acute leukemia

A Rationale for a New Operational Integrated Quality and Efficiency Index for Assessing the Performance of Hematological Services in Constituent Entities of the Russian Federation

AUTOIMMUNE THROMBOCYTOPENIA , ,

EN Parovichnikova1, TTs Garmaeva1, OV Lazareva1, KA Lukina1, YuA Chabaeva1, SM Kulikov1, VV Troitskaya1, TV Gaponova1, LI Menshikova2, VG Savchenko1

1 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 Federal Research Institute for Health Organization and Informatics, 11 Dobrolyubova str., Moscow, Russian Federation, 127254

For correspondence: Elena Nikolaevna Parovichnikova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: parovichnikova@gmail.com

For citation: Parovichnikova EN, Garmaeva TTs, Lazareva OV, et al. A Rationale for a New Operational Integrated Quality and Efficiency Index for Assessing the Performance of Hematological Services in Constituent Entities of the Russian Federation. Clinical oncohematology. 2022;15(1):1–15. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-1-15

ABSTRACT

Background. Since 2018 a widespread national project “Healthcare” has been implemented in the Russian Federation (RF) to improve the quality, efficiency, availability, and affordability of medical care in the profiles of specialties in constituent entities of the RF. Modern hematology as a medical field of high technology and crucial solutions is notable for its multi- and interdisciplinarity of most nosological forms, complexity of diagnostic process, multi-structuredness and diversity of related physician teams in different structural units and subdivisions. One of the key issues in federal projects is to determine the indicators for assessing the efficiency of regional hematological services in constituent entities of the RF.

Aim. To elaborate and substantiate a new integrated operational efficiency index for hematological services in constituent entities of the RF.

Materials & Methods. The analysis of data and assessment of feasibility of a new integrated operational index “early mortality in acute leukemia” (AL) were based on the results of 5 multi-center trials, including an epidemiological one.

Results. Multi-center clinical studies on AL are the only objective tools for assessing the treatment efficacy, its improvement, and further training of hematologists taking part in the trials. AL treatment requires well-developed infrastructure of hematological services involving not only staff matters and organization of hematologists’ activities, but also management of many highly important related subdivisions and laboratories, logistics of their interaction, time specifications, meeting clinical guidelines, and lastly, and most importantly, financial support.

Conclusion. The Unified State Information System “Hematology” is the only platform providing the objective information on patients’ vital status and enabling the use of the suggested integrated index for assessing the quality and efficiency of hematological services in the regions of the RF. This indicator of early mortality in AL patients less than 60 years of age is 15 % for acute myeloid leukemias and 10 % for acute lymphoblastic leukemias. Its low values would demonstrate that this or that constituent entity of the RF is provided with sufficient infrastructure, technologies, and a professional team to keep those patients alive who have severe but curable hematological diseases. The indicator of long-term survival or “life years gained” should become the main strategic criterion for the therapy efficacy in hematological diseases.

Keywords: hematological services, assessment of the medical care quality, early mortality, overall survival, acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia.

