelli Ramirez HL, Alvarez Alvarez CM, Rodriguez Reguero JJ, et al. Reversible pre-capillary pulmonary hypertension due to dasatinib. Respir Care. 2014;59(5):e77–e80. doi: 10.4187/respcare.02692.
  52. Khaid M, Hakemi E. Concominant development of pleural effusion and pulmonary arterial hypertension in a patient treated with dasatinib. Chest. 2014;146(4):893A. doi: 10.1378/chest.1995250.
  53. Tacoy G, Cengel A, Ozkurt ZN, et al. Dasatinib-induced pulmonary hypertension in acute lymphoblastic leukemia: case report. Turk Dern Ars. 2015;43(1):78–81. doi: 10.5543/tkda.2015.41763.
  54. Wang HC, Lee CS, Liu TC. Reversible dasatinib-related pulmonary arterial hypertension diagnosed by noninvasive echocardiography. Kaohsiung J Med Sci. 2015;31(3):165–6. doi: 10.1016/j.kjms.2014.11.010.
  55. Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128–37. doi: 10.1161/circulationaha.111.079921.
  56. Saglio G, Le Coutre P, Cortes J, et al. Safety and tolerability of dasatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (PH+ ALL), pooled analysis of over 2400 patients. Poster presented at: The 19th Congress of the European Hematology Association (EHA) Annual Meeting; June 12–15, 2014; Milan, Italy.
  57. Simmonneau G, Robbins I, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1):43–4. doi: 10.1016/j.jacc.2009.04.012.
  58. Shah NP, Wallis N, Farber HW. Clinical feature of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90(11):1060–4. doi: 10.1002/ajh.24174.
  59. US Food and Drug Administration. FDA Adverse Event Reporting System. US Food and Drug Administration, Silver Spring, MD. [Internet] Available from: http://www.fda.gov/cder/aers/default.htm (accessed 10.04.2015).
  60. Hoeper MM, Barst RJ, Bourge, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMP RES study. Circulation. 2013;127(10):1128–38. doi: 10.1161/circulationaha.112.000765.
  61. Novartis Efficacy, safety, tolerability and pharmacokinetics (pk) of nilotinib (AMN 107) in pulmonary arterial hypertension (PAH). [Internet] Available from: http://clinicaltrials.gov/ct2/show/NCT01179737 (accessed 20.04.2015).
  62. Al-Naamani N, Roberts KE, Hill NS, Preston IR. Imatinib as rescue therapy in a patient with pulmonary hypertension associated with Gaucher disease. Chest. 2014;146(3):e81– doi: 10.1378/chest.13-2795.
  63. Galie N, Humbert M, Vachiery J-L, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2015;37(1):67– doi: 10.1093/eurheartj/ehv317.
  64. Sprycel [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2015. [Internet] Available from: http://packageinserts.bms.com/pi/pi_sprycel.pdf (accessed 15.06.2016).
  65. Садыкова Д.И. Современные подходы к диагностике и лечению легочной гипертензии. Практическая медицина. 2012;7(62):21–6.
    [Sadykova DI. Modern approaches to diagnostic and treatment of pulmonary hypertension. Prakticheskaya meditsina. 2012;7(62):21–6. (In Russ)]
  66. Godinas L, Guingabert C, Seferian A, et al. Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword? Semin Respir Crit Care Med. 2013;34(5):714–24. doi: 10.1055/s-0033-1356494.
  67. Galie N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. The task force for the diagnosis and treatment of pulmonary hypertension of the ECS and ERS, endorsed by the ISHLT. Eur Heart J. 2009;30(20):2493–537. doi: 1093/eurheartj/ehp297.

 

Biochemical Markers of Cardiotoxicity of High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with Malignant Lymphoproliferative Disorders

COMPLICATIONS OF ANTITUMOR TREATMENT , ,

VO Sarzhevskii, DS Kolesnikova, VYa Mel’nichenko

NI Pirogov National Medical and Surgical Center, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Kolesnikova DS, Mel’nichenko VYa. Biochemical Markers of Cardiotoxicity of High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with Malignant Lymphoproliferative Disorders. Clinical oncohematology. 2016;9(4):465–73 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-465-473

ABSTRACT

Background. High-dose chemotherapy (HDCT) with autologous hematopoietic stem cells transplantation (auto-HSCT) is an effective therapeutic option for patients with Hodgkin’s lymphoma and aggressive non-Hodgkin’s lymphomas in those cases, when the standard chemotherapy combined with the radiation therapy proves to be ineffective. The HDCT and auto-HSCT are also basic treatment options for multiple myeloma. However, toxic effects of the transplantation, including cardiotoxicity, may significantly worsen the prognosis of patients who receive this treatment.

