acute myeloid leukemias

Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step

AUTOIMMUNE THROMBOCYTOPENIA

MA Granatkin1,2, EA Nikitin1,2, ES Mikhailov1, VA Doronin1, SV Minenko1, MM Okuneva1,2, NV Degtyareva1, ME Pochtar1,2, SA Lugovskaya1,2, YuN Kobzev1, OYu Vinogradova1, VV Ptushkin1,2

1 SP Botkin City Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993

For correspondence: Prof. Evgenii Aleksandrovich Nikitin, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)572-06-44; e-mail: eugene_nikitin@mail.ru

For citation: Granatkin MA, Nikitin EA, Mikhailov ES, et al. Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step. Clinical oncohematology. 2022;15(3):282–8. (In Russ).

DOI: 10.21320/2500-2139-2022-15-3-282-288

ABSTRACT

Background. The treatment of elderly patients with acute myeloid leukemias (AML) is one of the most formidable challenges in oncohematology. Hypomethylating drugs combined with venetoclax show relatively high efficacy and lower toxicity in elderly AML patients.

Aim. To retrospectively analyze the efficacy and tolerability of the combined azacitidine/venetoclax therapy in AML primary patients of older age as well as to determine a spectrum of issues related to the implementation of this regimen in real-world clinical practice.

Materials & Methods. The retrospective analysis enrolled a cohort of patients followed-up at the Botkin City Clinical Hospital (n = 35). The median age was 73 years (range 60–90 years), 57 % of patients were over 70 years of age. The median follow-up duration was 5.2 months (range 1.6–42.6 months). By the time of final analysis 15 patients were still receiving the therapy. The median of overall survival was 11.1 months (95% confidence interval [95% CI] 8.1–14.1 months). The causes of death in 20 patients were AML progression (n = 3), non-COVID-19 infectious complications (n = 3), and COVID-19 (n = 10). In 4 patients the cause of death remained unidentified.

Results. Complete remission (CR) was documented in 17 (48.5 %) patients; CR with incomplete hematologic recovery was identified in 9 (26 %) patients. The median time before achieving remission was 67 days (range 27–120 days). In 96 % of patients CR was achieved after 3 azacitidine/venetoclax cycles. The mean CR duration was 9.2 months (95% CI 5.7–12.6 months); the median time before loss of response was 19 months. Relapses were diagnosed in 5 patients. Neutropenia > grade 3 was identified in patients who achieved remission on subsequent therapy cycles in 100 % of cases (n = 26), anemia > grade 2 was reported in 9 (34 %) patients, and thrombocytopenia > grade 3 was detected in 13 (50 %) patients. Despite frequent neutropenia, patients with remission did not show any severe infectious complications.

Conclusion. The combined azacitidine/venetoclax therapy in elderly patients yields remission in more than 70 % of cases and is not marked by any severe infectious complications, despite developing neutropenia. Due to its ease of administration and low toxicity, this regimen can be performed in outpatient units.

Keywords: acute myeloid leukemias, efficacy of therapy, venetoclax, hypomethylating drugs.

Received: January 31, 2022

Accepted: May 5, 2022

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5. doi: 10.1182/blood-2005-09-3724.
  2. Creutzig U, Zimmermann M, Reinhardt D, et al. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups. Cancer. 2016;122(24):3821–30. doi: 10.1002/cncr.30220.
  3. Kantarjian H, Ravandi F, O’Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422–9. doi: 10.1182/blood-2010-03-276485.
  4. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood. 2015;126(3):291–9. doi: 10.1182/blood-2015-01-621664.
  5. Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375(21):2023–36. doi: 10.1056/NEJMoa1605949.
  6. Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28(4):556–61. doi: 10.1200/jco.2009.23.9178.
  7. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127(1):53–61. doi: 10.1182/blood-2015-08-604520.
  8. Guerra VA, DiNardo C, Konopleva M. Venetoclax-based therapies for acute myeloid leukemia. Best Pract Res Clin Haematol. 2019;32(2):145–53. doi: 10.1016/j.beha.2019.05.008.
  9. Серегин Г.З., Лифшиц А.В., Валиев Т.Т. Таргетные препараты в лечении острых миелоидных лейкозов у детей. Российский журнал детской гематологии и онкологии. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85.
    [Seregin GZ, Lifshits AV, Valiev TT. Targeted drugs in the treatment of acute myeloid leukemia in children. Russian Journal of Pediatric Hematology and Oncology. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85. (In Russ)]
  10. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617–29. doi: 10.1056/NEJMoa2012971.
  11. Pollyea DA, Pratz K, Letai A, et al. Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study. Am J Hematol. 2021;96(2):208–17. doi: 10.1002/ajh.26039.
  12. Pollyea DA, Bixby D, Perl A, et al. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021: Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2021;19(1):16–27. doi: 10.6004/jnccn.2021.0002.
  13. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41. doi: 10.1016/j.stem.2012.12.013.
  14. Pan R, Ruvolo VR, Wei J, et al. Inhibition of Mcl-1 with the pan–Bcl-2 family inhibitor (–)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015;126(3):363–72. doi: 10.1182/blood-2014-10-604975.
  15. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75. doi: 10.1158/2159-8290.Cd-13-0609.
  16. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016;6(10):1106–17. doi: 10.1158/2159-8290.Cd-16-0313.
  17. Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9. doi: 10.3109/10428194.2014.910657.
  18. Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70. doi: 10.1007/s00277-012-1537-8.
  19. Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58(9):1–17. doi: 10.1080/10428194.2017.1283032.
  20. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182/blood-2018-08-868752.
  21. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019;33(12):2795–804. doi: 10.1038/s41375-019-0612-8.

Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation

AUTOIMMUNE THROMBOCYTOPENIA ,

SN Bondarenko1, AG Smirnova1, BI Ayubova1, EV Karyagina2, OS Uspenskaya3, YuS Neredko4, AP Kochergina5, IA Samorodova6, EA Pashneva7, YuS Chernykh8, YuA Dunaev9, NB Esef’eva10, RK Il’yasov11, TI Brazhkina12, IA Novokreshchenova13, ZK Simavonyan14, EI Kuzub15, VI Bakhtina16, TI Olkhovich17, MV Burundukova18, EV Babenko1, YuD Oleinikova1, IM Barkhatov1, TL Gindina1, IS Moiseev1, AD Kulagin1

1 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022

2 Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205

3 Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

4 Stavropol Krai Clinical Oncology Dispensary, 182a Oktyabrskaya ul., Stavropol, Russian Federation, 355047

5 Krai Clinical Hospital, 1 Lyapidevskogo ul., Barnaul, Russian Federation, 656024

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

7 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki ul., Volgograd, Russian Federation, 400138

8 MF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina ul., Moscow, Russian Federation, 129110

9 Arkhangelsk Regional Clinical Hospital, 292 Lomonosova pr-t, Arkhangelsk, Russian Federation, 163045

10 Ulyanovsk Regional Clinical Hospital, 7 III Internatsionala ul., Ulyanovsk, Russian Federation, 432017

11 VM Efetov Crimea Republican Clinical Oncology Dispensary, 49A Bespalova ul., Simferopol, Russian Federation, 295007

12 Ivanovo Regional Clinical Hospital, 1 Lyubimova ul., Ivanovo, Russian Federation, 153040

13 RZhD-Meditsina Clinical Hospital, 15 1-i Krasnoflotskii per., Smolensk, Russian Federation, 214025

14 AI Burnazyan Federal Medical Biophysical Center, 23 Marshala Novikova ul., Moscow, Russian Federation, 123098

15 Rostov State Medical University Hospital, 29 Nakhichevanskii per., Rostov-on-Don, Russian Federation, 344022

16 Krasnoyarsk Krai Clinical Hospital, 3A Partizana Zheleznyaka ul., Krasnoyarsk, Russian Federation, 660022

17 Krasnoyarsk Interdistrict Clinical Hospital No. 7, 4 Akademika Pavlova ul., Krasnoyarsk, Russian Federation, 660003

18 Municipal Clinical Hospital No. 2, 21 Polzunova ul., Novosibirsk, Russian Federation, 630051

For correspondence: Sergei Nikolaevich Bondarenko, MD, PhD, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; Tel.: +7(921)994-35-70; e-mail: dr.sergeybondarenko@gmail.com

For citation: Bondarenko SN, Smirnova AG, Ayubova BI, et al. Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation. Clinical oncohematology. 2022;15(2):167–75. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-167-175

ABSTRACT

Background. The detection of FLT3-ITD mutation in acute myeloid leukemia (AML) patients is associated with poor prognosis and is an indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first remission. Midostaurin is the first FLT3 inhibitor approved for the treatment of AML patients with FLT3 mutation in the Russian Federation in November 2019. This study deals with the initial experiences of using midostaurin in several centers for hematology in the Russian Federation.

Aim. To analyze the initial experiences of using midostaurin at different AML stages.

Materials & Methods. The study enrolled 42 patients with newly diagnosed AML with FLT3 mutation, who were treated with midostaurin combined with chemotherapy. Allo-HSCT was performed in 11 patients.