Received: September 27, 2021

Accepted: December 15, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Приказ Минздрава России от 29.12.2012г. № 1706 «Об утверждении методических рекомендаций по разработке органами исполнительной власти субъектов Российской Федерации планов мероприятий («дорожных карт») «Изменения в отраслях социальной сферы, направленные на повышение эффективности здравоохранения в субъекте Российской Федерации».
    [Decree No. 1706 of the Ministry of Health of the Russian Federation dated December 29, 2012. On the approval of methodological guidelines for the development of action plans (roadmaps) by the executive authorities of constituent entities of the Russian Federation. Changes in the social sectors aimed at improving the efficiency of healthcare in constituent entities of the Russian Federation. (In Russ)]
  2. Валиев Т.Т., Шервашидзе М.А., Осипова И.В. и др. Лечение острого лимфобластного лейкоза у детей по протоколу ALL IC-BFM 2002: результаты мультицентрового ретроспективного исследования. Российский журнал детской гематологии и онкологии. 2021;8(3):59–70. doi: 10.21682/2311-1267-2021-8-3-59-70.
    [Valiev TT, Shervashidze MA, Osipova IV, et al. Treatment of acute lymphoblastic leukemia in children by ALL IC-BFM 2002 protocol: results of multicenter retrospective study. Russian Journal of Pediatric Hematology and Oncology. 2021;8(3):59–70. doi: 10.21682/2311-1267-2021-8-3-59-70. (In Russ)]
  3. Шервашидзе М.А., Валиев Т.Т. Совершенствование программ терапии острого лимфобластного лейкоза у детей: акцент на минимальную остаточную болезнь. Онкогематология. 2020;15(3):12–26. doi: 10.17650/1818­8346­2020­15­3­12­26.
    [Shervashidze MA, Valiev TT. Pediatric acute lymphoblastic leukemia treatment protocols improvement: emphasis on minimal residual disease. Oncohematology. 2020;15(3):12–26. doi: 10.17650/1818­8346­2020­15­3­12­26. (In Russ)]
  4. Berwick D, Fox D. Evaluating the Quality of Medical Care: Donabedian’s Classic Article 50 Years Later. Milbank Q. 2016;94(2):237–41. doi: 10.1111/1468-0009.12189.
  5. Donabedian A. Evaluating the quality of medical care. Milbank Q. 2005;83(4):691–729. doi: 10.1111/j.1468-0009.2005.00397.x.
  6. Mengis C, Aebi S, Tobler A, et al. Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials. J Clin Oncol. 2003;21(21):3933–9. doi: 10.1200/JCO.2003.03.186.
  7. Гармаева Т.Ц., Савченко В.Г., Лазарева О.В. и др. Организация выездных мероприятий с посещением профильных медицинских организаций (МО) субъектов РФ. Гематология и трансфузиология. 2020;65(S1):65.
    [Garmaeva TTs, Savchenko VG, Lazareva OV, et al. Organization of offsite events with visiting specialized healthcare organizations (HO) of constituent entities of the Russian Federation. Gematologiya i transfuziologiya. 2020;65(S1):65. (In Russ)]
  8. Федеральный закон от 29.07.2017 № 242-ФЗ «О внесении изменений в отдельные законодательные акты Российской Федерации по вопросам применения информационных технологий в сфере охраны здоровья».
    [Federal Law No. 242-FZ dated July 29, 2017. On amendments to certain legislative acts of the Russian Federation on information technology for health protection. (In Russ)]
  9. Злокачественные новообразования в России в 2019году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2020. 252 с.
    [Kaprin AD, Starinskii VV, Shakhzadova AO, eds. Zlokachestvennye novoobrazovaniya v Rossii v 2019 godu (zabolevaemost’ i smertnost’). (Malignant neoplasms in Russia in 2019 (incidence and mortality.) Moscow: MNIOI im. P.A. Gertsena — filial FGBU “NMITs radiologii” Publ.; 252 p. (In Russ)]
  10. Савченко В.Г., Паровичникова Е.Н., Клясова Г.А. и др. Итоги многоцентрового кооперированного исследования по лечению острых миелоидных лейкозов взрослых. Терапевтический архив. 1994;66(7):11–7.
    [Savchenko VG, Parovichnikova EN, Klyasova GA, et al. Results of a multicenter collaborative study on the treatment of acute myeloid leukemia in adults. Terapevticheskii arkhiv. 1994;66(7):11–7. (In Russ)]
  11. Савченко В.Г., Паровичникова Е.Н., Клясова Г.А., Исаев В.Г. Итоги двух с половиной лет работы российского многоцентрового исследования по лечению острых лейкозов взрослых. Терапевтический архив. 1995;67(7):8–12.
    [Savchenko VG, Parovichnikova EN, Klyasova GA, Isaev VG. Results of a two-and-a-half-year Russian multicenter study on the treatment of acute leukemia in adults. Terapevticheskii arkhiv. 1995;67(7):8–12. (In Russ)]
  12. Савченко В.Г., Паровичникова Е.Н., Клясова Г.А. и др. Результаты проводимых в течение 7 лет клинических исследований по лечению острых миелоидных лейкозов взрослых. Терапевтический архив. 1999;71(7):13–20.
    [Savchenko VG, Parovichnikova EN, Klyasova GA, et al. Results of 7-year clinical studies on the treatment of acute myeloid leukemia in adults. Terapevticheskii arkhiv. 1999;71(7):13–20. (In Russ)]
  13. Савченко В.Г., Паровичникова Е.Н., Исаев В.Г. и др. Лечение острых лимфобластных лейкозов взрослых как нерешенная проблема. Терапевтический архив. 2001;73(7):6–15.
    [Savchenko VG, Parovichnikova EN, Isaev VG, et al. Treatment of acute lymphoblastic leukemia in adults as an unsolved problem. Terapevticheskii arkhiv. 2001;73(7):6–15. (In Russ)]
  14. Савченко В.Г., Паровичникова Е.Н., Менделеева Л.П. и др. Многоцентровая кооперация — основа прогресса в лечении лейкозов. Терапевтический архив. 2005;77(7):5–11.
    [Savchenko VG, Parovichnikova EN, Mendeleeva LP, et al. Multicenter cooperation is a basis of progress in the treatment of leukemia. Terapevticheskii arkhiv. 2005;77(7):5–11. (In Russ)]
  15. Паровичникова Е.Н., Савченко В.Г., Исаев В.Г. и др. Итоги многоцентрового рандомизированного исследования по лечению острых миелоидных лейкозов взрослых. Терапевтический архив. 2007;79(7):14–9.
    [Parovichnikova EN, Savchenko VG, Isaev VG, et al. Results of a multicenter randomized study on the treatment of acute myeloid leukemia in adults. Terapevticheskii arkhiv. 2007;79(7):14–9. (In Russ)]
  16. Паровичникова Е.Н., Савченко В.Г., Клясова Г.А. и др. Токсичность различных протоколов лечения острых миелоидных лейкозов взрослых: результат четырех российских многоцентровых исследований. Терапевтический архив. 2010;82(7):5–11.
    [Parovichnikova EN, Savchenko VG, Klyasova GA, et al. Toxicity of different treatment protocols for acute myeloid leukemias in adults: the results of four Russian multicenter studies. Terapevticheskii arkhiv. 2010;82(7):5–11. (In Russ)]
  17. Соколов А.Н., Паровичникова Е.Н., Куликов С.М. и др. Долгосрочные результаты лечения острых миелоидных лейкозов у взрослых в многоцентровом клиническом исследовании ОМЛ 06.06. Клиническая онкогематология. 2012;5(1):30–8.
    [Sokolov AN, Parovichnikova EN, Kulikov SM, et al. Long-term results of acute myeloid leukemia treatment in adults in a multicenter clinical study of AML 06.06. Klinicheskaya onkogematologiya. 2012;5(1):30–8. (In Russ)]
  18. Паровичникова Е.Н., Клясова Г.А., Соколов А.Н. и др. Первые результаты лечения острых миелоидных лейкозов взрослых по протоколу ОМЛ-01.10 Научно-исследовательской группы гематологических центров России. Терапевтический архив. 2012;84(7):10–5.
    [Parovichnikova EN, Klyasova GA, Sokolov AN, et al. The first results of acute myeloid leukemia treatment in adults according to the AML-01.10 protocol of the Research Group of Hematological Centers in Russia. Terapevticheskii arkhiv. 2012;84(7):10–5. (In Russ)]
  19. Паровичникова Е.Н., Троицкая В.В., Клясова Г.А. и др. Лечение больных острыми миелоидными лейкозами по протоколу российского многоцентрового рандомизированного исследования ОМЛ-01.10: результаты координационного центра. Терапевтический архив. 2014;86(7):14–23.
    [Parovichnikova EN, Troitskaya VV, Klyasova GA, et al. Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: the coordinating center’s results. Terapevticheskii arkhiv. 2014;86(7):14–23. (In Russ)]
  20. Паровичникова Е.Н., Лукьянова И.А., Троицкая В.В. и др. Результаты программной терапии острых миелоидных лейкозов в ФГБУ «НМИЦ гематологии» Минздрава России. Терапевтический архив. 2018;90(7):14–22.
    [Parovichnikova EN, Lukyanova IA, Troitskaya VV, et al. Results of the program therapy of acute myeloid leukemia in the FGBU “NMITS Gematologii” of the Ministry of Health of Russia. Terapevticheskii arkhiv. 2018;90(7):14–22. (In Russ)]
  21. Buchner T, Schlenk RF, Schaich M, et al. Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup. J Clin Oncol. 2012;30(29):3604–10. doi: 10.1200/JCO.2012.42.2907.
  22. Othus M, Kantarjian H, Petersdorf S, et al Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. 2013;28(2):289–92. doi: 10.1038/leu.2013.176.
  23. Паровичникова Е.Н., Давидян Ю.Р., Исаев В.Г. и др. Итоги лечения острых лимфобластных лейкозов взрослых по протоколу ОЛЛ-2005 как основа для новых исследований. Терапевтический архив. 2009;81(7):8–15.
    [Parovichnikova EN, Davidyan YuR, Isaev VG, et al. Results of acute lymphoblastic leukemia treatment in adults according to the ALL-2005 protocol as a basis for new research. Terapevticheskii arkhiv. 2009;81(7):8–15. (In Russ)]
  24. Паровичникова Е.Н., Клясова Г.А., Троицкая В.В. и др. Эффективность лечения взрослых больных острым Т-лимфобластным лейкозом по протоколу ОЛЛ-2009 российской научно-исследовательской группы по изучению острых лейкозов. Терапевтический архив. 2013;85(8):29–34.
    [Parovichnikova EN, Klyasova GA, Troitskaya VV, et al. The efficacy of acute T-lymphoblastic leukemia treatment in adults according to the ALL-2009 protocol of the Russian research group for the study of acute leukemia. Terapevticheskii arkhiv. 2013;85(8):29–34. (In Russ)]
  25. Паровичникова Е.Н., Троицкая В.В., Соколов А.Н. и др. Промежуточные результаты по лечению острых Ph-негативных лимфобластных лейкозов у взрослых больных (итоги российской исследовательской группы по лечению острых лимфобластных лейкозов (RALL)). Онкогематология. 2014;9(3):6–15.
    [Parovichnikova EN, Troitskaya VV, Sokolov AN, et al. Interim outcomes of acute Ph-negative lymphoblastic leukemia treatment in adults (results of the Russian research group on the treatment of acute lymphoblastic leukemias (RALL)). Onkogematologiya. 2014;9(3):6–15. (In Russ)]
  26. Паровичникова Е.Н., Соколов А.Н., Троицкая В.В. и др. Острые Ph-негативные лимфобластные лейкозы взрослых: факторы риска при использовании протокола ОЛЛ-2009. Терапевтический архив. 2016;88(7):15–24.
    [Parovichnikova EN, Sokolov AN, Troitskaya VV, et al. Acute Ph-negative lymphoblastic leukemias in adults: ALL-2009 protocol risk factors. Terapevticheskii arkhiv. 2016;88(7):15–24. (In Russ)]
  27. Паровичникова Е.Н., Троицкая В.В., Соколов А.Н. и др. Острые В-лимфобластные лейкозы взрослых: выводы из российского проспективного многоцентрового исследования ОЛЛ-2009. Терапевтический архив. 2017;89(7):10–7.
    [Parovichnikova EN, Troitskaya VV, Sokolov AN, et al. Acute B-lymphoblastic leukemia in adults: findings of the Russian prospective multicenter study ALL-2009. Terapevticheskii arkhiv. 2017;89(7):10–7. (In Russ)]
  28. Gokbuget N, Beck J, Brandt K. Significant Improvement Of Outcome In Adolescents and Young adults (AYAs) Aged 15–35 Years With Acute Lymphoblastic Leukemia (ALL) With a Pediatric Derived Adult ALL Protocol; Results Of 1529 AYAs In 2 Consecutive Trials Of The German Multicenter Study Group For Adult ALL (GMALL). 2013;22(21):839. doi: 10.1182/blood.V122.21.839.839.
  29. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. 2005;106(12):3760–7. doi: 10.1182/blood-2005-04-1623.
  30. Francoise H, Thibaut L, Emmanuel R, et al. Pediatric-Inspired Therapy in Adults With Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia: The GRAALL-2003 Study. J Clin Oncol. 2009;27(6):911–8. doi:1200/JCO.2008.18.6916.
  31. Гайдамака Н.В., Паровичникова Е.Н., Гармаева Т.Ц. и др. Длительные аплазии костного мозга после химиотерапии у больных острыми лейкозами. Терапевтический архив. 2010;82(7):29–34.
    [Gaidamaka NV, Parovichnikova EN, Garmaeva TTs, et al. Long-term bone marrow aplasias after chemotherapy in acute leukemia patients. Terapevticheskii arkhiv. 2010;82(7):29–34. (In Russ)]
  32. Алгоритмы диагностики и программная терапия заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018.
    [Savchenko VG, ed. Algoritmy diagnostiki i programmnaya terapiya zabolevanii sistemy krovi. (Diagnostic algorithms and program therapy for hematological diseases.) Moscow: Praktika Publ.; 2018. (In Russ)]
  33. Ахмерзаева З.Х., Паровичникова Е.Н., Русинов М.А. и др. Эпидемиологическое исследование острых лейкозов в пяти регионах Российской Федерации. Гематология и трансфузиология. 2017;62(1):46–51. doi: 10.18821/0234-5730-2017-62-1-46-51.
    [Akhmerzaeva ZKh, Parovichnikova EN, Rusinov MA, et al. The epidemiological study of acute leukemia in five regions of the Russian Federation. Gematologiya i transfuziologiya. 2017;62(1):46–51. doi: 10.18821/0234-5730-2017-62-1-46-51. (In Russ)]
  34. Лукина К.А., Зайцев Д.А., Гармаева Т.Ц., Менделеева Л.П. Телемедицина как инструмент межрегионального дистанционного взаимодействия с профильными медицинскими организациями субъектов Российской Федерации: 5-летний опыт ФГБУ «НМИЦ гематологии» Минздрава России. Врач и информационные технологии. 2020;4:68–77. doi: 10.37690/1811-0193-2020-4-68-77.
    [Lukina KA, Zaytsev DA, Garmaeva TT, Mendeleeva LP. Telemedicine as a tool for remote interaction with regional hospitals: 5-year experience of the National Research Center for Hematology. Vrach i informatsionnye tekhnologii, 2020;4:68–77. doi: 10.37690/1811-0193-2020-4-68-77. (In Russ)]
  35. Железнякова И.А., Серяпина Ю.В., Михайлов И.А. и др. Методологические подходы к внедрению системы контроля качества медицинской помощи в медицинских организациях. Медицинские технологии. Оценка и выбор. 2020;42(4):13–20. doi: 10.17116/medtech
    [Zheleznyakova IA, Seryapina YuV, Mikhailov IA, et al. Methodological approaches to the development of medical care quality control at medical organizations. Medical Technologies. Assessment and Choice. 2020;42(4):13–20. doi: 10.17116/medtech20204204113. (In Russ)]
  36. Брескина Т.Н. Карта экспертизы качества медицинской помощи как основа организации контроля качества медицинской помощи в многопрофильном стационаре. Вестник Росздравнадзора. 2016;1:21–31.
    [Breskina TN. Medical quality evaluation card as a basis for medical care quality control at a multidisciplinary hospital. Vestnik Roszdravnadzora. 2016;1:21–31. (In Russ)]
  37. Сухоруких О.А., Лукьянцева Д.В., Омельяновский В.В. Критерии оценки качества медицинской помощи. Менеджмент качества в медицине. 2018;2:15–21.
    [Sukhorukikh OA, Lukyantseva DV, Omelyanovskii VV. Criteria for quality assessment of medical care. Menedzhment kachestva v meditsine. 2018;2:15–21. (In Russ)]
  38. Семочкин С.В., Толстых Т.Н., Архипова Н.В. и др. Клинико-эпидемиологическая характеристика острых миелоидных лейкозов у взрослых по данным муниципальных отделений гематологии Москвы. Терапевтический архив. 2015;87(7):26–32. doi: 10.17116/terarkh201587726-32.
    [Semochkin SV, Tolstykh TN, Arkhipova NV, et al. Clinical and epidemiological characteristics of acute myeloid leukemias in adults according to the data of the municipal hematology departments of Moscow. Terapevticheskii arkhiv. 2015;87(7):26–32. doi: 10.17116/terarkh201587726-32. (In Russ)]
  39. Лазарева О.В., Куликов С.М., Чабаева Ю.А. и др. Единая информационная система (ЕИС) «Гематология» — учет, регистрация и мониторинг пациентов с заболеваниями системы крови в РФ. Гематология и трансфузиология. 2020;65(S1):33.
    [Lazareva OV, Kulikov SM, Chabaeva YuA, et al. Unified information system (UIE) “Hematology”: administration, registration, and monitoring of patients with hematological diseases in the Russian Federation. Gematologiya i transfuziologiya, 2020;65(S1):33. (In Russ)]
  40. Куликов С.М., ГармаеваТ.Ц., Русинов М.А., Паровичникова Е.Н. Понятия, принципы и задачи популяционной гематологии. Клиническая онкогематология. 2017;10(2):250–7. doi: 10.21320/2500-2139-2017-10-2-250-257.
    [Kulikov SM, Garmaeva TTs, Rusinov MA, Parovichnikova EN. Concept, Principles, and Objectives of Population Hematology. Clinical oncohematology. 2017;10(2):250–7. doi: 10.21320/2500-2139-2017-10-2-250-257. (In Russ)]
  41. Куликов С.М., Чабаева Ю.А., Лазарева О.В. Цель создания новой национальной системы кодирования заболеваний системы крови. Гематология и трансфузиология. 2020;65(S1):32–3.
    [Kulikov SM, Chabaeva YuA, Lazareva OV. The purpose of creating a new national coding system for hematological diseases. Gematologiya i transfuziologiya. 2020;65(S1):32–3. (In Russ)]
  42. Баженов А.В., Галстян Г.М., Паровичникова Е.Н. и др. Роль интенсивной терапии в лечении больных острыми миелоидными лейкозами. Терапевтический архив. 2019;91(7):14–24. doi: 10.26442/00403660.2019.07.000321.
    [Bazhenov AV, Galstyan GM, Parovichnikova EN, et al. Role of the intensive care in treatment of patients with acute myeloid leukemia. Terapevticheskii arkhiv. 2019;91(7):14–24. doi: 10.26442/00403660.2019.07.000321. (In Russ)]
  43. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(1-S2):2–29.
    [Savchenko VG, Parovichnikova EN, Afanasyev BV. National clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfuziologiya. 2014;59(1-S2):2–29. (In Russ)]
  44. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. Клинические рекомендации российских экспертов по лечению больных острыми миелоидными лейкозами в возрасте моложе 60 лет. Терапевтический архив. 2014;86(7):4–13.
    [Savchenko VG, Parovichnikova EN, Afanasyev BV. Clinical guidelines of Russian experts for the treatment of acute myeloid leukemia patients less than 60 years of age. Terapevticheskii arkhiv. 2014;86(7):4–13. (In Russ)]
  45. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. Клинические рекомендации по диагностике и лечению острых лимфобластных лейкозов взрослых (редакция 2018 г.) Гематология и трансфузиология. 2018;63(1-S2):5–52.
    [Savchenko VG, Parovichnikova EN, Afanasyev BV. Clinical guidelines for the diagnosis and treatment of acute lymphoblastic leukemia in adults (edition 2018). Gematologiya i transfuziologiya. 2018;63(1-S2):5–52. (In Russ)]
  46. Приказ Минздрава России от 15 ноября 2012 г. № 930н «Об утверждении Порядка оказания медицинской помощи населению по профилю «гематология»». [Decree No. 930n of the Ministry of Health of the Russian Federation dated November 15, 2012. On the approval of medical care provision in the field of hematology. (In Russ)]