Aim. To evaluate changes in biochemical markers of cardiotoxicity (troponin and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) in patients with malignant lymphomas (receiving HDCT and auto-HSCT).

Materials & Methods. 157 patients were enrolled in the study. The sensitivity threshold of the troponin T test was 0.1 ng/mL and troponin I 0.001 ng/mL (highly sensitive troponin). Troponin T (conventional troponin) was measured in 56 patients, troponin I was assessed in 101 patients. Serum troponin levels were evaluated before the conditioning, on D0, D+7, and D+12. The level of NT-proBNP was assessed before the conditioning, on D0 and D+12.

Results. Increased troponin T level was observed in 2 of 56 patients (3.6 %), increased troponin I level — in 27 of 101 patients (26.7 %) (p < 0.01). Troponin levels were within normal limits in all patients at admission. Troponin T levels increased only on D+7. Troponin I level increased in 4 patients (4 %) on D0, in 17 patients (16.8 %) on D+7 and in 11 patients (10.9 %) on D+12. The median concentration of troponin I was 0.215 ng/mL after HDCT completion, 0.74 ng/mL on D+7 and 0.21 ng/mL on D+12. No cases of myocardial infarction were observed. NT-proBNP levels in most patients were within normal limits at admission (median level 79.2 pg/mL). The situation changed significantly after conditioning: in most patients the level was almost twice as high as the upper normal limit (medial 240.6 pg/mL). Significant differences in levels of NT-proBNP (p < 0.05) were observed at comparison of data before conditioning and D0, and before conditioning and D+12.

Conclusion. The data obtained confirm a significant impact of HDCT and auto-HSCT on the cardiovascular system of patients with malignant lymphomas. Further studies and observation of the patients are needed to clarify the prognostic significance of the findings related to cardiotoxicity (in particular, congestive heart failure).

Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, cardiotoxicity, troponin, NT-proBNP.

Received: June 13, 2016

Accepted: June 14, 2016

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REFERENCES

  1. Blay J, Gomez F, Sebban C, et al. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood. 1998;92(10):3562–8.
  2. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065–71. doi: 10.1016/s0140-6736(02)08938-9.
  3. NCCN Guidelines Version 3.2016, Non-Hodgkin’s lymphomas. pр. 56, 65. [Internet] Available from: https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf (accessed 14.06.2016).
  4. NCCN Guidelines Version 2.2016, Hodgkin lymphoma. pp. 20 [Internet]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf (accessed 14.06.2016).
  5. Cazin B, Gorin NC, Laporte JP, et al. Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer. 1986;57(10):2061–9. doi: 10.1002/1097-0142(19860515)57:10<2061::aid-cncr2820571031>3.0.co;2-h.
  6. Murdych T, Weisdorf DJ. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977–1997. Bone Marrow Transplant. 2001;28(3):283–7. doi: 10.1038/sj.bmt.1703133.
  7. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(3):337–41. doi: 10.1038/bmt.2012.5.
  8. Chi AK, Soubani AO, White AC, et al. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest. 2013;144(6):1913–22. doi: 10.1378/chest.12-1708.
  9. Chow EJ, Wong K, Lee SJ, et al. Late cardiovascular complications after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20(6):794–800. doi: 10.1016/j.bbmt.2014.02.012.
  10. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol. 2000;36(2):517–22. doi: 10.1016/S1062-1458(00)00186-0.
  11. Cardinale D, Sandri MT, Martinoni A, et al. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol. 2002;13(5):710–5. doi: 10.1093/annonc/mdf170.
  12. Sandri MT, Cardinale D, Zorzino L, et al. Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high-dose chemotherapy. Clin Chem. 2003;49(2):248–52. doi: 10.1373/49.2.248.
  13. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003;82(4):218–22.
  14. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749–54. doi: 10.1161/01.cir.0000130926.51766.cc.
  15. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351(2):145–53. doi: 10.1056/nejmoa035153.
  16. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005;16(5):798–804. doi: 10.1093/annonc/mdi152.
  17. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96(8):2641–8. doi: 10.1161/01.cir.96.8.2641.
  18. Suzuki T, Hayashi D, Yamazaki T, et al. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J. 1998;136(2):362–3. doi: 10.1053/hj.1998.v136.89908.
  19. Nousiainen T, Jantunen E, Vanninen E, et al. Acute neurohumoral and cardiovascular effects of idarubicin in leukemia patients. Eur J Haematol. 1998; 61(5):347–53. doi: 10.1111/j.1600-0609.1998.tb01099.x.
  20. Snowden JA, Hill GR, Hunt P, et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000;26(3):309–13. doi: 10.1038/sj.bmt.1702507.
  21. Chung T, Lim W-C, Sy R, et al. Subacute cardiac toxicity following autologous haematopoietic stem cell transplantation in patients with normal cardiac function. Heart. 2008;94(7):911–8. doi: 10.1136/hrt.2007.123299.
  22. Horacek JM, Pudil R, Tichy M, et al. Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia. Exp Oncol. 2007;29(3):243–7.
  23. Masuko M, Ito M, Kurasaki T, et al. Plasma brain natriuretic peptide during myeloablative stem cell transplantation. Intern Med. 2007;46(9):551–5. doi: 10.2169/internalmedicine.46.6188.
  24. Zver S, Zadnik V, Bunc M, et al. Cardiac toxicity of high-dose cyclophosphamide in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Int J Hematol. 2007;85(5):408–14. doi: 10.1532/ijh97.e0620.