Results. The 2-year overall survival (OS) was 51 %, and the 2-year event-free survival (EFS) was 45 %. After achieving remission, the 2-year disease-free survival (DFS) was 58 %. The 1-year DFS of allo-HSCT recipients was 86 % (95% confidence interval [95% CI] 60–100 %) vs. 66 % in patients treated with chemotherapy without allo-HSCT (95% CI 34–98 %), respectively (p = 0.5). Hyperleukocytosis at disease onset was associated with high relapse risk. Midostaurin had to be discontinued in 5 % of cases due to atrial fibrillation and QTc prolongation.

Conclusion. The present study demonstrates the safety and importance of including midostaurin in the regimens for treating AML with FLT3 mutation. Midostaurin assignment for maintenance therapy, after allo-HSCT as well as without performing it, can result in considerable improvement of OS and DFS.

Keywords: acute myeloid leukemias, FLT3 mutations, targeted therapy, midostaurin.

Received: December 27, 2021

Accepted: March 20, 2022

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Pemmaraju N, Kantarjian H, Ravandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? 2011;117(15):3293–304. doi: 10.1002/cncr.25908.
  2. Зайкова Е.К., Белоцерковская Е.В., Зайцев Д.В. и др. Молекулярная диагностика мутаций гена FLT3 у пациентов с острыми миелоидными лейкозами. Клиническая онкогематология. 2020;13(2):150–60. doi: 10.21320/2500-2139-2020-13-2-150-160.
    [Zaikova EK, Belotserkovskaya EV, Zaytsev DV, et al. Molecular Diagnosis of FLT3 Mutations in Acute Myeloid Leukemia Patients. Clinical oncohematology. 2020;13(2):150–60. doi: 10.21320/2500-2139-2020-13-2-150-160. (In Russ)]
  3. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. doi: 10.1056/NEJMoa1516192.
  4. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–65. doi: 10.1038/nrc1169.
  5. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326–35. doi: 10.1182/blood.v99.12.4326.
  6. Кузнецова С.А., Зарубина К.И., Паровичникова Е.Н., Судариков А.Б. Определение мутаций FLT3/ITD, NPM1, CEBPA у больных ОМЛ. Гематология и трансфузиология. 2014;59(1):99.
    [Kuznetsova SA, Zarubina KI, Parovichnikova EN, Sudarikov AB. Detection of FLT3/ITD, NPM1, CEBPA mutations in AML patients. Gematologiya i transfuziologiya. 2014;59(1):99. (In Russ)]
  7. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233–9.
  8. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–80. doi: 10.1182/blood-2002-05-1440.
  9. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18. doi: 10.1056/NEJMoa074306.
  10. Раджабова А.М., Волошин С.В., Мартынкевич И.С. и др. Роль мутаций гена FLT3 при острых миелоидных лейкозах: влияние на течение заболевания и результаты терапии. Гены и клетки. 2019;14(1):55–61. doi: 10.23868/201903007.
    [Radzhabova AM, Voloshin SV, Martynkevich IS, et al. Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy. Geny i kletki. 2019;14(1):55–61. doi: 10.23868/201903007. (In Russ)]
  11. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386–92. doi: 10.1182/blood-2009-03-209999.
  12. Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006;107(9):3700–7. doi: 10.1182/blood-2005-06-2596.
  13. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345–9. doi: 10.1038/sj.leu.2403838.
  14. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64. doi: 10.1056/NEJMoa1614359.
  15. Voso MT, Larson RA, Jones D, et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. 2020;4(19):4945–54. doi: 10.1182/bloodadvances.2020002904.
  16. Dohner K, Thiede C, Jahn N, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135(5):371–80. doi: 10.1182/blood.2019002697.
  17. Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–51. doi: 10.1182/blood-2018-08-869453.
  18. Roboz GJ, Strickland SA, Litzow MR, et al. Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Leuk Lymphoma. 2020;61(13):3146–53. doi: 10.1080/10428194.2020.1805109.
  19. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.

Pharmacoeconomic Analysis of Gilteritinib in the Therapy of Adult Patients with Relapsed/Refractory Acute Myeloid Leukemias with FLT3 Mutation

AUTOIMMUNE THROMBOCYTOPENIA ,

AS Kolbin1,2, YuM Gomon1, YuE Balykina2, MA Proskurin2

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

2 Saint Petersburg State University, 7/9 Universitetskaya emb., Saint Petersburg, Russian Federation, 199034

For correspondence: Yuliya Mikhailovna Gomon, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(911)960-62-68; e-mail: gomonmd@yandex.ru

For citation: Kolbin AS, Gomon YuM, Balykina YuE, Proskurin MA. Pharmacoeconomic Analysis of Gilteritinib in the Therapy of Adult Patients with Relapsed/Refractory Acute Myeloid Leukemias with FLT3 Mutation. Clinical oncohematology. 2022;15(1):85–96. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-85-96

ABSTRACT

Background. The implementation of new FLT3-targeted drugs in clinical practice has changed the approaches to the management of patients with acute myeloid leukemias (AML) with FLT3 mutation. One of these drugs is gilteritinib, approved by FDA in 2018 as a drug of choice in the therapy of adult patients with relapsed/refractory AML with FLT3 mutation.

Aim. To assess the economic feasibility of gilteritinib in the therapy of adult patients with relapsed/refractory AML with FLT3 mutation.

Materials & Methods. Pharmacoeconomic modelling was based on Markov and decision-tree models. Incremental cost-effectiveness ratio (ICER) was calculated relative to the efficiency indicator “overall survival”. Its values were compared with those calculated for venetoclax as reference drug, which has been already included in Essential Drug List and used as a first-line drug in this population if high-dose chemotherapy therapy is contraindicated. A Budget Impact Analysis has been made.

Results. Gilteritinib proved to be not only more effective in terms of overall survival (median 9.3 vs. 5.6 months), but also more cost-intensive (7,408,108 vs. 1,685,356 rubles a year) compared to the currently used polychemotherapy regimens. However, the difference of ICER with venetoclax was +4,89 % of total costs. The Budget Impact Analysis showed that the total economic load of implementing gilteritinib in clinical practice throughout 3 years will be 8,628,658,505 rubles.

Conclusion. Gilteritinib therapy is economically feasible and viable for adult patients with relapsed/refractory AML with FLT3 mutation.

Keywords: gilteritinib, FLT3 mutation, acute myeloid leukemias, pharmacoeconomics, incremental cost-effectiveness ratio.