Hemostasis Disorders in Patients with De Novo Acute Leukemias

AUTOIMMUNE THROMBOCYTOPENIA ,

OA Polevodova, GM Galstyan, VV Troitskaya, EB Orel, MYu Drokov, EN Parovichnikova

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

For correspondence: Gennadii Martinovich Galstyan, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: 8(495)612-48-59; e-mail: gengalst@gmail.com

For citation: Polevodova OA, Galstyan GM, Troitskaya VV, et al. Hemostasis Disorders in Patients with De Novo Acute Leukemias. Clinical oncohematology. 2021;14(2):231–8. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-231-238

ABSTRACT

Aim. To study hemostasis disorders in patients with de novo acute leukemias (AL) prior to chemotherapy.

Materials & Methods. The study enrolled 107 patients with newly diagnosed AL, aged 18–80 years and treated at the National Research Center for Hematology. Acute lymphoblastic leukemia (ALL) was identified in 37 patients, acute myeloid leukemia (AML) was diagnosed in 46 patients, and acute promyelocytic leukemia (APL) was reported in 24 patients. Hemorrhagic and thrombotic complications were analyzed; platelet count, APPT, prothrombin and fibrinogen concentration were determined; thromboelastography (TEG; native tests, functional fibrinogen tests) and rotation thromboelastometry (ROTEM; EXTEM, INTEM, FIBTEM, APTEM) were performed. The data were statistically processed using SAS 9.4 software.

Results. At AL onset hemorrhagic syndrome was detected in 34 (32 %) out of 107 patients. It was manifested by petechia (n = 16), subcutaneous hematomas (n = 12), gingival (n = 10) and nose (n = 6) bleeding, uterine bleeding (n = 2), hematuria (n = 2), gastrointestinal bleeding (n = 1), brain hemorrhage (n = 6), and periorbital hematoma (n = 1). According to TEG and ROTEM hypocoagulation was more common in APL patients. Hyperfibrinolysis could be detected using only ROTEM in 54 % of APL patients, in 8 % of ALL and 4 % of AML patients. Compared to other AL patients those with APL showed different parameters of fibrinogen concentration of < 1.75 g/L (sensitivity 83.3 %, specificity 83.13 %), D-dimer concentration of > 2686 µg/L (sensitivity 72.73 %, specificity 64.79 %), MCFFIBTEM < 12.5 mm (sensitivity 80 %, specificity 80 %), and МАFF < 9.7 mm (sensitivity 86.96 %, specificity 90.12 %).

Conclusion. The parameters that distinguish APL from other categories of AL patients are hypofibrinogenemia, higher D-dimer concentration, ROTEM changes, and hyperfibrinolysis.

Keywords: hemostatic system, acute leukemia, hemorrhagic syndrome, thrombosis, integral tests, thromboelastometry, thromboelastography.

Received: December 2, 2020

Accepted: March 5, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018. 1008 с.
    [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols in hematological diseases.) Moscow: Praktika Publ.; 2018. 1008 p. (In Russ)]
  2. Rea B, Frank D. An uncommon manifestation of acute leukemia. Gastrointest Endosc. 2017;86(1):240–2. doi: 10.1016/j.gie.2016.12.010.
  3. Gallo G, Bigliardi S, Cesinaro A. A case of extramedullary hematopoiesis presenting as hemorrhagic panniculitis and evolving in acute myeloid leukemia. J Cutan Pathol. 2019;46(10):775–7. doi: 10.1111/cup.13498.
  4. Lieberman F, Villgran V, Normolle D, et al. Intracranial Hemorrhage in Patients Newly Diagnosed with Acute Myeloid Leukemia and Hyperleukocytosis. Acta Haematol. 2017;138(2):116–8. doi: 10.1159/000478690.
  5. Галстян Г.М., Кречетова А.В., Троицкая В.В. и др. Высокодозная терапия концентратом антитромбина III больных септическим шоком в состоянии агранулоцитоза. Анестезиология и реаниматология. 2014;59(4):39–45.
    [Galstyan GM, Krechetova AV, Troitskaya VV, et al. High-dose therapy with antithrombin III in agranulocytosis patients with septic shock. Anesteziologiya i reanimatologiya. 2014;59(4):39–45. (In Russ)]
  6. Mitrovic M, Suvajdzic N, Bogdanovic A, et al. International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation >6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia. Med Oncol. 2013;30(1):478. doi: 10.1007/s12032-013-0478-y.
  7. Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J. 2015;5(4):e304. doi: 10.1038/bcj.2015.25.
  8. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108(4):689–95. doi: 10.1046/j.1365-2141.2000.01936.x.
  9. Breccia M, Latagliata R, Cannella L, et al. Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation. Haematologica. 2010;95(5):853–4. doi: 10.3324/haematol.2009.017962.
  10. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. 2008;111(7):3395–402. doi: 10.1182/blood-2007-07-100669.
  11. Дементьева И.И., Морозов Ю.А., Чарная М.А. и др. Технологии POINT OF CARE в клинике неотложных состояний. Клиническая лабораторная диагностика. 2013;7:5–10.
    [Dement’eva II, Morozov YuA, Charnaya MA, et al. POINT OF CARE technologies under clinic emergency conditions. Klinicheskaya laboratornaya diagnostika. 2013;7:5–10. (In Russ)]
  12. Lang T, Bauters A, Braun SL, et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinol. 2005;16(4):301–10. doi: 10.1097/01.mbc.0000169225.31173.19.
  13. Rollig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015;125(21):3246–52. doi: 10.1182/blood-2014-10-551507.
  14. Schochl H, Frietsch T, Pavelka M, et al. Hyperfibrinolysis After Major Trauma: Differential Diagnosis of Lysis Patterns and Prognostic Value of Thrombelastometry. J Trauma Inj Infect Crit Care. 2009;67(1):125–31. doi: 10.1097/TA.0b013e31818b2483.
  15. Баркаган З.С., Момот А.П. Диагностика и контролируемая терапия нарушений гемостаза. М.: Ньюдиамед, 2008. С. 103–13.
    [Barkagan ZS, Momot AP. Diagnostika i kontroliruemaya terapiya narushenii gemostaza. (Diagnosis and monitor therapy of hemostasis disorders.) Moscow: N’yudiamed Publ.; 2008. 103–13. (In Russ)]
  16. Буланов А.Ю., Яцков К.В., Буланова Е.Л. и др. Тромбоэластография: клиническая значимость теста на функциональный фибриноген. Вестник интенсивной терапии. 2017;1:5–11.
    [Bulanov AYu, Yatskov KV, Bulanova EL, et al. Thromboelastography: the clinical significance of the functional fibrinogen test. Vestnik intensivnoi terapii. 2017;1:5–11. (In Russ)]
  17. Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75(6):961–7. doi: 10.1097/TA.0b013e3182aa9c9f.
  18. Gonzalez E, Moore EE, Moore HB. Management of Trauma-Induced Coagulopathy with Thrombelastography. Crit Care Clin. 2017;33(1):119–34. doi: 10.1016/j.ccc.2016.09.002.
  19. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated Automated Thrombin Generation Measurement in Clotting Plasma. Pathophysiol Haemost Thromb. 2003;33(1):4–15. doi: 10.1159/000071636.
  20. McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: The SPRINT trial. Blood. 2004;104(5):1534–41. doi: 10.1182/blood-2003-12-4443.
  21. Савченко В.Г., Паровичникова Е.Н., Соколов А.Н. и др. Клинические рекомендации по диагностике и лечению острого промиелоцитарного лейкоза у взрослых. Национальное гематологическое общество. 2014. (электронный документ) Доступно по: https://docplayer.ru/50397388-Klinicheskie-rekomendacii-po-diagnostike-i-lecheniyu-ostrogo-promielocitarnogo-leykoza-u-vzroslyh.html. Ссылка активна на 5.02.2021.
    [Savchenko VG, Parovichnikova EN, Sokolov AN, et al. Clinical guidelines on diagnosis and treatment of adult acute promyelocytic leukemia. National Society of Hematology. 201 [Internet] Available from: https://docplayer.ru/50397388-Klinicheskie-rekomendacii-po-diagnostike-i-lecheniyu-ostrogo-promielocitarnogo-leykoza-u-vzroslyh.html. (accessed 02.2021) (In Russ)]
  22. Воробьев А.И., Бронштейн М.И., Баранов А.Е. О промиелоцитарном варианте острого лейкоза. Вестник АМН СССР. 1968;4:36–45.
    [Vorob’ev AI, Bronshtein MI, Baranov AE. On promyelocytic variant of acute leukemia. Vestnik AMN SSSR. 1968;4:36–45. (In Russ)]
  23. Avvisati G, ten Cate JW, Sturk A, et al. Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia. Br J Haematol. 1988;70(1):43–8. doi: 10.1111/j.1365-2141.1988.tb02432.x.
  24. Wijermans PW, Rebel VI, Ossenkoppele GJ, et al. Combined procoagulant activity and proteolytic activity of acute promyelocytic leukemic cells: reversal of the bleeding disorder by cell differentiation. Blood. 1989;73(3):800–5. doi: 10.1182/blood.V73.3.800.bloodjournal733800.
  25. Wada K, Takahashi H, Hanano M, et al. Plasma urokinase-type plasminogen activator in patients with leukemias. Leuk Lymphoma. 1994;15(5–6):499–502. doi: 10.3109/10428199409049754.
  26. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J Med. 1999;340(13):994–1004. doi: 10.1056/NEJM199904013401303.
  27. Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost. 2018;16(4):652–62. doi: 10.1111/jth.13957.
  28. Negrier C, Ninet J, Bordet J, et al. Use of calibrated automated thrombinography ± thrombomodulin to recognise the prothrombotic phenotype. Thromb Haemost. 2017;96(5):562–7. doi: 10.1160/th06-03-0179.
  29. Abuelkasem E, Lu S, Tanaka K, et al. Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation. Br J Anaesth. 2016;116(4):507–12. doi: 10.1093/bja/aew023.
  30. da Luz LT, Nascimento B, Rizoli S. Thrombelastography (TEG®): practical considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med. 2013;21(1):29. doi: 10.1186/1757-7241-21-29.
  31. Moore HB, Moore EE, Liras IN, et al. Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients. J Am Coll Surg. 2016;222(4):347–55. doi: 10.1016/J.JAMCOLLSURG.2016.01.006.
  32. Lou Y, Suo S, Tong H, et al. Hypofibrinogenemia as a clue in the presumptive diagnosis of acute promyelocytic leukemia. Leuk Res. 2016;50:11–6. doi: 10.1016/j.leukres.2016.09.006.
  33. Zhang X, Hu Y, Bao L, et al. Arsenic trioxide downregulates the expression of annexin II in bone marrow cells from patients with acute myelogenous leukemia. Chin Med J (Engl). 2009;122(17):1969–73. doi: 10.3760/cma.j.issn.0366-6999.2009.17.002.
  34. Stein EM, Tallman MS. Provocative pearls in diagnosing and treating acute promyelocytic leukemia. Oncology (Williston Park). 2012;26(7):636–41.
  35. Yanada M, Matsushita T, Asou N, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007;78(3):213–9. doi: 10.1111/j.1600-0609.2006.00803.x.
  36. Choudhry A, DeLoughery TG. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol. 2012;87(6):596–603. doi: 10.1002/ajh.23158.
  37. Grisariu S, Spectre G, Kalish Y, et al. Increased risk of central venous catheter–associated thrombosis in acute promyelocytic leukemia: a single-institution experience. 2013;90(5):397–403. doi: 10.1111/ejh.12087.

Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

VA Okhmat, GA Klyasova, EN Parovichnikova, VV Troitskaya, EO Gribanova, VG Savchenko

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

For correspondence: Vladimir Aleksandrovich Okhmat, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)614-92-72; e-mail: okhmatvladimir@mail.ru

For citation: Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia. Clinical oncohematology. 2018;11(1):100-9.

DOI: 10.21320/2500-2139-2018-11-1-100-109

ABSTRACT

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Materials & Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months.

Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p < 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, p < 0.0001), compared to combination therapy (37 % vs. 18 %, p = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, p = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23–24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %).

Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (> 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37–48 % of cases.

Keywords: acute leukemia, AML, ALL, febrile neutropenia, fever of unknown origin, clinically and microbiologically defined infections, antibiotics.

Received: July 2, 2017

Accepted: October 20, 2017

Read in PDF 

REFERENCES

  1. Паровичникова Е.Н., Троицкая В.В., Клясова Г.А. и др. Лечение больных острыми миелоидными лейкозами по протоколу российского многоцентрового рандомизированного исследования ОМЛ-01.10: результаты координационного центра. Терапевтический архив. 2014;86(7):14–23. [Parovichnikova EN, Troitskaya VV, Klyasova GA, et al. Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: The coordinating center’s results. Terapevticheskii arkhiv. 2014;86(7):14–23. (In Russ)]
  2. Паровичникова Е.Н., Клясова Г.А., Исаев В.Г. и др. Первые итоги терапии Ph-негативных острых лимфобластных лейкозов взрослых по протоколу Научно-исследовательской группы гематологических центров России ОЛЛ-2009. Терапевтический архив. 2011;83(7):11–7. [Parovichnikova EN, Klyasova GA, Isaev VG, et al. Pilot results of therapy of adult Ph-negative acute lymphoblastic leukemia according to the protocol of Research Group of Russian Hematological Centers ALL-2009. Terapevticheskii arkhiv. 2011;83(7):11–7. (In Russ)]
  3. Войцеховский В.В., Груздова А.В., Филатова Е.А. и др. Анализ инфекционных осложнений гемобластозов в Амурской области.Бюллетень физиологии и патологии дыхания. 2012;46:64–8. [Voitsekhovskii VV, Gruzdova AV, Filatova EA, et al. The analysis of infectious complications of hemoblastosis in the Amur region. Byulleten’ fiziologii i patologii dykhaniya. 2012;46:64–8. (In Russ)]
  4. Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect. 2013;68(4):321–31. doi: 10.1016/j.jinf.2013.12.006.
  5. Клясова Г.А. Антимикробная терапия. В кн.: Программное лечение заболеваний системы крови: сборник алгоритмов диагностики и протоколов лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2012. С. 827–54. [Klyasova GA. Antimicrobial therapy. In: Savchenko VG, ed. Programmnoe lechenie zabolevanii sistemy krovi: sbornik algoritmov diagnostiki i protokolov lecheniya zabolevanii sistemy krovi. (Program treatment of blood system diseases.) Moscow: Praktika Publ.; 2012. pp. 829–53. (In Russ)]
  6. Averbuch D, Cordonnier C, Livermore DM, et al. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: Guidelines of the 4th European conference on Infections in Leukemia (ECIL-4, 2011). Haematologica. 2013;98(12):1836–47. doi: 10.3324/haematol.2013.091330.
  7. Tumbarello M, Sanguinetti M, Montuori E, et al. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother. 2007;51(6):1987–94. doi:10.1128/AAC.01509–06.
  8. Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В. и др. Национальные клинические рекомендации по диагностике и лечению острых миелоидных лейкозов взрослых. Гематология и трансфузиология. 2014;59(S2):2–29. [Savchenko VG, Parovichnikova EN, Afanas’ev BV, et al. National clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. Gematologiya i transfusiologiya. 2014;59(S2):2–29. (In Russ)]
  9. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55.
  10. Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013;98(12):1826–35. doi: 10.3324/haematol.2013.091025.
  11. Клясова Г.А., Коробова А.Г., Фролова И.Н. и др. Детекция энтеробактерий с продукцией β-лактамаз расширенного спектра у больных острыми миелоидными лейкозами и лимфомами при поступлении в стационар. Гематология и трансфузиология. 2016;61(1):25–32. doi: 10.18821/0234-5730-2016-61-1-25-32. [Klyasova GA, Korobova AG, Frolova IN, et al. Detection of extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E) among patients with acute myeloid leukemia and lymphoma upon admission to hospital. Gematologiya i transfusiologiya. 2016;61(1):25–32. doi: 10.18821/0234-5730-2016-61-1-25-32. (In Russ)]
  12. Охмат В.А., Клясова Г.А., Коробова А.Г. и др. Следует ли назначать карбапенемы всем больным с фебрильной нейтропенией и колонизацией энтеробактериями с продукцией β-лактамаз расширенного спектра? Онкогематология. 2016;11(3):49–57. doi: 10.17650/1818-8346-2016-11-3-49-57. [Okhmat VA, Klyasova GA, Korobova AG. Should to all patients with febrile neutropenia and colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae carbapenems be appointed? Oncohematology. 2016;11(3):49–57. doi: 10.17650/1818-8346-2016-11-3-49-57. (In Russ)]
  13. Aynioglu Mujeeb VR, Jambunathan P, Tyagi A. Comparison of Efficacy of Piperacillin/Tazobactam Vs Cefoperazone/Sulbactam as Empirical Therapy in Patients with Febrile Neutropenia. Ann Int Med Dent Res. 2017;3(2):51–5. doi: 10.21276/aimdr.2017.3.2.me12.
  14. Demir HA, Kutluk T, Ceyhan M, et al. Comparison of sulbactam-cefoperazone with carbapenems as empirical monotherapy for febrile neutropenic children with lymphoma and solid tumors. Pediatr Hematol Oncol. 2011;28(4):299–310. doi: 3109/08880018.2011.552937.
  15. Jing Y, Li J, Yuan L, et al. Piperacillin‐tazobactam vs. imipenem‐cilastatin as empirical therapy in hematopoietic stem cell transplantation recipients with febrile neutropenia. Clin Transplant. 2016;30(3):263–9. doi: 1111/ctr.12685.
  16. Охмат В.А., Клясова Г.А., Паровичникова Е.Н. и др. Спектр и этиология инфекционных осложнений у больных острыми миелоидными лейкозами на этапах индукции и консолидации ремиссии. Гематология и трансфузиология. 2017;62(1):9–15. [Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Spectrum and epidemiology of infection complications in patients with acute myeloid leukemia during induction and consolidation chemotherapy. Gematologiya i transfusiologiya. 2017;62(1):9–15. (In Russ)]
  17. Pizzo PA. After empiric therapy: what to do until the granulocyte comes back. Rev Infect Dis. 1987;9(1):214–9. doi: 1093/clinids/9.1.214.
  18. Link H, Maschmeyer G, Meyer PF, et al. Interventional antimicrobial therapy in febrile neutropenic patients. Ann Hematol. 1994;69(5):231–43. doi: 1007/BF01700277.
  19. Viscoli C, Cometta A, Kern WV, et al. Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients. Clin Microbiol Infect. 2006;12(3):212–6. doi: 10.1111/j.1469-0691.2005.01297.x.

Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression

MYELOID TUMORS , ,

NN Mamaev, YaV Gudozhnikova, TL Gindina, IM Barkhatov, AI Shakirova, VA Katerina, MV Gubina, ES Nikolaeva, EV Semenova, OV Paina, EI Darskaya, OV Pirogova, VV Porunova, IS Moiseev, IA Mikhailova, BI Ayubova, VM Kravtsova, SN Bondarenko, LS Zubarovskaya, BV Afanas’ev

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

For correspondence: Nikolai Nikolaevich Mamaev, PhD, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Gudozhnikova YaV, Gindina TL, et al. Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression. Clinical oncohematology. 2018;11(1):78-88.

DOI: 10.21320/2500-2139-2018-11-1-78-88

ABSTRACT

Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression.

Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2–3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/104 copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH.

Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/104 copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion.

Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.

Keywords: acute leukemia, induction chemotherapy, molecular monitoring, WT1.