 

Single-Photon Emission Computed Tomography Synchronized with ECG as Method for Evaluation of Cardiotoxicity of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoproliferative Disorders

COMPLICATIONS OF ANTITUMOR TREATMENT , , ,

VO Sarzhevskii, DS Kolesnikova, MN Vakhromeeva, VYa Mel’nichenko

N.I. Pirogov National Medical and Surgical Center under the Ministry of Health of the Russian Federation, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Kolesnikova DS, Vakhromeeva MN, Mel’nichenko VYa. Single-Photon Emission Computed Tomography Synchronized with ECG as Method for Evaluation of Cardiotoxicity of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoproliferative Disorders. Clinical oncohematology. 2015;8(1):84–90 (In Russ).

ABSTRACT

Background. High-dose chemotherapy (HDC) with autologous hematopoietic stem cells transplantation (auto-HSCT) is currently widely used for the treatment of relapsed and refractory to standard chemotherapy cases of malignant lymphoproliferative disorders. Cardiac monitoring of patients treated with HDC with subsequent auto-HSCT is performed by means of ECG and Echo-CG in most cases. The method of single-photon emission computed tomography of the left ventricle (LV) synchronized with ECG (gated-SPECT) is rarely used to assess cardiotoxic effect of HDC and auto-HSCT.

Objective. To evaluate perfusion and regional myocardial function of the left ventricle (LV) in patients with malignant lymphomas receiving HDC and auto-HSCT.

Methods. The study included 69 patients (37 with Hodgkin’s lymphoma, 19 with non-Hodgkin’s lymphoma, and 13 with multiple myeloma). The median age was 36 year (range from 19 to 66 years); 40 females, 29 males. Perfusion and regional LV function at rest before the HDC and auto-HSCT (point 1) and at discharge (point 2) were assessed. Each study was performed on a double-headed rotating gamma camera Forte (Philips, USA). 740 MBq of technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) was used as a radiopharmaceutical. Semiquantitative assessment of tomoscintigrams was performed using polar diagrams (20-segment model); they were used for complex analysis of perfusion and LF myocardium function parameters.

Results. The total area of hypoperfusion, expressed as a percentage of the area of the LV myocardium, did not change significantly during treatment (p > 0.05). However, the segmental analysis demonstrated a statistically significant decrease in the median uptake level of the radiopharmaceutical in 1, 2, 4, 7, 8, 10, 13, 16, 17, and 19 segments (p < 0.05). The total ejection fraction (TEF) did not change (median TEF was 59.5 % at point 1 and 58 % at point 2). But it showed a statistically significant decrease in median of local systolic thickening in 2, 3, 5, 7, 8, 9, 10, 11, 12, 15, 17, 18, 19, and 20 segments of the left ventricle (p < 0.05).

Conclusions. HDC and auto-HSCT significantly change perfusion and regional LV myocardial function in patients with malignant lymphomas. The changes demonstrate diffuse myocardial damage. Gated-SPECT can be considered a promising method for assessing cardiotoxicity of HDC and auto-HSCT.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, cardiotoxicity, gated-SPECT.