Received: July 8, 2021

Accepted: November 21, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Клинические рекомендации «Острые миелоидные лейкозы» (электронный документ). М., 2020 г. Доступно по: https://oncology-association.ru/files/clinical-guidelines-2020/ostrye_mieloidnye_lejkozy.pdf. Ссылка активна на 16.06.2021.
    [Klinicheskie rekomendatsii “Ostrye mieloidnye leikozy”. (Clinical guidelines “Acute myeloid leukemias”.) (Internet) Moscow; 2020. Available from: https://oncology-association.ru/files/clinical-guidelines-2020/ostrye_mieloidnye_lejkozy.pdf. (accessed 16.06.2021) (In Russ)]
  2. Серегин Г.З., Лифшиц А.В., Валиев Т.Т. Таргетные препараты в лечении острых миелоидных лейкозов у детей. Российский журнал детской гематологии и онкологии. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85.
    [Seregin GZ, Lifshits AV, Valiev TT. Targeted drugs in the treatment of acute myeloid leukemia in children. Russian Journal of Pediatric Hematology and Oncology. 2020;7(3):78–85. doi: 10.21682/2311-1267-2020-7-3-78-85. (In Russ)]
  3. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454–64. doi: 10.1056/NEJMoa1614359.
  4. Cornelissen JJ, Gratwohl A, Schlenket RF, et The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: An integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9(10):579–90. doi: 10.1038/nrclinonc.2012.150.
  5. Peri AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728–40. doi: 10.1056/NEJMoa1902688.
  6. Центр экспертизы контроля качества медицинской помощи. Методические рекомендации по проведению сравнительной клинико-экономической оценки лекарственного препарата (электронный документ). М., 2018. Доступно по: https://rosmedex.ru/wp-content/uploads/2019/06/MR-KE%60I_novaya-redaktsiya_2018-g.pdf. Ссылка активна на 16.06.2021.
    [Tsentr ekspertizy kontrolya kachestva meditsinskoi pomoshchi. Metodicheskie rekomendatsii po provedeniyu sravnitel’noi kliniko-ekonomicheskoi otsenki lekarstvennogo preparate. (Center for Expertise of Healthcare Quality Control. Methodological guidelines for comparative clinical and economic evaluation of drugs.) (Internet) Available from: https://rosmedex.ru/wp-content/uploads/2019/06/MR-KE%60I_novaya-redaktsiya_2018-g.pdf. (accessed 16.06.2021) (In Russ)]
  7. Государственный реестр лекарственных средств (электронный документ). Доступно по: http://grls.rosminzdrav.ru/default.aspx. Ссылка активна на 16.06.2021.
    [Gosudarstvennyi reestr lekarstvennykh sredstv. (State Register of Drugs.) (Internet) Available from: http://grls.rosminzdrav.ru/default.aspx. (accessed 16.06.2021) (In Russ)]
  8. Российский фармацевтический портал (электронный документ). Доступно по: https://www.pharmindex.ru/ Ссылка активна на 16.06.2021.
    [Rossiyskiy farmacevticheskiy portal. (Russian Pharmaceutics Portal.) (Internet) Available from: https://www.pharmindex.ru/ (accessed 16.2021) (In Russ)]
  9. Постановление Правительства от 07.12.2019 № 1610 «О программе государственных гарантий бесплатного оказания гражданам медицинской помощи на 2020 г. и на плановый период 2021 и 2022 гг.».
    [Government decree 1610 dated 07.12.2019. On the program of state guarantees of free healthcare provision for 2020 and for the planning period of 2021 and 2022. (In Russ)]
  10. Методические рекомендации по способам оплаты медицинской помощи за счет средств обязательного медицинского страхования (электронный документ). Доступно по: https://rosmedex.ru/wp-content/uploads/2019/07/Metod-rekomendatsii-red.ot-02.07.2019.pdf. Ссылка активна на 16.06.2021.
    [Metodicheskie rekomendacii po sposobam oplaty medicinskoy pomoschi za schet sredstv obyazatelnogo strahovaniya. (Methodological guidelines for methods of medical care payment covered by compulsory health insurance.) (Internet) Available from: https://rosmedex.ru/wp-content/uploads/2019/07/Metod-rekomendatsii-red.ot-02.07.2019.pdf. (accessed 16.06.2021) (In Russ)]
  11. Приказ Министерства здравоохранения и социального развития РФ «Об утверждении стандарта медицинской помощи больным миелоидным лейкозом (миелолейкозом), лейкозом уточненного клеточного типа». М., 2006.
    [Decree of the Ministry of Health and Social Development of the Russian Federation. On the approval of the medical care standard for patients with myeloid leukemia and leukemia of a specified cell type. Moscow; 2006. (In Russ)]
  12. Прейскурант платных медицинских услуг ФГБУ РосНИИГТ ФМБА России (электронный документ). Доступно по: http://www.bloodscience.ru/patient/price/ Ссылка активна на 16.06.2021.
    [Preiskurant platnykh meditsinskikh uslug FGBU RosNIIGT FMBA Rossii. (Price list for paid medical services of the Russian Research Institute of Hematology and Transfusiology.) (Internet) Available from: http://www.bloodscience.ru/patient/price/ (accessed06.2021) (In Russ)]
  13. Приказ Минздрава № 345н и Минтруда № 372н «Положение об организации оказания паллиативной медицинской помощи, включая порядок взаимодействия медицинских организаций, организаций социального обслуживания и общественных объединений, иных некоммерческих организаций, осуществляющих свою деятельность в сфере охраны здоровья». М., 2019.
    [Decree No. 345n of the Ministry of Health and No. 372n of the Ministry of Labor of the Russian Federation. On the organization of palliative services with interaction of healthcare providers, social services, non-governmental associations, and other non-commercial organizations involved in healthcare. Moscow; 2019. (In Russ)]
  14. Федеральный закон от 24.11.1995 № 181 «О социальной защите инвалидов в Российской Федерации».
    [Federal Law No. 181 dated 24.11.1995. On social protection of people with disabilities in the Russian Federation. (In Russ)]
  15. Joshi N, Hensen M, Patel S et al. Health State Utilities for Acute Myeloid Leukaemia: A Time Trade-off Study. PharmacoEconomics. 2019;37(1):85–92. doi: 10.1007/s40273-018-0704-8.
  16. National Cancer Institute Surveillance, Epidemiology, and End Results Program: Cancer stat facts: leukemia—acute myeloid leukemia. Available from: https://seer.cancer.gov/statfacts/html/amyl.html. (accessed 16.06.2021).
  17. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood. 2015;126(3):291–9. doi: 10.1182/blood-2015-01-621664.
  18. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670– doi: 10.1200/JCO.2011.38.9429.
  19. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–24. doi: 10.1002/cncr.22496.
  20. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617–29. doi: 10.1056/NEJMoa2012971.
  21. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. doi: 10.1182/blood-2018-08-868752.
  22. Wei AH, Strickland SA Jr, Hou J-Z, et al. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol. 2019;37(15):1277–84. doi: 10.1200/JCO.18.01600.
  23. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016;6(10):1106–17. doi: 10.1158/2159-8290.CD-16-0313.

Current State of Diagnosis and Treatment of Acute Myeloid Leukemias in Adult Patients in the Republic of Kazakhstan

AUTOIMMUNE THROMBOCYTOPENIA ,

AA Klodzinskii1, IA Pivovarova1, LG Turgunova2, AZh Anafina2, AV Zinchenko1

1 Center for Hematology, branch of Karaganda Center for Hematology, 41/43 Erubaeva str., Karaganda, Republic of Kazakhstan, 100012

2 Medical University of Karaganda, 40 Gogolya str., Karaganda, Republic of Kazakhstan, 100008

For correspondence: Aimzhan Zharkynovna Anafina, 40 Gogolya str., Karaganda, Republic of Kazakhstan, 100008; Tel.: +7(701)493-54-16; e-mail: aimzhan_31_08@mail.ru

For citation: Klodzinskii AA, Pivovarova IA, Turgunova LG, et al. Current State of Diagnosis and Treatment of Acute Myeloid Leukemias in Adult Patients in the Republic of Kazakhstan. Clinical oncohematology. 2022;15(1):69–75. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-69-75

ABSTRACT

Background. In recent years, the incidence of acute myeloid leukemias (AML) globally has continued to increase. Current approaches to AML treatment remain a challenge for the healthcare in many countries. There are only single studies on the analysis of AML state in adult patients in Kazakhstan. Over the last 10 years in Kazakhstan, no results of AML monitoring in adult patients have been available.

Aim. To study the characteristics of clinical course and treatment outcomes in AML in the Central Kazakhstan and in the city of Ust-Kamenogorsk, East Kazakhstan Region.

Materials & Methods. The study enrolled 86 AML patients (46 men and 40 women), the median age was 60.5 years (range 19–86 years); 64 (74.4 %) patients were from Karaganda Region, 15 (17.4 %) patients were from Ust-Kamenogorsk, and 7 (8.1 %) patients were from other regions of Kazakhstan. The analysis covered the structure and treatment outcomes in newly diagnosed AML patients within the period from 2018 to June, 2021. Statistical analysis of data was made using SPSS Statistics 23.0.

Results. The analysis of diagnostic techniques showed that myelogram and immunophenotyping were used in 98.8 %, cytogenetic assay was made in 18 %, and molecular analysis was performed in 59.3 % of patients. The “7+3” remission induction was administered in 54.6 % of patients, 20.9 % of patients were treated with hypomethylating agents and low doses of cytarabine, and 24.4 % of patients were on palliative and supportive therapy. Out of 47 patients treated with the “7+3” remission induction, complete clinical hematological remission was reached in 29 (61.7 %) patients. Primary resistance was reported in 21.3 % of patients. Early mortality (death within 30 days from the start of induction) rate was 17 %. High-dose cytarabine consolidation (1.5–3 g/m2 twice every other day, 2–3 courses) was administered to 75.8 % of patients. All the allogeneic bone marrow transplantations (n = 7) were performed at the National Research Center for Oncology and Transplantology in Nur-Sultan. The median overall survival in the group of standard “7+3” chemotherapy recipients was 11 months (range 1–83 months), and the median disease-free survival was 9 months (range 2–79 months).

Conclusion. The study presents the characteristics and short-term outcomes of treatment of adult AML patients in Kazakhstan. The study limitations were a short follow-up period and enrollment of patients only from two regions of Kazakhstan. It is necessary to continue improving the current standards of AML diagnosis and treatment of adult patients.

Keywords: Kazakhstan, acute myeloid leukemias, diagnosis, treatment.