Received: August 18, 2017

Accepted: November 12, 2017

Read in PDF 

REFERENCES

  1. Cilloni D, Gottardi A, De Micheli D, et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leikemia. 2002;16(10):2115–21. doi: 10.1038/sj.leu.2402675.
  2. Hochenstein P, Hastie ND. The many facets of the Wilms’ tumor gene, WT1. Hum Mol Genet. 2006;15(15):R196–R201. doi: 10.1093/hmg/ddl196.
  3. Ujj Z, Buglyo G, Udvardy M, et al. WT1 overexpression affecting clinical outcome in non-Hdgkin lymphomas and adult acute lymphoblastic leukemia. Pathol Oncol Res. 2014;20(3):20565–70. doi: 10.1007/s12253-013-9729-7.
  4. Мамаев Н.Н., Гудожникова Я.В., Горбунова А.В. Гиперэкспрессия гена WT1 при злокачественных опухолях системы крови: теоретические и клинические аспекты (обзор литературы). Клиническая онкогематология. 2016;9(3):257–64. doi: 10.21320/2500-2139-2016-9-3-257-264. [Mamaev NN, Gudozhnikova YaV, Gorbunova AV. WT1 Gene Overexpression in Oncohematological Disorders: Theoretical and Clinical Aspects (Literature Review). Clinical oncohematology. 2016;9(3):257–64. doi: 10.21320/2500-2139-2016-9-3-257-264. (In Russ)]
  5. Miwa H, Beran M, Anders GF. Expression of the Wilms’ tumor gene (WT1) in human leukemias. Leukemia. 1992;6(5):405–9.
  6. Bergmann L, Miething C, Maurer U, et al. High levels of Wilms’ tumor gene (WT1) mRNA in acute myeloid leukemia are associated with a worse long-turn outcome. Blood. 1997;90(3):1217–25.
  7. Lasa A, Carricondo M, Estevii S, et al. WT1 monitoring in core binding factor AML comparison with specific chimeric products. Leuk Res. 2009;33(12):1643–9. doi: 10.1016/j.leukres.2009.03.046.
  8. Zhao XS, Jin S, Zhu H-Y, et al. Wilms’ tumor 1 gene expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011;47(4):499–507. doi: 10.1038/bmt.2011.121.
  9. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Трансплантация гемопоэтических стволовых клеток при остром миелоидном лейкозе с транслокацией t(8;21)(q22;q22). Клиническая онкогематология. 2013;6(4):439–44.[Mamayev NN, Gorbunova AV, Gindina TL, et al. Hematopoietic Stem Cell Transplantation in AML Patients with t(8;21)(q22;q22) Translocation. Klinicheskaya onkogematologiya. 2013;6(4):439–44. (In Russ)]
  10. Мамаев Н.Н., Семенова Е.В., Станчева Н.В. и др. Аллогенная трансплантация гемопоэтических стволовых клеток при остром лимфобластном лейкозе с транслокацией t(12;21)(p13;q22). Клиническая онкогематология. 2014;7(3):327–34. [Mamaev NN, Semenova EV, Stancheva NV, et al. Allogeneic Hematopoietic Stem Cell Transplantation for ALL Patients with t(12;21)(p13;q22) Translocation. Klinicheskaya onkogematologiya. 2014;7(3):327–34. (In Russ)]
  11. Мамаев Н.Н., Горбунова А.В., Бархатов И.М. и др. Молекулярный мониторинг течения острых миелоидных лейкозов по уровню экспрессии гена WT1 после аллогенной трансплантации гемопоэтических стволовых клеток. Клиническая онкогематология. 2015;8(3):309–20. doi: 10.21320/2500-2139-2015-8-3-309-320. [Mamaev NN, Gorbunova AV, Barkhatov IM, et al. Molecular Monitoring of WT1 Gene Expression Level in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2015;8(3):309–20. doi: 10.21320/2500-2139-2015-8-3-309-320. (In Russ)]
  12. Гиршова Л.Л., Будаева И.Г., Овсянникова Е.Г. и др. Прогностическое значение и корреляция динамики гиперэкспрессии гена WT1 и мутации гена NPM1 у пациентов с острым миелобластным лейкозом. Клиническая онкогематология. 2017;10(4):485–93. doi: 10.21320/2500-2139-2017-10-4-485-493. [Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93. doi: 10.21320/2500-2139-2017-10-4-485-493. (In Russ)]
  13. Alonso-Dominiquez JM, Tenorio M, Velasco D, et al. Correlation of WT1 expression with the burden of total and residual leukemic blasts in bone marrow samples of acute myeloid leukemia patients. Cancer Genet. 2012;205(4):190–1. (Letter to the Editor). doi: 10.1016/j.cancergen.2012.02.008.
  14. Cilloni D, Giuseppe S, Gottardi E, et al. WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome. Acta Hematol. 2004;112(1–2):79–84. doi: 10.1159/000077562.
  15. Weisser M, Kern W, Rauhut S, et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia. 2005;19(8):1416–23. doi: 10.1038/sj.leu.2403809.
  16. Cilloni D, Renneville A, Hermitte F, et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia. A European LeukemiaNet study. J Clin Oncol. 2009;27(31):5195–201. doi: 10.1200/jco.2009.22.4865.
  17. Ostergaard M, Olesen LH, Hasle H, et al. WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukemia patients – results from a single-centre study. Br J Haematol. 2004;125(5):590–600. doi: 10.1111/j/1365-2141.2004.04952.x.
  18. Candoni A, Toffoletti E, Gallina R, et al. Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia. Clin Transplant. 2011;25(2):308–16. doi: 10..1111/j.1399-0012.201001251.x.
  19. Rossi G, Minervini MM, Carella AM, et al. Comparison between multiparameter flow cytometry and WT1 RNA quantification in monitoring minimal residual disese in acute myeloid leukemia without specific molecular targets. Leuk Res. 2011;36(4):401–6. doi: 10.1016/j.leukres.2011.11.020.
  20. Kwon M, Martinez-Laperche C, Infante M, et al. Evaluation of minimal residual disease by real-time quantitative PCR of Wilms’ Tumor 1 expression in patients with acute myelogenous leukemia after allogeneic stem cell transplantation: Correlation with flow cytometry and chimerism. Biol Blood Marrow Transplant. 2012;18(8):1235–42. doi: 10.1016/j.bbmt.2012.01.012.
  21. Nomdedeu JF, Esquirol A, Carricondo M, et al. Bone marrow WT1 levels in allogeneic hematopoietic stem cell transplant (HCT) for acute myeloid leukemia and myelodysplasia: Clinically relevant time-points and 100 copies threshold value. Biol Blood Marrow Transplant. 2018;24(1):55–63. doi: 10.1016/j.bbmt.2017.09.001.
  22. Ogawa H, Tamaki Y, Ikeegame K, et al. The usefulness of monitoring WT1 gene transcripts for the prediction of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood. 2003;101(5):1698–704. doi: 10.1182/blood-2002-06-1831.
  23. Ommen HB, Nyvold CG, Braendstrup K, et al. Relapse prediction in acute myeloid leukemia patients in complete remission using WT1 as a molecular marker: development of a mathematical model to predict time from molecular to clinical relapse and define optimal sampling intervals. Br J Haematol. 2008;141(6):782–91. doi: 10.1111/j.1365-2141.2008.07132.x.
  24. Lange T, Hubmann M, Burkhurdt R, et al. Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia. 2011;25(3):498–505. doi: 10.1038/leu.2010.283.
  25. Pozzi S, Geraldi S, Tedfone E, et al. Leukemia relapse after allogeneic transplants for acute myeloid leukemia: predictive role of WT1 expression. Br J Haematol. 2013;160(4):503–9. doi: 10.1111/bjh.12181.
  26. Yoon JH, Kim HJ, Shin SH, et al. BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML. Eur J Haematol. 2013;91(2):112–21. doi: 10.1111/ejh.12142.
  27. Yoon JH, Kim HJ, Kim JW, et al. Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation. Bone Marrow Transplant. 2014;49(12):1466–74. doi: 10.1038/bmt.2014.180.
  28. Messina C, Sala E, Carraba M, et al. Early post-allogeneic transplantation WT1 transcript positivity predicts AML relapse. Bone Marrow Transplant. 2015;50(S1):236–7. doi: 10.1038/bmt.2015.29.
  29. Boublikova L, Kalinova M, Ryan J, et al. Wilms’ tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. Leukemia. 2006;20(2):254–63. doi: 10.1038/sj.leu.2404047.
  30. Lapillonne H, Renneville A, Auvrignon A, et al. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol. 2006;24(10):1507–15. doi: 10.1200/jco.2005.03.5303.
  31. Busse A, Gokbuget N, Sechl JM, et al. Wilms’ tumor gene 1 (WT1) expression in subtypes of acute lymphoblastic leukemia (ALL) of adults and impact on clinical outcome. Ann Hematol. 2009,88(12):1199–205. doi: 10.1007/s00277-009-0746-2.
  32. .Sadek HA, El-Metnawey WH, Shaheen IA, et al. Quantitative assessment of Wilms’ tumor 1 (WT1) gene transcripts in Egyptian acute lymphoblastic leukemia patients. J Invest Med. 2011;59(8):1258–62. doi: 10.2130/JIM.0b013e31822a24f7.33.
  33. Mossalam GI, Abdel Hamid TM, Mahmoud HK. Prognostic significance of WT1 expression at diagnosis and end of induction in Egyptian adult acute myeloid leukemia patients. Hematology. 2013;18(2):69–73. doi: 10.1179/1607845412Y.0000000048.34.
  34. Capelli D, Attolico I, Saraceli F, et al. Early cumulative incidence of relapse in 80 acute leukemia patients after chemotherapy and transplant post-consolidation treatment prognostic role of post-induction WT1. Bone Marrow Transplant. 2015;50(S1):262–3. doi: 10.1038/bmt.2015.29.35.
  35. Ujj Z, Buglyo G, Udvardy M, et al. WT1 expression in adult acute myeloid leukemia: assessing its presence, magnitude and temporal changes as prognostic factors. Pathol Oncol Res. 2016;22(1):217–21. doi: 10.1007/s12253-015-0002-0.
  36.  Гиршова Л.Л., Овсянникова Е.Г., Кузин С.О. и др. Молекулярный мониторинг уровня транскрипта RUNX1-RUNX1T1 при острых миелобластных лейкозах на фоне терапии. Клиническая онкогематология. 2016;9(4):456–64. doi: 10.21320/2500-2139-2016-9-4-456-464. [Girshova LL, Ovsyannikova EG, Kuzin SO, et al. Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment. Clinical oncohematology. 2016;9(4):456–64. doi: 10.21320/2500-2139-2016-9-4-456-464. (In Russ)]
  37. Nomdedeu JF, Hoyos M, Carricondo M, et al. Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia. 2013;27(11):2157–64. doi: 10.1038/leu.2013.111.38.
  38. Schmid C, Schleuning M, Tischer J, et al. Early allo-SCT for AML with a complex aberrant karyotype – results from a prospective pilot study. Bone Marrow Transplant. 2012;47(1):46–53. doi: 10.1038/bmt.2011.15.39.
  39. Мамаев Н.Н, Горбунова А.В, Гиндина Т.Л. и др. Стойкое восстановление донорского гемопоэза у больной с посттрансплантационным рецидивом острого миеломонобластного лейкоза с inv(3)(q21q26), моносомией 7 и экспрессией онкогена EVI1 после трансфузий донорских лимфоцитов и использования гипометилирующих агентов. Клиническая онкогематология. 2014;7(1):71–5. [Mamayev NN, Gorbunova AV, Gindina TL, et al. Stable donor hematopoiesis reconstitution after post­transplantation relapse of acute myeloid leukemia in patient with inv(3)(q21q26), –7 and EVI1 oncogene overexpression treated by donor lymphocyte infusions and hypomethylating agents. Klinicheskaya onkogematologiya. 2014;7(1):71–5. (In Russ)
  40. Гиндина Т.Л., Мамаев Н.Н., Паина О.В. и др. Острый лимфобластный лейкоз c транслокацией t(4;11)(q21;q23)/KMT2A-AFF1: результаты аллогенной трансплантации гемопоэтических стволовых клеток у детей и взрослых. Клиническая онкогематология. 2017;10(3):342–50. doi: 10.21320/2500-2139-2017-10-3-342-350. [Gindina TL, Mamaev NN, Paina OV, et al. Acute Lymphoblastic Leukemia with t(4;11)(q21;q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults. Clinical oncohematology. 2017;10(3):342–50. doi: 10.21320/2500-2139-2017-10-3-342-350. (In Russ)]

Classification of Conditioning Regimens for Bone Marrow Transplantation: Historical Background and Current Perspectives

BONE MARROW TRANSPLANTATION , , , , , ,

KN Melkova, GD Petrova, NV Gorbunova, TZ Chernyavskaya, OP Trofimova

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Kapitolina Nikolaevna Melkova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: frolov63@bk.ru

For citation: Melkova KN, Petrova GD, Gorbunova NV, et al. Classification of Conditioning Regimens for Bone Marrow Transplantation: Historical Background and Current Perspectives. Clinical oncohematology. 2017;10(4):494–500 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-494-500

ABSTRACT

Hematopoietic stem cells transplantation is a current standard treatment for many oncohematological diseases. The milestone of any type of transplantation is the choice of conditioning regimen. This article presents the principles of classification of conditioning regimens in terms of myeloablativity and discusses the concepts of “autologous transplantation”, “high-dose chemotherapy supported by hematopoietic stem cells”, “allogeneic transplantation” and “immunotherapy”. Up-to-date uniform classification of conditioning regimens may serve an important prognostic component in assessing both the risks and efficacy of hematopoietic stem cells transplantation.