Received: July 23, 2014

Accepted: November 5, 2014

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REFERENCES

  1. Passweg JR, Baldomero H, Peters C, et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant. 2014;49(6):744–50. doi: 10.1038/bmt.2014.55.
  2. Popplewell LL, Forman SJ. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transplant. 2002;29(4):277–84. doi: 10.1038/sj.bmt.1703382.
  3. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114(3):600–7. doi: 10.1046/j.1365-2141.2001.02976.x.
  4. Germano G, Kiat H, Kavanagh P, et al. Automatic quantification and review of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med. 1995;36:2138–47.
  5. Germano G, Kavanagh P, Berman D, et al. An automatic approach to the analysis quantification and review of perfusion and function from myocardial perfusion SPECT imaging. Intern J Card Im. 1997;13(4):337–46.
  6. Girinsky T, Cordova A, Rey A, et al. Thallium-201 scintigraphy is not predictive of late cardiac complications in patients with Hodgkin’s disease treated with mediastinal radiation. Int J Radiat Oncol Biol Phys. 2000;48(5):1503–6. doi: 10.1016/s0360-3016(00)00807-5.
  7. Glanzmann C, Kaufmann P, Jenni R, et al. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol. 1998;46(1):51–62. doi: 10.1016/s0167-8140(97)00125-4.
  8. Gustavsson A, Eskilsson J, Landberg T, et al. Late cardiac effects after mantle radiotherapy in patients with Hodgkin’s disease. Ann Oncol. 1990;1:355–63.
  9. Salloum E, Jillella AP, Nadkarni R, et al. Assessment of pulmonary and cardiac function after high dose chemotherapy with BEAM and peripheral blood progenitor cell transplantation. Cancer. 1998;82(8):1506–12. doi: 10.1002/(sici)1097-0142(19980415)82:8<1506::aid-cncr12>3.0.co;2-8.
  10. Hertenstein B, Stefanic M, Schmeiser T, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. 1994;12(5):998–1004.
  11. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749–54. doi: 10.1161/01.cir.0000130926.51766.cc.
  12. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003;82(4):218–22.
  13. Pihkala J, Saarinen UM, Lundstrоm U, et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant. 1994;13(2):149–55.
  14. Zver S, Zadnik V, Cernelc P, et al. Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Int J Hematol. 2008;88(2):227–36. doi: 10.1007/s12185-008-0112-5.

Gastrointestinal Complications after High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in Oncohematological Patients

COMPLICATIONS OF ANTITUMOR TREATMENT , ,

V.O. Sarzhevskiy, E.G. Smirnova, V.Yа. Melnichenko

N.I. Pirogov National Medical and Surgical Centre of RF MH, Moscow, Russian Federation

For citation: Sarzhevskiy V.O., Smirnova E.G., Mel’nichenko V.Ya. Gastrointestinal Complications after High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in Oncohematological Patients. Klin. onkogematol. 2014; 7(3): 343–53 (In Russ.).

ABSTRACT

Different gastrointestinal disorders with different degrees of severity are diagnosed in almost all oncohematological patients receiving the high-dose chemotherapy (HDC) with autologous bone marrow transplantation (transplantation of peripheral hematopoietic stem cells). The mentioned disorders (mucositis) significantly impair the quality of life, promote the development of infectious complications, and, in some cases, can cause a lethal outcome. Authors emphasize the importance of GIT disorders due to HDC with autologous bone marrow transplantation, present etiological and pathogenetic factors of mucosites and give a detailed description of the clinical evaluation, test methods, prevention and treatment of such transplantation complications in oncohematological patients.

Keywords: high dose chemotherapy, autologous bone marrow transplantation, mucositis.