Received: September 7, 2021

Accepted: December 10, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Miranda-Filho A, Pineros M, Ferlay J, et al. Epidemiological patterns of leukaemia in 184 countries: a population-based study. Lancet Haematol. 2018;5(1):e14–e24. doi: 10.1016/S2352-3026(17)30232-6.
  2. The global burden of haematological diseases. Lancet Haematol. 2020;7(12):e851. doi: 10.1016/S2352-3026(20)30370-7.
  3. Igissinov N, Kulmirzayeva D, Moore MA, et al. Epidemiological Assessment of Leukemia in Kazakhstan, 2003–2012. Asian Pac J Cancer Prev. 2014;15(16):6969–72. doi: 10.7314/apjcp.2014.15.16.6969.
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. doi: 10.3322/caac.21387.
  5. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392(10147):593–606. doi: 10.1016/S0140-6736(18)31041-9.
  6. Dong Y, Shi O, Zeng Q, et al. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9:14. doi: 10.1186/s40164-020-00170-6.
  7. Meillon-Garcia LA, Demichelis-Gomez R. Access to Therapy for Acute Myeloid Leukemia in the Developing World: Barriers and Solutions. Curr Oncol Rep. 2020;22(12):125. doi: 10.1007/s11912-020-00987-8.
  8. Колеснев А.В., Клодзинский А.А., Гайнутдинова О.В. и др. Острый миелобластный лейкоз у взрослых: первые результаты лечения по протоколу AML 2012/203KZ/VII. Международный симпозиум, посвященный памяти Раисы Максимовны Горбачевой «Трансплантация гемопоэтических стволовых клеток у детей и взрослых», 19–21 сентября 2013 г. Астана, Республика Казахстан.
    [Kolesnev AV, Klodzinskii AA, Gainutdinova OV, et al. Acute myeloblastic leukemia in adults: first outcomes of treatment according to AML 2012/203KZ/VII regimen. International symposium in memory of Raisa Maksimovna Gorbacheva “Hematopoietic Stem Cell Transplantation in Children and Adults”. Astana; September 19–21, 2013. (In Russ)]
  9. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.
  10. Тургунова Л.Г., Шилова В.Н., Недова О.И. и др. Результаты лечения острых лейкозов у взрослых. Астана медициналык журналы. 2005;3:94–6.
    [Turgunova LG, Shilova VN, Nedova OI, et al. Outcomes of acute leukemia treatment in adults. Astana meditsinalyk zhurnaly. 2005;3:94–6. (In Russ)]
  11. Jacob S, Jacob SE, Suryanarayana BS, et al. Clinical Profile and Short Term Outcome of Adult Patients with Acute Myeloid Leukemia. Indian J Hematol Blood Transfus. 2019;5(3):431–6. doi: 10.1007/s12288-018-1051-9.
  12. Noone AM, Howlader N, Krapcho M, et al. SEER cancer statistics review, 1975–2015. Bethesda: National Cancer Institute; 2018.
  13. Colunga-Pedraza PR, Gomez-Cruz GB, Colunga-Pedraza JE, Ruiz-Arguelles GJ. Geographic hematology: some observations in Mexico. Acta Haematol. 2018;140(2):114–20. doi: 10.1159/000491989.
  14. Gomez-Almaguer D, Marcos-Ramirez ER, Montano-Figueroa EH, et al. Acute leukaemia characteristics are different around the world: the Mexican perspective. Clin Lymphoma Myeloma Leuk. 2017;17(1):46–51. doi: 10.1016/j.clml.2016.09.003.
  15. Rao AV. Fitness in the elderly: how to make decisions regarding acute myeloid leukemia induction. Hematology Am Soc Hematol Educ Program. 2016;2016(1):339–47. doi: 10.1182/asheducation-2016.1.339.
  16. Kayal S, Sengar M, Jain H, et al. Induction Related Mortality in Acute Myeloid Leukemia: Multivariate Model of Predictive Score from the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Blood. 2019;134(Suppl_1):2615. doi: 10.1182/blood-2019-127623.
  17. 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. Leukemia. 2014;28(2):289–92. doi: 10.1038/leu.2013.176.
  18. Ho G, Jonas BA, Li Q, et al. Early mortality and complications in hospitalized adult Californians with acute myeloid leukaemia. Br J Haematol. 2017;177(5):791–9. doi: 10.1111/bjh.14631.
  19. Demichelis R, Zapata N, Leyto F, et al. Survival analysis of adult patients with acute myeloid leukemia (AML) treated with intensive chemotherapy: results of a Mexican national AML registry. Clin Lymphoma Myeloma Leuk. 2019;19(1):S209–S2010. doi: 10.1016/j.clml.2019.07.074.
  20. Benicio MTL, Ribeiro AFT, Americo AD, et al. Evaluation of the European LeukemiaNet recommendations for predicting outcomes of patients with acute myeloid leukemia treated in low- and middle-income countries (LMIC): a Brazilian experience. Leuk Res. 2017;60:109–14. doi: 10.1016/j.leukres.2017.07.005.
  21. Malkan UY, Gunes G, Eliacik E. The factors affecting early death after the initial therapy of acute myeloid leukemia. Int J Clin Exp Med. 2015;8(12):22564–9.
  22. Reville PK, Gonzalez GMN, Ravandi F, et al. Predictors of Early Mortality, Response, and Survival in Newly Diagnosed Acute Myeloid Leukemia (AML) Using a Contemporary Academic Cohort. Blood. 2020;136(Suppl 1):44–5. doi: 10.1182/blood-2020-141837.
  23. Master S, Mansour R, Devarakondaet SS, et al. Predictors of Survival in Acute Myeloid Leukemia by Treatment Modality. Anticancer Res. 2016;36(4):1719–27.
  24. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275–91. doi: 10.1182/blood-2017-09-801498.
  25. Philip C, George B, Ganapule A, et al. Acute myeloid leukaemia: challenges and real world data from India. Br J Haematol. 2015;170(1):110–7. doi: 10.1111/bjh.13406.
  26. Loke J, Malladi R, Moss P, et al. The role of allogeneic stem cell transplantation in the management of acute myeloid leukaemia: a triumph of hope and experience. Br J Haematol. 2020;188(1):129–46. doi: 10.1111/bjh.16355.

Technical Aspects of Minimal Residual Disease Detection by Multicolor Flow Cytometry in Acute Myeloid Leukemia Patients

AUTOIMMUNE THROMBOCYTOPENIA , ,

IV Galtseva, YuO Davydova, NM Kapranov, KA Nikiforova, EN Parovichnikova

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

For correspondence: Yuliya Olegovna Davydova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: 8(495)612-62-21; e-mail: juliya89mur@yandex.ru

For citation: Galtseva IV, Davydova YuO, Kapranov NM, et al. Technical Aspects of Minimal Residual Disease Detection by Multicolor Flow Cytometry in Acute Myeloid Leukemia Patients. Clinical oncohematology. 2021;14(3):503–12. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-503-512

ABSTRACT

Detection and monitoring of minimal residual disease (MRD) are essential components of programmed therapy.They are crucial for the choice of treatment strategy and for prognostic purposes practically in all hematologic diseases. MRD is often detected by multicolor flow cytometry, the method with fairly high specificity and sensitivity. However, to identify MRD in acute myeloid leukemia patients is one of the most challenging tasks flow cytometry specialists are faced with. Cytometric data analysis requires the expert knowledge of immunophenotype of all maturing bone marrow cells. Besides, MRD analysis in acute myeloid leukemia has not been standardized while approaches suggested by different studies vary considerably. The present paper reports the experience of MRD analysis, demonstrates the gating strategy, immunophenotype description of normal non-tumor hematopoietic cells, and presents some examples of MRD assessment. Additionally, panels of monoclonal antibodies are provided, along with an evaluation of their advantages and disadvantages.

Keywords: minimal residual disease, acute myeloid leukemias, flow cytometry, gating, immunophenotyping.