Keywords: conditioning regimens, allogeneic hematopoietic stem cell transplantation, autologous hematopoietic stem cell transplantation, total therapeutic exposure, acute leukemia, Hodgkin’s lymphoma, multiple myeloma.

Received: March 29, 2017

Accepted: July 8, 2017

Read in PDF

REFERENCES

  1. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50(4):476–82. doi: 10.1038/bmt.2014.312.
  2. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Трансплантация костного мозга при острых лейкозах. Клиническая онкогематология. 2010;3(4):395–9.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Bone Marrow Transplantation in Case of Acute Leukemia. Klinicheskaya onkogematologiya. 2010;3(4):395–9. (In Russ)]
  3. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Аутологичная трансплантация гемопоэтических стволовых клеток при первично-рефрактерном течении лимфомы Ходжкина: мнимый цугцванг или промежуточный ход? Клиническая онкогематология. 2015;8(3):321–30. doi: 10.21320/2500-2139-2015-8-3-321-330.[Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug? Clinical oncohematology. 2015;8(3):321–30. doi: 10.21320/2500-2139-2015-8-3-321-330. (In Russ)]
  4. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Первично-рефрактерное течение лимфомы Ходжкина и аутологичная трансплантация гемопоэтических стволовых клеток. Результаты одноцентрового проспективного исследования. Российский онкологический журнал. 2015;20(3):4–11.[Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Primary-Refractory Course of Hodgkin’s Lymphoma and Autologous Hematopoietic Stem Cell Transplantation. Results of Single Center Prospective Study. Rossiiskii onkologicheskii zhurnal. 2015;20(3):4–11. (In Russ)]
  5. Петрова Г.Д., Мелкова К.Н., Горбунова Н.В. и др. Аутологичная трансплантация гемопоэтических стволовых клеток для консолидации ремиссии острого миелобластного лейкоза с факторами неблагоприятного прогноза в дебюте заболевания. Онкогематология. 2016;11(1):52–61. doi: 10.17650/1818-8346-2016-11-1-52-61.[Petrova GD, Melkova KN, Gorbunova NV, et al. Autologous Hematopoietic Stem Cell Transplantation for Remission Consolidation of Acute Myeloblastic Leukemia with Factors of Poor Prognosis in Disease Onset. Oncohematology. 2016;11(1):52–61. doi: 10.17650/1818-8346-2016-11-1-52-61. (In Russ)]
  6. Мелкова К.Н., Петрова Г.Д., Чернявская Т.З. Заготовка гемопоэтических стволовых клеток для проведения аутологичной трансплантации у пациентов с лимфомой Ходжкина неблагоприятного прогноза. Вестник ФГБНУ «РОНЦ им. Н.Н. Блохина». 2015;26(3):51–6.[Melkova KN, Petrova GD, Chernyavskaya TZ. Hematopoietic Stem Cells Preparation for Autologous Transplantation in Patients with Hodgkin’s Lymphoma of Poor Prognosis. Vestnik FGBNU «RONTs im. N.N. Blokhina». 2015;26(3):51–6. (In Russ)]
  7. Чернявская Т.З., Мелкова К.Н., Горбунова Н.В. и др. Использование стимулированного костного мозга для трансплантации в онкологии. Онкология. 2012;(2, приложение):28–33.[Chernyavskaya TZ, Melkova KN, Gorbunova NV, et al. Usage of Stimulated Bone Marrow for Oncology Transplantation. Onkologiya. 2012;(2 Suppl):28–33. (In Russ)]
  8. Melkova K, Chernyavskaya T, Abdusalamov S, et al. Application of autologous stimulated bone marrow as a source of hematopoietic material for transplantation. Cell Ther Transplant. 2011;3(12):33.
  9. Melkova K, Chernyavskaya T, Abdusalamov S, et al. Using stimulated bone marrow as a source of hematopoietic stem cells for allogenic transplantation. Cell Ther Transplant. 2011;3(12):34.
  10. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Интенсивная сопроводительная терапия в онкологии и гематологии. Вестник московского онкологического общества. 2011;2:3–4.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Intensive Supportive Therapy in Oncology and Hematology. Vestnik moskovskogo onkologicheskogo obshchestva. 2011;2:3–4. (In Russ)]
  11. Мелкова К.Н., Абдусаламов С.Н., Горбунова Н.В. и др. Интенсивная сопроводительная терапия в гематологии. Клиническая онкогематология. 2011;4(1):70–4.[Melkova KN, Abdusalamov SN, Gorbunova NV, et al. Intensive Supportive Therapy in Hematology. Klinicheskaya onkogematologiya. 2011;4(1):70–4. (In Russ)]
  12. Мелкова К.Н. Аллогенная трансплантация костного мозга. Клиническая онкогематология. 2012;5(1):1–12.[Melkova KN. Allogeneic Bone Marrow Transplantation. Klinicheskaya onkogematologiya. 2012;5(1):1–12. (In Russ)]
  13. Vriesendorp HM. Aims of the conditioning. Exp Hematol. 2003;31(10):844–54. doi: 10.1016/s0301-472x(03)00229-7.
  14. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation. Haematologica. 2004;89(10):1238–47.
  15. Мелкова К.Н., Горбунова Н.В., Чернявская Т.З. и др. Тотальное облучение организма человека при трансплантации костного мозга. Клиническая онкогематология. 2012;5(2):96–114.[Melkova KN, Gorbunova NV, Chernyavskaya TZ, et al. Total Human Body Irradiation at Bone Marrow Transplantation. Klinicheskaya onkogematologiya. 2012;5(2):96–114. (In Russ)]
  16.  Gratwohl A, Carreras E. Principles of conditioning. In: Apperley J, Carreras E, Gluckman E, Masszi T, eds. Hematopoietic Stem Cell Transplantation, 6th edition. Genoa: Forum service editore; 2012. pp. 122–37.
  17. Bensinger WI. High-dose preparatory regimens. In: Forman SJ, Negrin RS, Antin JH, eds. Thomas’ Hematopoietic Cell Transplantation, 5th edition. Willey Blackwell; 2016. Vol. 1. pp. 223–31.
  18. Лебеденко И.М., Ратнер Т.Г., Водяник В.В. и др. Проведение тотального облучения пациента перед трансплантацией костного мозга. Радиационная онкология и ядерная медицина. 2012;2:30–6.[Lebedenko IM, Ratner TG, Vodyanik VV, et al. Performance of Total Patient Irradiation before Bone Marrow Transplantation. Radiatsionnaya onkologiya i yadernaya meditsina. 2012;2:30–6. (In Russ)]
  19. Лебеденко И.М., Ратнер Т.Г., Водяник В.В. и др. Техническое и дозиметрическое обеспечение тотального облучения пациента перед трансплантацией костного мозга. Медицинская физика. 2012;3(55):11–9.[Lebedenko IM, Ratner TG, Vodyanik VV, et al. Technical and Radiation-Monitoring Supply of Total Patient Irradiation before Bone Marrow Transplantation. Meditsinskaya fizika. 2012;3(5):11–9. (In Russ)]
  20. Лебеденко И.М., Чернявская Т.З., Ставицкий Р.В. и др. Технический контроль состояния организма и его систем в процессе химио-лучевой терапии и трансплантации костного мозга при острых лейкозах. Медицинская техника. 2014;5:32–7.[Lebedenko IM, Chernyavskaya TZ, Stavitskii RV, et al. Technical Control of Patient’s Body State and Its Systems in Process of Chemoradiotherapy and Bone Marrow Transplantation. Meditsinskaya tekhnika. 2014;5:32–7. (In Russ)]
  21. Storb RF, Champlin R, Riddell SR, et al. Non-myeloablative transplants for malignant disease. Hematology Am Soc Hematol Educ Program. 2001;1:375–91. doi: 10.1182/asheducation-2001.1.375.
  22. Мелкова К.Н., Петрова Г.Д. Материалы 41-го конгресса Европейского общества по трансплантации костного мозга. Клиническая онкогематология. 2015;8(3):343–52.[Melkova KN, Petrova GD. Materials of 41st Congress of European Society of Bone Marrow Transplantation. Clinical oncohematology. 2015;8(3):343–52. (In Russ)]
  23. Sorror ML, Maris MB, Storer B, et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood. 2004;104(4):961–8. doi: 10.1182/blood-2004-02-0545.
  24. Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15(3):367. doi: 10.1016/j.bbmt.2008.12.497.
  25. Khouri I, Giralt S, Champlin R. Non-Myeloablative Allogeneic Hematopoietic Transplantation and Induction of Graft-Versus-Malignancy. In: Bashey A, Ball ED, eds. Cancer Treatment and Research. Boston: Springer; 2002. рр. 137–47. doi: 10.1007/978-1-4615-0919-6_7.

Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia

LYMPHOID TUMORS , , ,

GA Tsaur1,2,3, C Meyer4, TO Riger1,2, AM Kustanovich5, EV Fleischman6, YuV Ol’shanskaya7, AM Popov7, OI Sokova6, EA Matveeva7, OV Nikulina1,2, AE Drui1,2, OR Arakaev1,2, OV Streneva1,2, SA Rumyantsev7, EV Shorikov1,2, AG Solodovnikov2, LI Savel’ev1,2, R Marschalek4, LG Fechina1

 1 Regional Children’s Clinical Hospital No. 1, 32 Serafimy Deryabinoi str., Ekaterinburg, Russian Federation, 620149

2 Research Institute of Medical Cell Technologies, 22a K. Marksa str., Ekaterinburg, Russian Federation, 620026

3 First President of Russia B.N. Yeltsin Ural Federal University , 19 Mira str., Ekaterinburg, Russian Federation, 620002

4 Diagnostic Center of Acute Leukemia, Institute of Pharmaceutical Biology/ZAFES, Goethe-University of Frankfurt, N230, Max-von-Laue Str. 9, Frankfurt am Main Deutschland, 60438

5 Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, 43 Frunzenskaya str., Borovlyany, Minsk District, Belarus, 223053

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

7 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

For correspondence: Grigorii Anatol’evich Tsaur, PhD, 32 Serafimy Deryabinoi str., Ekaterinburg, Russian Federation, 620149; Tel.: +7(343)216-25-17; e-mail: tsaur@mail.ru

For citation: Tsaur GA, Meyer C, Riger TO, et al. Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia. Clinical oncohematology. 2016;9(1):22–9 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-22-29

ABSTRACT

Aim. To evaluate the relation between genomic DNA breakpoints in MLL and translocation partner genes (TPG) and clinical parameters of infant AL.