Address correspondence to: vladsar@pochta.ru

Accepted: May 26, 2014

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REFERENCES

  1. Damon L., Rugo H., Tolaney S. et al. Cytoreduction of lymphoid malignancies and mobilization of blood hematopoietic progenitor cells with high doses of cyclophosphamide and etoposide plus filgrastim. Biol. Blood Marrow Transplant. 2006; 12(3): 316–24.
  2. Bishton M.J., Lush R.J., Byrne J.L. et al. Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant-eligible patients with non-Hodgkin lymphoma and Hodgkin disease. Br. J. Haematol. 2007; 136(5): 752–61.
  3. Milone G., Leotta S., Battiato K. et al. Intermediate dose etoposide plus G-CSF 16 g/kg is more effective than cyclophosphamide 4 g/m(2) plus G-CSF 10 g/kg in PBSC mobilization of lymphoma patients. Leuk. Lymphoma 2007; 48(10): 1950–60.
  4. Lu H., Li J.Y., Ge Z. et al. High-dose etoposide with granulocyte colonystimulating factor for mobilization of autologous peripheral blood stem/progenitor cells in patients with hematologic malignancies. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006; 14(2): 397–9.
  5. Bolwell B.J., Kalaycio M., Sobecks R. et al. A multivariable analysis of factors influencing mucositis after autologous progenitor cell transplantation. Bone Marrow Transplant. 2002; 30(9): 587–91.
  6. Grazziutti M.L., Dong L., Miceli M.H. et al. Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model. Bone Marrow Transplant. 2006; 38(7): 501–6.
  7. Blijlevens N., Schwenkglenks M., Bacon P. et al. Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy—European Blood and Marrow Transplantation Mucositis Advisory Group. J. Clin. Oncol. 2008; 26(9): 1519–25.
  8. Blanes M., Lahuerta J.J., Gonzalez J.D. et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach. Biol. Blood Marrow Transplant. 2013; 19(1): 69–74.
  9. Jantunen E., Kuittinen T., Nousiainen T. et al. BEAC or BEAM for high-dose therapy in patients with non-Hodgkin’s lymphoma? A single centre analysis on toxicity and efficacy. Leuk. Lymphoma 2003; 44(7): 1151–8.
  10. Jo J.C., Kang B.W., Jang G. et al. BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: comparative analysis of efficacy and toxicity. Ann. Hematol. 2008; 87(1): 43–8.
  11. Kim J.E., Lee D.H., Yoo C. et al. BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: a single center comparative analysis of efficacy and toxicity. Leuk. Res. 2011; 35(2): 183–7.
  12. Dean R.M., Pohlman B., Sweetenham J.W. et al. Superior survival after replacing oral with intravenous busulfan in autologous stem cell transplantation for non-Hodgkin lymphoma with busulfan, cyclophosphamide and etoposide. Br. J. Haematol. 2010; 148(2): 226–34.
  13. Spielberger R., Stiff P., Bensinger W. et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N. Engl. J. Med. 2004; 351(25): 2590–8.
  14. Krishnan A., Palmer J.M., Tsai N.C. et al. Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy versus total body irradiation-based conditioning for poor-risk diffuse large cell lymphoma. Biol. Blood Marrow Transplant. 2012; 18(3): 441–50.
  15. Paris F., Fuks Z., Kang A. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293: 293–7.
  16. Wearing H.J., Sherratt J.A. Keratinocyte growth factor signaling: a mathematical model of dermalepidermal interaction in epidermal wound healing. Math. Biosci. 2000; 165: 41–62.
  17. Sonis S. Pathobiology of oral mucositis: novel insights and opportunities. J. Supp. Oncol. 2007; 5: 3–11.
  18. Wardley A.M., Jayson G.C., Swindell R. et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br. J. Haematol. 2000; 110(2): 292–9.
  19. Vokurka S., Bystricka E., Koza V. et al. Higher incidence of chemotherapy induced oral mucositis in females: a supplement of multivariate analysis to a randomized multicentre study. Supp. Care Cancer 2006; 14(9): 974–6.
  20. Hahn T., Zhelnova E., Sucheston L. et al. A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol. Blood Marrow Transplant. 2010; 16(6): 801–8.
  21. Grazziutti M.L., Dong L., Miceli M.H. et al. Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model. Bone Marrow Transplant. 2006; 38(7): 501–6.
  22. Krishna S.G., Zhao W., Grazziutti M.L. et al. Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications. Cancer 2011; 117(3): 648–55.