Received: June 9, 2021

Accepted: September 5, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642–9. doi: 10.1200/JCO.2003.04.036.
  2. Pui CH, Campana D. New definition of remission in childhood acute lymphoblastic leukemia. Leukemia. 2000;14(5):783–5. doi: 10.1038/sj.leu.2401780.
  3. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275–91. doi: 10.1182/blood-2017-09-801498.
  4. Гальцева И.В., Давыдова Ю.О., Паровичникова Е.Н. Определение минимальной измеримой остаточной болезни у взрослых больных острыми лейкозами. Гематология и трансфузиология. 2020;65(4):460–72. doi: 10.35754/0234-5730-2020-65-4-460-472.
    [Galtseva IV, Davydova YO, Parovichnikova EN. Detection of measurable residual disease in adults with acute leukaemia. Russian journal of hematology and transfusiology. 2020;65(4):460–72. doi: 10.35754/0234-5730-2020-65-4-460-472. (In Russ)]
  5. Shen Z, Gu X, Mao W, et al. Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: Systematic review and meta-analysis. BMC Cancer. 2018;18(1):755. doi: 10.1186/s12885-018-4670-5.
  6. Leung W, Pui C-H, Coustan-Smith E, et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood. 2012;120(2):468–72. doi: 10.1182/blood-2012-02-409813.
  7. Norkin M, Katragadda L, Zou F, et al. Minimal residual disease by either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell transplant is associated with poor outcome in acute myeloid leukemia. Blood Cancer J. 2017;7(12):634. doi: 10.1038/s41408-017-0007-x.
  8. Anthias C, Dignan FL, Morilla R, et al. Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML. Bone Marrow Transplant. 2014;49(5):679–83. doi: 10.1038/bmt.2014.9.
  9. Buckley SA, Wood BL, Othus M, et al. Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis. Haematologica. 2017;102(5):865–73. doi: 10.3324/haematol.2016.159343.
  10. Wood BL. Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom. 2016;90(1):47–53. doi: 10.1002/cyto.b.21239.
  11. Wood BL. Multicolor immunophenotyping: human immune system hematopoiesis. Methods Cell Biol. 2004;75:559–76. doi: 10.1016/s0091-679x(04)75023-2.
  12. Wood BL. Flow cytometric monitoring of residual disease in acute leukemia. In: Czader M, ed. Hematological Malignancies. Methods in Molecular Biology (Methods and Protocols). Vol. 999. Totowa: Humana Press; 2013. pp. 123–36. doi: 10.1007/978-1-62703-357-2_8.
  13. Лобанова Т.И., Гальцева И.В., Паровичникова Е.Н. Исследование минимальной остаточной болезни у пациентов с острыми миелоидными лейкозами методом многоцветной проточной цитофлуориметрии (обзор литературы). Онкогематология. 2018;13(1):83–102. doi: 10.17650/1818-8346-2018-13-1-83-102.
    [Lobanova TI, Galtseva IV, Parovichnikova EN. Minimal residual disease assesment in patients with acute myeloid leukemia by multicolour flow cytometry (literature review). Oncohematology. 2018;13(1):83–102. doi: 10.17650/1818-8346-2018-13-1-83-102. (In Russ)]
  14. Tien HF, Wang CH. CD7 positive hematopoietic progenitors and acute myeloid leukemia and other minimally differentiated leukemia. Leuk Lymphoma. 1998;31(1–2):93–8. doi: 10.3109/10428199809057588.
  15. Jorgensen JL, Chen SS. Monitoring of minimal residual disease in acute myeloid leukemia: methods and best applications. Clin Lymphoma Myeloma Leuk. 2011;11(Suppl 1):S49–53. doi: 10.1016/j.clml.2011.03.023.
  16. Jaso JM, Wang SA, Jorgensen JL, Lin P. Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future. Bone Marrow Transplant. 2014;49(9):1129–38. doi: 10.1038/bmt.2014.99.
  17. Buldini B, Maurer-Granofszky M, Varotto E, Dworzak MN. Flow-cytometric monitoring of minimal residual disease in pediatric patients with acute myeloid leukemia: recent advances and future strategies. Front Pediatr. 2019;7:412. doi: 10.3389/fped.2019.00412.
  18. Wood BL. Acute myeloid leukemia minimal residual disease detection: the difference from normal approach. Curr Protoc Cytom. 2020;93(1):e73. doi: 10.1002/cpcy.73.
  19. Ostendorf BN, Flenner E, Florcken A, Westermann J. Phenotypic characterization of aberrant stem and progenitor cell populations in myelodysplastic syndromes. PLoS One. 2018;13(5):e0197823. doi: 10.1371/journal.pone.0197823.
  20. Goardon N, Marchi E, Atzberger A, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell. 2011;19(1):138–52. doi: 10.1016/j.ccr.2010.12.012.
  21. Shameli A, Dharmani-Khan P, Luider J, et al. Exploring blast composition in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms: CD45RA and CD371 improve diagnostic value of flow cytometry through assessment of myeloblast heterogeneity and stem cell aberrancy. Cytom Part B: Clin Cytom. 2020:1–16. doi: 10.1002/cyto.b.21983. Epub ahead of print.
  22. Bill M, van Kooten Niekerk BP, Woll SP, et al. Mapping the CLEC12A expression on myeloid progenitors in normal bone marrow; implications for understanding CLEC12A-related cancer stem cell biology. J Cell Mol Med. 2018;22(4):2311–8. doi: 10.1111/jcmm.13519.
  23. Eissens DN, Spanholtz J, van der Meer A, et al. Defining early human NK cell developmental stages in primary and secondary lymphoid tissues. PLoS One. 2012;7(2):e30930. doi: 10.1371/journal.pone.0030930.
  24. Stetler-Stevenson M, Paiva B, Stoolman L, et al. Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. Cytom Part B: Clin Cytom. 2016;90(1):26–30. doi: 10.1002/cyto.b.21249.
  25. Palmieri R, Piciocchi A, Arena V, et al. Clinical relevance of- limit of detection (LOD) – limit of quantification (LOQ) – based flow cytometry approach for measurable residual disease (MRD) assessment in acute myeloid leukemia (AML). Blood. 2020;136(Suppl 1):37–8. doi: 10.1182/blood-2020-139557.

Acute Myeloid Leukemia as Second Tumor in a Patient with Burkitt’s Lymphoma: Literature Review and a Case Report

AUTOIMMUNE THROMBOCYTOPENIA ,

TT Valiev1, TYu Pavlova1, AM Kovrigina2, IN Serebryakova1

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

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

For correspondence: Timur Teimurazovich Valiev, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: timurvaliev@mail.ru

For citation: Valiev TT, Pavlova TYu, Kovrigina AM, Serebryakova IN. Acute Myeloid Leukemia as Second Tumor in a Patient with Burkitt’s Lymphoma: Literature Review and a Case Report. Clinical oncohematology. 2021;14(2):167–72. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-167-172

ABSTRACT

The application of highly effective tumor treatment protocols in children and increasing number of patients healed resulted in a growing focus on long-term effects of chemotherapy. One of the most dangerous complications of a first malignant neoplasm (MN) is the development of second MNs. Cytostatic drugs of the epipodophyllotoxin group and alkylating agents contribute to secondary acute myeloid leukemias (AML), the rare and prognostically very unfavorable second MNs. The present article provides a review of literature on risks of secondary hematological MNs associated with the therapy of first tumors. It also contains a case report of successful treatment of AML which occurred after Burkitt’s lymphoma therapy.

Keywords: second malignant neoplasms, acute myeloid leukemias, Burkitt’s lymphoma, children.

Received: December 10, 2020

Accepted: March 1, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Altekruse S, Kosary C, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2007. Bethesda: National Cancer Institute; 2007.
  2. Meadows A, Friedman D, Neglia J, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009;27(14):2356–62. doi: 10.1200/JCO.2008.21.1920.
  3. Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102(14):1083–95. doi: 10.1093/jnci/djq238.
  4. O’Brien MM, Donaldson SS, Balise RR, et al. Second malignant neoplasms in survivors of pediatric Hodgkin’s lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol. 2010;28(7):1232–9. doi: 10.1200/JCO.2009.24.8062.
  5. Dorffel W, Riepenhausenl M, Luders H, et al. Secondary Malignancies Following Treatment for Hodgkin’s Lymphoma in Childhood and Adolescence. Dtsch Arztebl Int. 2015;112(18):320–7. doi: 10.3238/arztebl.2015.0320.
  6. Bhatia S, Yasui Y, Robison L, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group. J Clin Oncol. 2003;21(23):4386–94. doi: 10.1200/JCO.2003.11.059.
  7. Pui C, Behm F, Raimondi S, et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med. 1989;321(3):136–42. doi: 10.1056/NEJM198907203210302.
  8. Pui C. Therapy-related myeloid leukaemia. Lancet. 1990;336(8723):1130–1. doi: 10.1016/0140-6736(90)92607-j.
  9. Ratain M, Rowley J. Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. Ann Oncol. 1992;3(2):107–11. doi: 10.1093/oxfordjournals.annonc.a058121.
  10. Tallman MS, Gray R, Bennett JM, et al. Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience. J Clin Oncol. 1995;13(7):1557–63. doi: 10.1200/JCO.1995.13.7.1557.
  11. Hijiya N, Ness K, Ribeiro R, Hudson M. Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer. 2009;115(1):23–35. doi: 10.1002/cncr.23988.
  12. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of tumours of hematopoietic and lymphoid tissues. Revised 4th edition. Lion: IARC Press; 2017. p. 581.
  13. Verdeguer A, Ruiz JG, Ferris J, et al. Acute non-lymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide. Med Pediatr Oncol. 1992;20(1):48–52. doi: 10.1002/mpo.2950200110.
  14. Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, et al. Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epi-doxorubicin and cisplatinum or cyclophosphamide for breast cancer. J Clin Oncol. 1992;10(9):1444–51. doi: 10.1200/JCO.1992.10.9.1444.
  15. Donatini B, Krupp P. Secondary pre-leukemia and etoposide. Lancet. 1991;338(8777):1269. doi: 10.1016/0140-6736(91)92133-M.
  16. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325(24):1682–7. doi: 10.1056/NEJM199112123252402.
  17. Ballen KK, Antin JH. Treatment of therapy related acute myelogenous leukemia and myelodysplastic syndromes. Hematol Oncol Clin N Am. 1993;7(2):477–93. doi: 10.1016/s0889-8588(18)30253-3.
  18. Aguilera DG, Vaklavas C, Tsimberidou AM, et al. Pediatric Therapy-related Myelodysplastic Syndrome/Acute Myeloid Leukemia: The MD Anderson Cancer Center Experience. J Pediatr Hematol Oncol. 2009;31(11):803–11. doi: 10.1097/MPH.0b013e3181ba43dc.
  19. De Witte T, Hermans J, van Biezen J, et al. Prognostic variables in bone marrow transplantation for secondary leukemia and myelodysplastic syndrome: a survey of the working party on leukemia. Bone Marrow Transplant. 1991;7(2):40.
  20. Larson RA. Etiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2007;2007(1):453–9. doi: 10.1182/asheducation-2007.1.453.
  21. Xinan (Holly) Yang, Bin Wang, John M. Cunningham Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles. BMC Med Genom. 2015;8(2):S6. doi: 10.1186/1755-8794-8-S2-S6.
  22. Ковригина А.М. Пересмотренная классификация ВОЗ опухолей гемопоэтической и лимфоидной ткани, 2017 г. (4-е издание): миелоидные неоплазии. Архив патологии. 2018;80(6):43–9. doi: 10.17116/patol20188006143.
    [Kovrigina AM. A revised 4 edition WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, 2017: myeloid neoplasms. Arkhiv patologii. 2018;80(6):43–9. doi: 10.17116/patol20188006143. (In Russ)]
  23. Itzykson R, Kosmider O, Fenaux P. Somatic mutations and epigenetic abnormalities in myelodysplastic syndromes. Best Pract Res Clin Haematol. 2013;26(4):355–64. doi: 10.1016/j.beha.2014.01.001.
  24. Семенова Н.Ю., Бессмельцев С.С., Ругаль В.И. Биология ниши гемопоэтических стволовых клеток. Клиническая онкогематология. 2014;7(4):501–11.
    [Semenova NYu, Bessmeltsev SS, Rugal VI. Biology of Hematopoietic Stem Cell Niche. Klinicheskaya onkogematologiya. 2014;7(4):501–11. (In Russ)]
  25. Rihani R, Bazzeh F, Faqih N, Sultan I. Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer. 2010;116(18):4385–94. doi: 10.1002/cncr.25313.
  26. Nottage K, Lanktot J, Li Zh, et al. Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study. 2011;117(23):6315–8. doi: 10.1182/blood-2011-02-335158.
  27. Валиев Т.Т. Лимфома Беркитта у детей: 30 лет терапии. Педиатрия. Журнал им. Г.Н. Сперанского. 2020;99(4):35–41.
    [Valiev TT. Burkitt’s lymphoma in children: 30 years of therapy. Zhurnal im. G.N. Speranskogo. 2020;99(4):35–41. (In Russ)]
  28. Павлова Т.Ю., Валиев Т.Т. Вторые злокачественные опухоли у лиц, перенесших онкологическое заболевание в детстве. Педиатрия. Consilium Medicum. 2020;2:12–6. doi: 10.26442/26586630.2020.2.200234.
    [Pavlova TYu, Valiev TT. Second malignant tumors in pediatric cancer survivors. Consilium Medicum. 2020;2:12–6. doi: 10.26442/26586630.2020.2.200234. (In Russ)]
  29. Lee S-S. Therapy-related Acute Myeloid Leukemia Following Treatment for Burkitt’s Lymphoma. Chonnam Med J. 2017;53(3):229–30. doi: 10.4068/cmj.2017.53.3.229.
  30. Ripperger T, Bielack SS, Borkhardt B, et al. Childhood cancer predisposition syndromes—A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet Part A. 2017;173(4):1017–37. doi: 10.1002/ajmg.a.38142.