Methods. 68 infants (29 boys and 39 girls with median age of 4.8 mo) with MLL-rearranged acute lymphoblastic leukemia (ALL) (n = 46), acute myeloid leukemia (AML) (n = 20) and mixed phenotype acute leukemia (MPAL) (n = 2) were included in the current study.

Results. 5-year EFS was significantly lower in patients with breakpoints in intron 11 (n = 29) in comparison to patients with breakpoint localized from intron 7 to exon 11 (n = 17) (0.16 ± 0.07 vs 0.38 ± 0.14, p = 0.039). While cumulative incidence of relapse was remarkably higher in the first group of patients (0.74 ± 0.09 vs 0.52 ± 0.17, p = 0.045). Although in Cox regression model including breakpoint location in intron 11 together with age, immunophenotype, initial white blood cell count, initial CNS involvement, type of MLL rearrangements, absolute blast number at day 8 of dexamethasone profase, minimal residual disease (MRD) at time point 4 (TP4) of MLL-Baby protocol, the only significant covariate was the presence of MRD at TP4 (HR 5.994, 95% CI 2.209–16.263, p < 0.001). In 22 AML patients there was not any correlation between breakpoint location and treatment outcome.

Conclusion. Breakpoints in intron 11 of MLL gene led to significantly worse outcome in infants with ALL, treated by MLL-Baby protocol, although this parameter was overcome by MRD-positivity at TP4. The latter was the only independent covariate in multivariate analysis. Our data provide additional information of molecular genetic features of MLL-rearranged infant AL.

Keywords: acute leukemia, infants, 11q23/MLL rearrangements, MLL-Baby, treatment outcome.

Received: September 14, 2015

Accepted: October 20, 2015

Read in PDF (RUS)pdficon

REFERENCES

  1. Moorman A, Richards S, Robinson H, et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood. 2007;109(6):2327–30. doi: 10.1182/blood-2006-08-040436.
  2. Moorman A, Ensor H, Richards S, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010;11(5):429–38. doi: 10.1016/s1470-2045(10)70066-8.
  3. Fischer U, Forster M, Rinaldi A, et al. Genomics and drug profiling of fatal TCF3-HLF–positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet. 2015;47(9):1020–9. doi: 10.1038/ng.3362.
  4. Creutzig U, van den Heuvel-Eibrink M, Gibson B, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood. 2012;120(16):3187–205. doi: 10.1182/blood-2012-03-362608.
  5. Kuiper R, Waanders E, van der Velden V, et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia. 2010;24(7):1258–64. doi: 10.1038/leu.2010.87.
  6. Dorge P, Meissner B, Zimmermann M, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428–32. doi: 10.3324/haematol.2011.056135.
  7. den Boer M, van Slegtenhorst M, de Menezes R, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34. doi: 10.1016/s1470-2045(08)70339-5.
  8. Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children’s Cancer and Leukemia Study Group, Japan. Leukemia. 1999;13(1):38–43. doi: 10.1038/sj.leu.2401241.
  9. Reaman G. Biology and treatment of infant leukemias. In: Pui C-H, ed. Treatment of acute leukemias: new directions for clinical research. Totowa: Humana Press; 2003. p. 75–83.
  10. Pieters R. Biology and treatment of infant leukemias. In: Pui C-H, ed. Treatment of acute leukemias: new directions for clinical research. Totowa: Humana Press; 2003. p. 61–73.
  11. Pieters R. Infant acute lymphoblastic leukemia: Lessons learned and future directions. Curr Hematol Malig Rep. 2009;4(3):167–74. doi: 10.1007/s11899-009-0023-4.
  12. Pieters R, Schrappe M, de Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. The Lancet. 2007;370:240–50. doi: 10.1016/s0140-6736(07)61126-x.
  13. Popov A, Buldini B, de Lorenzo P, et al. Identification of low risk group in infants with acute lymphoblastic leukemia by flow cytometric minimal residual disease measurement at day 15 of Interfant-99 and Interfant-06 protocols treatment. Blood (ASH Annual Meeting Abstracts). 2013;122(21): Abstract 1333.
  14. van der Velden V, Corral L, Valsecchi M-G, et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23(6):1073–9. doi: 10.1038/leu.2009.17.
  15. Pui C-H, Raimondi S, Srivastava D, et al. Prognostic factors in infants with acute myeloid leukemia. Leukemia. 2000;14(4):684–7. doi: 10.1038/sj.leu.2401725.
  16. Tomizawa D, Koh K, Sato T, et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia. 2007;22(11):2258–63. doi: 10.1038/sj.leu.2404903.
  17. Stam R, Schneider P, de Lorenzo P, et al. Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia. Blood. 2007;110(7):2774–5. doi: 10.1182/blood-2007-05-091934.
  18. Ho P, Alonzo T, Gerbing R, et al. High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in paediatric acute myeloid leukaemia: a report from the children’s oncology group. Br J Haematol. 2013;162(5):670–7. doi: 10.1111/bjh.12444.
  19. Stam R, Schneider P, Hagelstein J, et al. Gene expression profiling–based dissection of MLL translocated and MLL germ-line acute lymphoblastic leukemia in infants. Blood. 2010;115(14):2835–44. doi: 10.1182/blood-2009-07-233049.
  20. Zangrando A, Dell’orto M, te Kronnie G, Basso G. MLL rearrangements in pediatric acute lymphoblastic and myeloblastic leukemias: MLL specific and lineage specific signatures. BMC Med Genom. 2009;2:36. doi: 10.1186/1755-8794-2-36.
  21. Emerenciano M, Meyer C, Mansur M, et al. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia. Br J Haematol. 2013;161(2):224–36. doi: 10.1111/bjh.12250.
  22. Roessler T, Marschalek R. An alternative splice process renders the MLL protein either into a transcriptional activator or repressor. Pharmazie. 2013;86:601–7. doi: 10.1055/s-0033-1343653.
  23. Bennett J, Catovsky D, Daniel M, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–8. doi: 10.1111/j.1365-2141.1976.tb03563.x.
  24. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9(10):1783–6.
  25. Bene MC, Nebe T, Bettelheim P, et al. Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. Leukemia. 2011;25(4):567–74. doi: 10.1038/leu.2010.312.
  26. Vardiman J, Thiele J, Arber D, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51. doi: 10.1182/blood-2009-03-209262.
  27. Цаур Г.А., Наседкина Т.В., Попов А.М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни острым лимфобластным лейкозом. Онкогематология. 2010;2:46–54.
    [Tsaur GA, Nasedkina TV, Popov AM, et al. Time to molecular remission as prognostic factor in infant acute lymphoblastic leukemia. Onkogematologiya. 2010;2:46–54. (In Russ)]
  28. Цаур Г.А., Флейшман Е.В., Попов А.М. и др. Цитогенетическая и молекулярно-генетическая характеристика острых лейкозов у детей первого года жизни. Клиническая онкогематология. 2011;4(2):134–41.
    [Tsaur GA, Fleischman EV, Popov AM, et al. Cytogenetics and molecular genetics of acute leukemias in infants. Klinicheskaya onkogematologiya. 2011;4(2):134–41. (In Russ)]
  29. Цаур Г.А., Плеханова О.М., Гиндина Т.Л. и др. Применение метода флуоресцентной гибридизации in situ для выявления перестроек гена MLL при острых лейкозах у детей первого года жизни. Медицинская генетика. 2012;7(121):35–45.
    [Tsaur GA, Plekhanova OM, Gindina TL, et al. Use of fluorescence in situ hybridization technique to detect MLL gene rearrangements in acute leukemias in infants. Meditsinskaya genetika. 2012;7(121):35–45. (In Russ)]
  30. Meyer C, Schneider B, Reichel M, et al. Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci USA. 2005;102(2):449–54. doi: 10.1073/pnas.0406994102.
  31. Цаур Г.А., Meyer C., Попов А.М. и др. Исследование структуры химерных генов с участием гена MLL при острых лейкозах у детей первого года жизни. Гематология и трансфузиология. 2014;59(1):29–37.
    [Tsaur GA, Meyer C, Popov AM, et al. Evaluation of structure of chimeric genes involving MLL gene in infant acute leukemia. Gematologiya i transfuziologiya. 2014;59(1):29–37. (in Russ)]
  32. Nilson I, Lochner K, Siegler G, et al. Exon/intron structure of ALL1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukemias. Br J Haematol. 1996;94(4):966–72. doi: 10.1046/j.1365-2141.1996.d01-1748.x.
  33. Gabert J, Beillard E, van der Velden V, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program. Leukemia. 2003;17(12):2318–57. doi: 10.1038/sj.leu.2403135.
  34. Jansen M, van der Velden V, van Dongen J. Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and LightCycler. Leukemia. 2005;19(11):2016. doi: 10.1038/sj.leu.2403939.
  35. Цаур Г.А., Друй А.Е., Попов А.М. и др. Возможность использования микроструйных биочипов для оценки качества и количества РНК у детей с онкологическими и онкогематологическими заболеваниями. Вестник Уральской медицинской академической науки. 2011;4:107–11.
    [Tsaur GA, Druy АЕ, Popov АМ, et al. Microfluidic biochips for RNA quantity and quality evaluation in children with oncological and oncohematological disorders. Vestnik Ural’skoi meditsinskoi akademicheskoi nauki. 2011;4:107–11. (In Russ)]
  36. Fechina L, Shorikov E, Tsaur G, et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood (ASH Annual Meeting Abstracts). 2007;110(11): Abstract 832А.
  37. Fechina L, Shorikov E, Streneva O, et al. Does ATRA confirm to play a role in the better relapse free survival of infants with acute lymphoblastic leukemia? Blood (ASH Annual Meeting Abstracts). 2011;118(21): Abstract 1515.
  38. Цаур Г.А., Попов А.М., Алейникова О.В. и др. Характеристика перестроек 11q23 (MLL) у детей первого года жизни с острым лимфобластным лейкозом. Онкогематология. 2011;3:57–64.
    [Tsaur GA, Popov AM, Aleinikova OV, et al. Detection of 11q23 (MLL) rearrangements in infant acute lymphoblastic leukemia. Onkogematologiya. 2011;3:57–64. (In Russ)]
  39. Reaman GH, Sposto R, Sensel M, et al. Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children’s Cancer Group. J Clin Oncol. 1999;17(2):445–55.
  40. Conter V, Bartram C, Valsecchi M-G, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFMALL 2000 study. Blood. 2010;115(16):3206–14. doi: 10.1182/blood-2009-10-248146.
  41. Basso G, Veltroni M, Valsecchi M-G, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol. 2009;27(31):5168–74. doi: 10.1200/jco.2008.20.8934.
  42. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program). 2010;2010:7–12. doi: 10.1182/asheducation-2010.1.7.
  43. Цаур Г.А., Попов A.M., Наседкина Т.В. и др. Прогностическое значение минимальной остаточной болезни, определенной путем выявления химерных транскриптов у детей первого года жизни, больных острым лимфобластным лейкозом, получающих терапию по протоколу MLL-Baby. Гематология и трансфузиология. 2012;57(4):12–22.
    [Tsaur GA, Popov AM, Nasedkina TV, et al. Prognostic significance of minimal residual disease detected by PCR for fusion gene transcripts in infant acute lymphoblastic leukemia treated by MLL-baby protocol. Gematologiya i transfuziologiya. 2012;57(4):12–22. (In Russ)]
  44. Burmeister T, Marschalek R, Schneider B, et al. Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations. Leukemia. 2006;20(3):451–7. doi: 10.1038/sj.leu.2404082.