  23. Bensinger W., Schubert M., Ang K.K. et al. NCCN Task Force Report: prevention and management of mucositis in cancer care. J. Natl. Compr. Cancer Netw. 2008; 6(Suppl. 1): S1–21.
  24. Atkinson K., Champlin R., Ritz J. et al. (eds.) Clinical Bone Marrow and Blood Stem Cell Transplantation, 3rd edn. Cambridge University Press, 2004: 276–7.
  25. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Published August 9, 2006. Available at: www.ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf.
  26. Forbes G.M., Rule S.A., Herrmann R.P. et al. A prospective study of screening upper gastrointestinal (GI) endoscopy prior to and after bone marrow transplantation (BMT). Aust. N. Z. J. Med. 1995; 25(1): 32–6.
  27. Vishny M.L., Blades E.W., Creger R.J. et al. Role of upper endoscopy in evaluation of upper gastrointestinal symptoms in patients undergoing bone marrow transplantation. Cancer Invest. 1994; 12(4): 384–9.
  28. Tsirigotis P., Triantafyllou K., Girkas K. et al. Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study. Bone Marrow Transplant. 2008; 42(5): 337–43.
  29. Avivi I., Avraham S., Koren-Michowitz M. et al. Oral integrity and salivary profile in myeloma patients undergoing high-dose therapy followed by autologous SCT. Bone Marrow Transplant. 2009; 43(10): 801–6.
  30. Blijlevens N.M., Donnelly J.P., de Pauw B.E. Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant. Bone Marrow Transplant. 2005; 35(7): 707–11.
  31. Johansson J.E., Brune M., Ekman T. The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensity conditioning. Bone Marrow Transplant. 2001; 28(8): 737–42.
  32. van Kraaij M.G., Dekker A.W., Verdonck L.F. et al. Infectious gastroenteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients. Bone Marrow Transplant. 2000; 26(3): 299–303.
  33. Chakrabarti S., Collingham K.E., Stevens R.H. et al. Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study. Bone Marrow Transplant. 2000; 25(3): 277–82.
  34. Davila M.L. Neutropenic enterocolitis. Curr. Opin. Gastroenterol. 2006; 22(1): 44–7.
  35. Ullery B.W., Pieracci F.M., Rodney J.R. et al. Neutropenic enterocolitis. Surg. Infect. (Larchmt.) 2009; 10(3): 307–14.
  36. Arango J.I., Restrepo A., Schneider D.L. et al. Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma. Bone Marrow Transplant. 2006; 37(5): 517–21.
  37. Tomblyn M., Gordon L., Singhal S. et al. Rarity of toxigenic Clostridium difficile infections after hematopoietic stem cell transplantation: implications for symptomatic management of diarrhea. Bone Marrow Transplant. 2002; 30(8): 517–9.
  38. Avery R., Pohlman B., Adal K. et al. High prevalence of diarrhea but infrequency of documented Clostridium difficile in autologous peripheral blood progenitor cell transplant recipients. Bone Marrow Transplant. 2000; 25(1): 67–9.
  39. Ramsey D.J., Schey S.A. Cytomegalovirus colitis after autologous transplantation for multiple myeloma. Br. J. Haematol. 2000; 110(4): 894–6.
  40. Cohen Y., Paltiel O., Amir G. et al. Unusual cytomegalovirus complications after autologous stem cell transplantation for large B cell lymphoma: massive gastrointestinal hemorrhage followed by a communicating hydrocephalus. Bone Marrow Transplant. 2002; 29(8): 715–6.
  41. MASCC/ISOO evidence-based clinical practice guidelines for mucositis secondary to cancer therapy. http://www.mascc.org/assets/GuidelinesTools.
  42. Yamagata K., Arai C., Sasaki H. et al. The effect of oral management on the severity of oral mucositis during hematopoietic SCT. Bone Marrow Transplant. 2012; 47(5): 725–30. doi: 10.1038/bmt.2011.171.
  43. Stiff P.J., Emmanouilides C., Bensinger W.I. et al. Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J. Clin. Oncol. 2006; 24(33): 5186–93.
  44. Abidi M.H., Agarwal R., Tageja N. et al. A phase I dose-escalation trial of high-dose melphalan with palifermin for cytoprotection followed by autologous stem cell transplantation for patients with multiple myeloma with normal renal function. Biol. Blood Marrow Transplant. 2013; 19(1): 56–61.