CAR T-Cell Therapy with NKG2D Chimeric Antigen Receptor in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

AUTOIMMUNE THROMBOCYTOPENIA

KA Levchuk1, EV Belotserkovskaya1,2, DYu Pozdnyakov1, LL Girshova1, AYu Zaritskey1, AV Petukhov1,2,3

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

3 Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340

For correspondence: Kseniya Aleksandrovna Levchuk, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: levchuk_ka@almazovcentre.ru

For citation: Levchuk KA, Belotserkovskaya EV, Pozdnyakov DYu, et al. CAR T-Cell Therapy with NKG2D Chimeric Antigen Receptor in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome. Clinical oncohematology. 2021;14(1):138–48. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-138-148

ABSTRACT

NK-cells as innate immunity elements manifest key reactions of antitumor immune response. NKG2D is an activating transmembrane receptor of NK-cells which is responsible for cytotoxicity initiation in response to the binding of specific ligands of genetically modified cells. Selective expression of NKG2D ligands provides a unique perspective on the therapy of wide variety of tumors. Acute myeloid leukemias (AML) are malignant hematological tumors with a high relapse risk. Due to the complexity of AML treatment strategy it is necessary to develop new approaches to tumor elimination using novel genetic constructs. Currently available CAR T-cell drugs with NKG2D receptor are successfully subjected to clinical studies in AML patients and prove their high therapeutic potential.

Keywords: acute myeloid leukemias, chimeric antigen receptor, adoptive therapy, NKG2D, NK-cells.