Selection of patients for iron-chelating therapy

COMPLICATIONS OF SUPPORTIVE THERAPY , , , , , ,

S.V. Gritsaev, B. Davaasambuu, N.A. Romanenko, and K.M. Abdulkadyrov

Russian Research Institute of Hematology and Transfusiology, FMBA, Saint Petersburg, Russian Federation

ABSTRACT

Emergence of iron aggressive forms in patients with hematological or oncohematological diseases is potentially life-threatening. This can be caused by several situations: multiple allogeneic RBC transfusions, increased intestinal absorption of iron, or damaging effects of chemotherapeutic agents. The objective of the study was to identify candidates for iron-chelating therapy. The data on 727 patients with screening blood tests were analyzed. The highest serum ferritin level was revealed in patients with thalassemia, PMF, or MDS. They received 80, 37, or 35 RBC transfusions, respectively. The lowest serum ferritin levels were found in patients with CLL or hemolytic anemia that received lesser number of RBC transfusions, namely, 18.5 and 16.5, respectively. The correlation between serum ferritin level and the total number of RBC transfusions was revealed: r = 0.462; p = 0.000. We concluded that iron-chelating therapy is primarily indicated to the patients with MDS or PMF in whom the high serum ferritin level is due to excessive post-transfusion iron.

Keywords: myelodysplastic syndromes, primary myelofibrosis, thalassemia, acute leukemia, multiple myeloma, serum ferritin, allogeneic RBC transfusions.

Read in PDF (RUS)pdficon

REFERENCES

  1. Cazzola M., Della Porta M.G., Malcovati L. Clinical relevance of anemia and transfusion iron overload in myelodysplastic syndromes. Hematology (Am. Soc. Hematol. Educ. Program) 2008; 166–75.
  2. Gattermann N. Pathophysiological and clinical aspects of iron chelation therapy in MDS. Curr. Pharmac. Design 2012; 18: 3222–34.
  3. Gattermann N., Rachmilewitz E.A. Iron overload in MDS — pathophysiology, diagnosis, and complications. Ann. Hematol. 2011; 90: 1–10.
  4. Ghoti H., Fibach E., Merkel D. et al. Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in ironoverloaded patients with myelodysplastic syndromes. Haematologica 2010; 95: 1433–4.
  5. Leitch H.A. Controversies surrounding iron chelation therapy for MDS. Blood Rev. 2011; 25: 17–31.
  6. Origa R., Galanello R., Ganz T. et al. Liver iron concentrations and urinary hepcidin in b-thalassemia. Haematologica 2007; 92: 583–8.
  7. Park S., Sapena R., Keladi C. et al. Ferritin level at diagnosis is not correlated with poorer survival in non RBC transfusion dependent lower risk de novo MDS. Leuk. Res. 2011; 35: 1530–3.
  8. Knovich M.A., Storey J.A., Coffman L.G., Torti S.V. Ferritin for the clinician. Blood Rev. 2009; 23: 95–104.
  9. Armand P., Kim H.T. Rhodes J. et al. Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation. Biol. Blood Marrow Transplant. 2011; 17: 852–60.
  10. Brittenham G.M., Cohen A.R., McLaren C.E. et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am. J. Hematol. 1993; 42: 81–5.
  11. Roghi A., Cappellini M.D., Wood J.C. et al. Absence of cardiac siderosis despite hepatic iron overload in Italian patients with thalassemia intermedia: an MRI T2* study. Ann. Hematol. 2010; 89: 585–9.
  12. Taher A., Rassi F.E., Ismaeel H. et al. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica 2008; 93: 1584–5.
  13. Piga A., Longo F., Duca L. et al. High nontransferrin bound iron levels and heart disease in thalassemia major. Am. J. Hematol. 2009; 84: 29–33.
  14. Sahlstedt L., von Bonsdorff L., Ebeling F. et al. Non-transferrin-bound iron in haematological patients during chemotherapy and conditioning for autologous stem cell transplantation. Eur. J. Haematol. 2009; 83: 455–9.
  15. Sahlstedt L., Ebeling F. von Bonsdorff L. et al. Non-transferrin-bound iron during allogeneic stem cell transplantation. Br. J. Haematol. 2001; 113: 836–8.
  16. Andrews N.C. Disorders of iron metabolism. New Engl. J. Med. 1999; 341: 1986–95.
  17. Porter J.B. Practical management of iron overload. Br. J. Haematol. 2001; 115: 239–52.
  18. Dreyfus F. The deleterious effects of iron overload in patients with myelodysplastic syndromes. Blood Rev. 2008; 22(Suppl. 2): S29–34.
  19. Malcovati L., Porta M.G., Pascutto C. et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J. Clin. Oncol. 2005; 23: 7594–603.
  20. Pakbaz Z., Fischer R., Fung E. et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr. Blood Cancer 2007; 49: 329–32.
  21. Karam L.B., Disco D., Jackson S.M. et al. Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels. Pediatr. Blood Cancer 2008; 50: 62–5.
  22. Nielsen P., Gunther U., Durken M. et al. Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance. J. Lab. Clin. Med. 2000; 135: 413–8.
  23. Valent P., Krieger O., Stauder R. et al. Iron overload in myelodysplastic syndromes (MDS) — diagnosis, management, and response criteria: a proposal of the Austrian MDS platform. Eur. J. Clin. Invest. 2008; 38: 143–9.
  24. Alessandrino E.P., Della Porta M.G., Bacigalupo A. et al. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. Haematologica 2010; 95: 476–84.
  25. Pullarkat V. Iron overload in patients undergoing hematopoietic stem cell transplantation. Adv. Hematol. 2010; pii: 345756.
  26. Грицаев С.В., Абдулкадыров К.М., Шихбабаева Д.И. Миелодиспла- стический синдром (МДС) и перегрузка железом (результаты скрининго- вого обследования 289 больных de novo МДС). Фарматека 2010; 10: 60–7. Gritsayev S.V., Abdulkadyrov K.M., [Shikhbabayeva D.I. Miyelodisplasticheskiy sindrom (MDS) i peregruzka zhelezom (rezultaty skriningovogo obsledovaniya 289 bolnykh de novo MDS) (Myelodisplastic syndrome (MDS) and iron overload (screening study results in 289 patients with de novo MDS)). Farmateka 2010; 10: 60–7.]
  27. Pullarkat V., Blanchard S., Tegtmeier B. et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2008; 42: 799–805.
  28. Kushner J.P., Porter J.P., Olivieri N.F. Secondary iron overload. Hematology (Am. Soc. Hematol. Educ. Program) 2001: 47–61.
  29. Angelucci E., Barosi G., Camaschella C. et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008; 93: 741–52.
  30. de Swart L., Smith A., Fenaux P. et al. Transfusion-dependency is the most important prognostic factor for survival in 1000 newly diagnosed MDS patients with low- and intermediate-1 risk MDS in the European LeukemiaNet MDS registry. Blood 2011; 118: Abstract 2775.
  31. Armand P., Sainvil M.-M., Kim H.T. et al. Pre-transplantation iron chelation in patients with MDS or acute leukemia and iron overload undergoing myeloablative allo-SCT. Bone Marrow Transplantat. 2012 May 21. doi: 10.1038/ bmt.2012.94.
  32. Cappellini M.D., Porter J., El-Beshlawy A. et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica 2010; 95: 557–66.
  33. Cilloni D., Messa E., Biale L. et al. High rate of erythroid response during iron chelation therapy in a cohort of 105 patients affected by hematologic malignancies with transfusional iron overload: an Italian multicenter retrospective study. Blood 2011; 118: Abstract 611.
  34. Gattermann N., Finelli C., Della Porta M. et al. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica 2012; 97: 1364–71.
  35. Neukirchen J., Fox F., Kundgen A. et al. Improved survival in MDS patients receiving iron chelation therapy — a matched pair analysis of 188 patients from the Dusseldorf MDS registry. Leuk. Res. 2012; 36: 1067–70.
  36. Pullarkat V. Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye? Blood 2009; 114: 5251–5.
  37. Leitch H.A., Chase J.M., Goodman T.A. et al. Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy. Hematol. Oncol. 2010; 28: 40–8.
  38. Armand P., Kim H.T., Cutler S.C. et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109: 4586–8.
  39. Kanda J., Kawabata H., Chao N.J. Iron overload and allogeneic hematopoietic stem-cell transplantation. Expert Rev. Hematol. 2011; 4: 71–80.
  40. Lim Z.Y., Fiaccadori V., Gandhi S. et al. Impact of pre-transplant serum ferritin on outcomes of patients with myelodysplastic syndromes or secondary acute myeloid leukemia receiving reduced intensity conditioning allogeneic haematopoietic stem cell transplantation. Leuk. Res. 2010; 34: 723–7.
  41. Maradei S.C., Maiolino A., de Azevedo A.M. et al. Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation. Blood 2009; 114: 1270–5.
  42. Platzbecker U., Bornhauser M., Germing U. et al. Red blood cell transfusion-dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndromes (MDS). Biol. Blood Marrow Transplant. 2008; 14: 1217–25.
  43. Tanaka V., Tachibana N., Numata A. et al. A prognostic score with pretransplant serum ferritin and disease status predicts outcome following reduced-intensity SCT. Bone Marrow Transplant. 2012; 47: 596–7.
  44. Lee J.W., Kang H.J., Kim E.K. et al. Effect of iron overload and ironchelating therapy on allogeneic hematopoietic SCT in children. Bone Marrow Transplant. 2009; 44: 793–7.
  45. Fritsch A., Langebrake C., Nielsen P. et al. Deferasirox (Exjade®) given during conditioning regimen (FLAMSA/Busulfan/ATG) reduces the appearance of labile plasma iron in patients undergoing allogeneic stem cell transplantation. Blood 2011; 118: Abstract 3023.
  46. Armand P., Sainvil M.-M., Kim H.T. et al. Does iron overload really matter in stem cell transplantation? Am. J. Hematol. 2012; 87: 569–72.
  47. Pardanani A., Tefferi A. Prognostic relevance of anemia and transfusion dependency in myelodysplastic syndromes and primary myelofibrosis. Haematologica 2011; 96: 8–10.
  48. Ali S., Pimentel J.D., Munoz J. et al. Iron overload in allogeneic hematopoietic stem cell transplant recipients. Arch. Pathol. Lab. Med. 2012; 136: 532–8.