  45. Abidi M.H., Agarwal R., Ayash L. et al. Melphalan 180 mg/m2 can be safely administered as conditioning regimen before an autologous stem cell transplantation (ASCT) in multiple myeloma patients with creatinine clearance 60 mL/min/1.73 m2 or lower with use of palifermin for cytoprotection: results of a phase I trial. Biol. Blood Marrow Transplant. 2012; 18(9): 1455–61.
  46. Lilleby K., Garcia P., Gooley T. et al. A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006; 37(11): 1031–5.
  47. Salvador P., Azusano C., Wang L. et al. A pilot randomized controlled trial of an oral care intervention to reduce mucositis severity in stem cell transplant patients. J. Pain Sympt. Manage 2012; 44(1): 64–73.
  48. Vokurka S., Bystricka E., Scudlova J. et al. The risk factors for oral mucositis and the effect of cryotherapy in patients after the BEAM and HD-l-PAM 200 mg/m(2) autologous hematopoietic stem cell transplantation. Eur. J. Oncol. Nurs. 2011; 15(5): 508–12.
  49. Antunes H.S., de Azevedo A.M., da Silva Bouzas L.F. et al. Low-power laser in the prevention of induced oral mucositis in bone marrow transplantation patients: a randomized trial. Blood 2007; 109(5): 2250–5.
  50. Silva G.B., Mendonca E.F., Bariani C. et al. The prevention of induced oral mucositis with low-level laser therapy in bone marrow transplantation patients: a randomized clinical trial. Photomed. Laser Surg. 2011; 29(1): 27–31.
  51. Schubert M.M., Eduardo F.P., Guthrie K.A. et al. A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Supp. Care Cancer 2007; 15(10): 1145–54.
  52. Spencer A., Horvath N., Gibson J. et al. Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation. Bone Marrow Transplant. 2005; 35(10): 971–7.
  53. Gabriel D.A., Shea T.C., Serody J.S. et al. Cytoprotection by amifostine during autologous stem cell transplantation for advanced refractory hematologic malignancies. Biol. Blood Marrow Transplant. 2005; 11(12): 1022–30.
  54. Phillips G.L. 2nd, Bernstein S.H., Liesveld J.L. et al. A Phase I trial: dose escalation of melphalan in the ‘BEAM’ regimen using amifostine cytoprotection. Biol. Blood Marrow Transplant. 2011; 17(7): 1033–42.
  55. Wasko-Grabowska A., Rzepecki P., Oborska S. et al. Efficiency of supersaturated calcium phosphate mouth rinse treatment in patients receiving highdose melphalan or BEAM prior to autologous blood stem cell transplantation: a single-center experience. Transplant. Proc. 2011; 43(8): 3111–3.
  56. Васильева В.А., Кузьмина Л.А., Клясова Г.А. и др. Опыт применения фосфата кальция у больных после высокодозной полихимиотерапии и трансплантации гемопоэтических стволовых клеток. Гематол. и транс- фузиол. 2012; 57(3): 11–3. [Vasil’eva V.A., Kuz’mina L.A., Klyasova G.A. et al. An experience in the use of potassium phosphate in patients after the high-dose polychemotherapy and transplantation of hemopetic stem cells. Gematol. i transfuziol. 2012; 57(3): 11–3. (In Russ.)]
  57. Oblon D.J., Paul S.R., Oblon M.B. et al. Propantheline protects the oral mucosa after high-dose ifosfamide, carboplatin, etoposide and autologous stem cell transplantation. Bone Marrow Transplant. 1997; 20(11): 961–3.
  58. Lockhart P.B., Brennan M.T., Kent M.L. et al. Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation. Bone Marrow Transplant. 2005; 35(7): 713–20.
  59. Costa L.J., Micallef I.N., Inwards D.J. et al. Effect of the dose per body weight of conditioning chemotherapy on severity of mucositis and risk of relapse after autologous haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br. J. Haematol. 2008; 143(2): 268–73.
  60. Eisen D., Essell J., Broun E.R. et al. Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy. Bone Marrow Transplant. 2003; 31(1): 51–5.
  61. Lovenich H., Schutt-Gerowitt H., Keulertz C. et al. Failure of anti-infective mouth rinses and concomitant antibiotic prophylaxis to decrease oral mucosal colonization in autologous stem cell transplantation. Bone Marrow Transplant. 2005; 35(10): 997–1001.
  62. Strupp C., Sudhoff T., Germing U. et al. Transdermal fentanyl during high-dose chemotherapy and autologous stem cell support. Oncol. Rep. 2000; 7(3): 659–61. 63. Pinana J.L., Montesinos P., Martino R. et al. Incidence, risk factors, and outcome of bacteremia following autologous hematopoietic stem cell transplantation in 720 adult patients. Ann. Hematol. 2014; 93(2): 299–307