Received: August 22, 2020

Accepted: December 5, 2020

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Arber D, Orazi A, Hasserjian R. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.
  2. Bullinger L, Dohner K, Dohner H. Genomics of Acute Myeloid Leukemia Diagnosis and Pathways. J Clin Oncol. 2017;35(9):934–46. doi: 10.1200/JCO.2016.71.2208.
  3. The Leukemia & Lymphoma Society Updated data on blood cancers. Facts 2018–2019. Available from: https://www.lls.org/facts-and-statistics/facts-and-statistics-overview/facts-and-statistics (accessed 30.11.2020).
  4. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.
  5. Herold T, Rothenberg-Thurley M, Grunwald VV, et al. Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia Leukemia. [published online ahead of print, 2020 Mar 30] doi: 10.1038/s41375-020-0806-0.
  6. Estey EH, Schrier SL. Prognosis of the myelodysplastic syndromes in adults. UpToDate. 2017. Available from: https://www.uptodate.com/contents/prognosis-of-the-myelodysplastic-syndromes-in-adults (accessed 28.11.2020).
  7. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. 2005;106(4):1154–63. doi: 10.1182/blood-2005-01-0178.
  8. Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol. 2009;145(3):318–32. doi: 10.1111/j.1365-2141.2009.07604.x.
  9. Lowenberg G. Strategies in the treatment of acute myeloid leukemia. Haematologica. 2004;89(9):1029–32.
  10. Burnett AK. Acute myeloid leukemia: Treatment of adults under 60 years. Rev Clin Exp Hematol. 2002;6(1):26–45. doi: 10.1046/j.1468-0734.2002.00058.x.
  11. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. 2000;14(3):476–9. doi: 10.1038/sj.leu.2401568.
  12. Giles F, O’Brien S, Cortes J, et al. Outcome of patients with acute myelogenous leukemia after second salvage therapy. 2005;104(3):547–54. doi: 10.1002/cncr.21187.
  13. Leopold LH, Willemze R. The treatment of acute myeloid leukemia in first relapse: A comprehensive review of the literature. Leuk Lymphoma. 2002;43(9):1715–27. doi: 10.1080/1042819021000006529.
  14. Lee S, Tallman MS, Oken MM, et al. Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. 2000;14(8):1345–8. doi: 10.1038/sj.leu.2401853.
  15. Patel SA, Gerber JM. A User’s Guide to Novel Therapies for Acute Myeloid Leukemia. Clin Lymphoma Myel Leuk. 2020;20(5):277–88. doi: 10.1016/j.clml.2020.01.011.
  16. Kucukyurt S, Eskazan AE. New drugs approved for acute myeloid leukemia in 2018. Br J Clin Pharmacol. 2018;85(12):2689–93. doi: 10.1111/bcp.14105.
  17. Spear P, Wu MR, Sentman ML, Sentman CL. NKG2D ligands as therapeutic targets. Cancer Immun. 2013;13:8.
  18. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. 2012;120(12):2454–65. doi: 10.1016/s0145-2126(13)70009-2.
  19. Blum WG. Hypomethylating agents in myelodysplastic syndromes. Clin Adv Hematol Oncol. 2011;9(2):123–8.
  20. Семочкин С.В., Толстых Т.Н., Иванова В.Л. и др. Азацитидин в лечении миелодиспластических синдромов: клиническое наблюдение и обзор литературы. Клиническая онкогематология. 2012;5(3):233–8.
    [Semochkin SV, Tolstykh TN, Ivanova VL, et al. Azacitidine in the treatment of myelodysplastic syndromes: case report and literature review. Klinicheskaya onkogematologiya. 2012;5(3):233–8. (In Russ)]
  21. Ширин А.Д., Баранова О.Ю. Гипометилирующие препараты в онкогематологии. Клиническая онкогематология. 2016;9(4):369–82. doi: 10.21320/2500-2139-2016-9-4-369-382.
    [Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82. doi: 10.21320/2500-2139-2016-9-4-369-382. (In Russ)]
  22. Richard-Carpentier G, DeZern AE, Takahashi K, et al. Preliminary Results from the Phase II Study of the IDH2-Inhibitor Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS). 2019;134(1):678. doi: 10.1182/blood-2019-130501.
  23. Foran JM, DiNardo CD, Watts JM, et al. Ivosidenib (AG-120) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome: Updated Enrollment of a Phase 1 Dose Escalation and Expansion Study. 2019;134(1):4254. doi: 10.1182/blood-2019-123946.
  24. Garcia JS. Prospects for Venetoclax in Myelodysplastic Syndromes. Hematol Oncol Clin N Am. 2020;34(2):441–8. doi: 10.1016/j.hoc.2019.10.005.
  25. Germing U, Schroeder T, Kaivers J, et al. Novel therapies in low- and high-risk myelodysplastic syndrome. Exp Rev Hematol. 2019;12(10):893–908. doi: 10.1080/17474086.2019.1647778.
  26. Platzbecker U. Treatment of MDS. 2019;133(10):1096–107. doi: 10.1182/blood-2018-10-844696.
  27. Swoboda DM, Sallman DA. Mutation-Driven Therapy in MDS. Curr Hematol Malig Rep. 2019;14(6):550–60. doi: 10.1007/s11899-019-00554-4.
  28. Миелодиспластические синдромы. Интервью с С.В. Грицаевым. Клиническая онкогематология. 2018;11(2):125–37.
    [Myelodysplastic syndromes. Interview with SV Gritsaev. Clinical oncohematology. 2018;11(2):125–37. (In Russ)]
  29. Manley PW, Weisberg E, Sattler M, et al. Midostaurin, a Natural Product-Derived Kinase Inhibitor Recently Approved for the Treatment of Hematological Malignancies. 2018;57(5):477–8. doi: 10.1021/acs.biochem.7b01126.
  30. Liu X, Gong Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res. 2019;7(1):22. doi: 10.1186/s40364-019-0173-z.
  31. Kim ES. Enasidenib: First Global Approval. 2017;77(15):1705–11. doi: 10.1007/s40265-017-0813-2.
  32. Garcia-Aranda M, Perez-Ruiz E, Redondo M. Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int J Mol Sci. 2018;19(12):3950. doi: 10.3390/ijms19123950.
  33. Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. Leukemia and Lymphoma Society Blood Cancer Research Partnership. N Engl J Med. 2016;375(2):143–53. doi: 10.1056/NEJMoa1601202.
  34. Li F, Sutherland MK, Yu C, et al. Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia. Mol Cancer Ther. 2018;17(2):554–64. doi: 10.1158/1535-7163.MCT-17-0742.
  35. Mawad R, Gooley TA, Rajendran JG, et al. Radiolabeled AntiCD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2014;20(9):1363–8. doi: 10.1016/j.bbmt.2014.05.014.
  36. Guy DG, Uy GL. Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia. Curr Hematol Malig Rep. 2018;13(6):417– doi: 10.1007/s11899-018-0472-8.
  37. Di Stasi A, Jimenez AM, Minagawa K, et al. Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies. Front Immunol. 2015;6:36. doi: 10.3389/fimmu.2015.00036.
  38. Van Acker HH, Versteven M, Lichtenegger FS, et al. Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia. J Clin Med. 2019;8(5):579. doi: 10.3390/jcm8050579.
  39. Yabe T, McSherry C, Bach FH, et al. A multigene family on human chromosome 12 encodes natural killer-cell lectins. 1993;37(6):455–60. doi: 10.1007/bf00222470.
  40. Houchins JP, Yabe T, McSherry C, Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med. 1991;173(4):1017–20. doi: 10.1084/jem.173.4.1017.
  41. Upshaw JL, Arneson LN, Schoon RA, et al. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006;7(5):524–32. doi: 10.1038/ni1325.
  42. Diefenbach A, Tomasello E, Lucas M, et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol. 2002;3(12):1142–9. doi: 10.1038/ni858.
  43. Duan S, Guo W, Xu Z, et al. Natural killer group 2D receptor and its ligands in cancer immune escape. Mol Cancer. 2019;18(1):29. doi: 10.1186/s12943-019-0956-8.
  44. Wu J, Song Y, Bakker AB, et al. An activating immunoreceptor complex formed by NKG2D and DAP10. 1999;285(5428):730–2. doi: 10.1126/science.285.5428.730.
  45. Ogasawara K, Lanier LL. NKG2D in NK and T cell-mediated immunity. J Clin Immunol. 2005;25(6):534–40. doi: 10.1007/s10875-005-8786-4.
  46. Gilfillan S, Ho EL, Cella M, et al. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat Immunol. 2002;3(12):1150–5. doi: 10.1038/ni857.
  47. Groh V, Rhinehart R, Randolph-Habecker J, et al. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2001;2(3):255–60. doi: 10.1038/85321.
  48. Jamieson AM, Diefenbach A, McMahon CW, et al. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. 2002;17(1):19–29. doi: 10.1016/s1074-7613(02)00333-3.
  49. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3(10):781–90. doi: 10.1038/nri1199.
  50. Roberts AI, Lee L, Schwarz E, et al. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol. 2001;167(10):5527–30. doi: 10.4049/jimmunol.167.10.5527.
  51. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23(1):225–74. doi: 10.1146/annurev.immunol.23.021704.115526.
  52. Raulet DH, Gasser S, Gowen BG, et al. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol. 2013;31(1):413–41. doi: 10.1146/annurev-immunol-032712-095951.
  53. Stephens HA. MICA and MICB genes: can the enigma of their polymorphism be resolved?. Trends Immunol. 2001;22(7):378–85. doi: 10.1016/s1471-4906(01)01960-3.
  54. Carapito R, Bahram S. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunol Rev. 2015;267(1):88–116. doi: 10.1111/imr.12328.
  55. Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. 2005;434(7035):864–70. doi: 10.1038/nature03482.
  56. Gorgoulis VG, Vassiliou LV, Karakaidos P, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. 2005;434(7035):907–13. doi: 10.1038/nature03485.
  57. Maeda T, Towatari M, Kosugi H, Saito H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood. 2000;96(12):3847–56. doi: 1182/blood.v96.12.3847.
  58. Diermayr S, Himmelreich H, Durovic B, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. 2008;111(3):1428–36. doi: 10.1182/blood-2007-07-101311.
  59. Chang YH, Connolly J, Shimasaki N, et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res. 2013;73(6):1777–86. doi: 10.1158/0008-5472.CAN-12-3558.
  60. Hamerman JA, Ogasawara K, Lanier LL. Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol. 2004;172(4):2001–5. doi: 10.4049/jimmunol.172.4.2001.
  61. Carlsten M, Bjorkstrom NK, Norell H, et al. DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells. Cancer Res. 2007;67(3):1317–25. doi: 10.1158/0008-5472.CAN-06-2264.
  62. McGilvray RW, Eagle RA, Rolland P, et al. ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients. Int J Cancer. 2010;127(6):1412–20. doi: 10.1002/ijc.25156.
  63. Cathro HP, Smolkin ME, Theodorescu D, et al. Relationship between HLA class I antigen processing machinery component expression and the clinicopathologic characteristics of bladder carcinomas. Cancer Immunol Immunother. 2010;59(3):465–72. doi: 10.1007/s00262-009-0765-9.
  64. Seitz S, Hohla F, Schally AV, et al. Inhibition of estrogen receptor positive and negative breast cancer cell lines with a growth hormone-releasing hormone antagonist. Oncol Rep. 2008;20(5):1289–94.
  65. Mamessier E, Sylvain A, Thibult ML, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 2011;121(9):3609–22. doi: 10.1172/JCI45816.
  66. Busche A, Goldmann T, Naumann U, et al. Natural killer cell-mediated rejection of experimental human lung cancer by genetic overexpression of major histocompatibility complex class I chain-related gene A. Hum Gene Ther. 2006;17(2):135–46. doi: 10.1089/hum.2006.17.135.
  67. Platonova S, Cherfils-Vicini J, Damotte D, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011;71(16):5412–22. doi: 10.1158/0008-5472.CAN-10-4179.
  68. Jinushi M, Takehara T, Tatsumi T, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer. 2003;104(3):354–61. doi: 10.1002/ijc.10966.
  69. Watson NF, Spendlove I, Madjd Z, et al. Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer. 2006;118(6):1445–52. doi: 10.1002/ijc.21510.
  70. Sconocchia G, Spagnoli GC, Del Principe D, et al. Defective infiltration of natural killer cells in MICA/B-positive renal cell carcinoma involves beta(2)-integrin-mediated interaction. 2009;11(7):662–71. doi: 10.1593/neo.09296.
  71. Wu JD, Higgins LM, Steinle A, et al. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004;114(4):560–8. doi: 10.1172/JCI22206.
  72. Salih HR, Antropius H, Gieseke F, et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. 2003;102(4):1389–96. doi: 10.1182/blood-2003-01-0019.
  73. Diermayr S, Himmelreich H, Durovic B, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. 2008;111(3):1428–36. doi: 10.1182/blood-2007-07-101311.
  74. Sconocchia G, Lau M, Provenzano M, et al. The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions. 2005;106(10):3666–72. doi: 10.1182/blood-2005-02-0479.
  75. Nuckel H, Switala M, Sellmann L, et al. The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. 2010;24(6):1152–9. doi: 10.1038/leu.2010.74.
  76. Zhang B, Kracker S, Yasuda T, et al. Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. 2012;148(4):739–51. doi: 10.1016/j.cell.2011.12.031.
  77. Girlanda S, Fortis C, Belloni D, et al. MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells costimulates pamidronate-activated gammadelta lymphocytes. Cancer Res. 2005;65(16):7502–8. doi: 10.1158/0008-5472.CAN-05-0731.
  78. Paschen A, Sucker A, Hill B, et al. Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin Cancer Res. 2009;15(16):5208–15. doi: 10.1158/1078-0432.CCR-09-0886.
  79. Verhoeven DH, de Hooge AS, Mooiman EC, et al. NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol Immunol. 2008;45(15):3917–25. doi: 10.1016/j.molimm.2008.06.016.
  80. Friese MA, Platten M, Lutz SZ, et al. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res. 2003;63(24):8996–9006.
  81. Raffaghello L, Prigione I, Airoldi I, et al. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. 2004;6(5):558–68. doi: 10.1593/neo.04316.
  82. Chitadze G, Lettau M, Bhat J, et al. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17. Int J Cancer. 2013;133(7):1557–66. doi: 10.1002/ijc.28174.
  83. Zhang T, Lemoi BA, Sentman CL. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. 2005;106(5):1544–51. doi: 10.1182/blood-2004-11-4365.
  84. Zhang T, Barber A, Sentman CL. Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Cancer Res. 2006;66(11):5927–33. doi: 10.1158/0008-5472.CAN-06-0130.
  85. Barber A, Zhang T, DeMars LR, et al. Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res. 2007;67(10):5003–8. doi: 10.1158/0008-5472.CAN-06-4047.
  86. Barber A, Zhang T, Megli CJ, et al. Chimeric NKG2D receptor-expressing T cells as an immunotherapy for multiple myeloma. Exp Hematol. 2008;36(10):1318–28. doi: 10.1016/j.exphem.2008.04.010.
  87. Barber A, Meehan KR, Sentman CL. Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther. 2011;18(5):509–16. doi: 10.1038/gt.2010.174.
  88. Barber A, Rynda A, Sentman CL. Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J Immunol. 2009;183(11):6939–47. doi: 10.4049/jimmunol.0902000.
  89. Zhang T, Sentman CL. Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Res. 2011;71(6):2066–76. doi: 10.1158/0008-5472.CAN-10-3200.
  90. Zhang T, Sentman CL. Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells. J Immunol. 2013;190(5):2455–63. doi: 10.4049/jimmunol.1201314.
  91. Lehner M, Gotz G, Proff J, et al. Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2):e31210. doi: 10.1371/journal.pone.0031210.
  92. Song DG, Ye Q, Santoro S, et al. Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther. 2013;24(3):295–305. doi: 10.1089/hum.2012.143.
  93. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi: 10.1126/scitranslmed.3002842.
  94. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. doi: 10.1126/scitranslmed.3005930.
  95. Meehan KR, Talebian L, Tosteson TD, et al. Adoptive cellular therapy using cells enriched for NKG2D+CD3+CD8+ T cells after autologous transplantation for myeloma. Biol Blood Marrow Transplant. 2013;19(1):129–37. doi: 10.1016/j.bbmt.2012.08.018.
  96. Nakajima J, Murakawa T, Fukami T, et al. A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous gammadelta T cells. Eur J Cardiothorac Surg. 2010;37(5):1191–7. doi: 10.1016/j.ejcts.2009.11.051.
  97. Abe Y, Muto M, Nieda M, et al. Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma. Exp Hematol. 2009;37(8):956–68. doi: 10.1016/j.exphem.2009.04.008.
  98. Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006;6(5):383–93. doi: 10.1038/nri1842.
  99. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest. 2007;117(5):1204–12. doi: 10.1172/JCI31446.
  100. Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36(2):133–51. doi: 10.1097/CJI.0b013e3182829903.
  101. Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. doi: 10.1038/mt.2010.24.
  102. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. 2005;105(8):3051–7. doi: 10.1182/blood-2004-07-2974.
  103. Sentman CL, Meehan KR. NKG2D CARs as cell therapy for cancer. Cancer J. 2014;20(2):156–9. doi: 10.1097/PPO.0000000000000029.
  104. Lonez C, Hendlisz A, Shaza L, et al. Celyad’s novel CAR T-cell therapy for solid malignancies. Curr Res Transl Med. 2018;66(2):53–6. doi: 10.1016/j.retram.2018.03.001.
  105. Baumeister SH, Murad J, Werner L, et al. Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Cancer Immunol Res. 2019;7(1):100–12. doi: 10.1158/2326-6066.CIR-18-0307.
  106. Al-Homsi S, Purev E, Lewalle P, et al. Interim Results from the Phase I Deplethink Trial Evaluating the Infusion of a NKG2D CAR T-Cell Therapy Post a Non-Myeloablative Conditioning in Relapse or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients. 2019;134(Suppl_1):3844. doi: 10.1182/blood-2019-128267.
  107. Liu H, Wang S, Xin J, et al. Role of NKG2D and its ligands in cancer immunotherapy. Am J Cancer Res. 2019;9(10):2064–78.

Identification of Mutations in IDH1/2, DNMT3A, ASXL1 Genes of Genome Epigenetic Regulation and Their Co-Occurrence with FLT3, NPM1, RUNX1 Mutations in Acute Myeloid Leukemia

AUTOIMMUNE THROMBOCYTOPENIA ,

EV Belotserkovskaya1,2, EK Zaikova1,2, AV Petukhov1,2,3, ON Demidov2, KA Levchuk1, IG Budaeva1, DV Zaitsev1, YuD Rogovaya1, AA Shatilova1, KV Bogdanov1, YuV Mirolyubova1, TS Nikulina1, AYu Zaritskey1, LL Girshova1

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

3 Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340

For correspondence: Ekaterina Vasilevna Belotserkovskaya, PhD in Biology, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: belotserkovskaya.ev@gmail.com

For citation: Belotserkovskaya EV, Zaikova EK, Petukhov AV, et al. Identification of Mutations in IDH1/2, DNMT3A, ASXL1 Genes of Genome Epigenetic Regulation and Their Co-Occurrence with FLT3, NPM1, RUNX1 Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2021;14(1):13–21. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-13-21

ABSTRACT

Aim. To identify mutations in IDH1/IDH2, DNMT3A, and ASXL1 genes responsible for genome epigenetic regulation and their co-occurrence with FLT3, NPM1, and RUNX1 mutations in newly diagnosed adult acute myeloid leukemias (AML).

Materials & Methods. The study included 56 patients with newly diagnosed AML treated at the VA Almazov National Medical Research Center. Among them there were 34 men and и 22 women aged 18–76 years (median 46 years). Mutation status of IDH1, IDH2, DNMT3A, and ASXL1 genes of epigenetic regulation was assessed by Sanger sequencing method. Molecular genetic analysis of FLT3, NPM1, and RUNX1-RUNX1T1 genes was performed using commercial kits.

Results. Mutations in epigenetic regulation genes were detected in 14 (25 %) out of 56 patients. Mutation prevalence was not associated with risk groups (p = 0.072). IDH1/2 mutations were identified in 15.6 % of patients and were significantly oftener observed concurrent with NPM1 mutations (62.5 %; p = 0.01) compared to patients with wild-type IDH1/2. In most patients IDH1/2 mutations were associated with normal karyotype (p = 0.002). DNMT3A (R882) mutation was identified in 4 (7.1 %) out of 56 patients within the analyzed group. In 6 patients (11.1 %) ASXL1 mutations were detected co-occurring with RUNX1-RUNX1T1 and FLT3-ITD mutations.

Conclusion. Mutations in epigenetic regulation genes are often identified in AML patients and can be concurrent with abnormalities in NPM1, FLT3 и RUNX1 genes.

Keywords: acute myeloid leukemias, IDH1, IDH2, DNMT3A, and ASXL1 genes of epigenetic regulation, epigenetic factors.

Received: August 20, 2020

Accepted: December 2, 2020

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Wang M, Yang C, Zang L, et al. Molecular mutations and their cooccurrences in cytogenetically normal Acute Myeloid Leukemia. Stem Cells Int. 2017;2017:1–11. doi: 10.1155/2017/6962379.
  2. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. doi: 1182/blood-2016-08-733196.
  3. Gambacorta V, Gnani D, Vago L, et al. Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects. Front Cell Dev Biol. 2019;7:207. doi: 10.3389/fcell.2019.00207.
  4. Santini Hypomethylating agents in the treatment of acute myeloid leukemia: A guide to optimal use. Crit Rev Oncol Hemat. 2009;140:1–7. doi: 10.1016/j.critrevonc.2019.05.013.
  5. Kim Enasidenib: First Global Approval. Drugs. 2017;77(15):1705–11. doi: 10.1007/s40265-017-0813-2.
  6. Liu X, Gong Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res. 2019;7(1):22. doi: 10.1186/s40364-019-0173-z.
  7. Cai SF, Levine RL. Genetic and epigenetic determinants of AML pathogenesis. Semin Hematol. 2018;56(2):84–9. doi: 10.1053/j.seminhematol.2018.08.001.
  8. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16. doi: 10.1182/blood-2015-03-631747.
  9. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477. doi: 10.1056/nejmoa1409405.
  10. Bowman RL, Busque L, Levine RL. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell. 2018;22(2):157–70. doi: 10.1016/j.stem.2018.01.011.
  11. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111–21. doi: 10.1056/nejmoa1701719.
  12. Buscarlet M, Provost S, Zada YF, et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130(6):753–62. doi: 10.1182/blood-2017-04-777029.
  13. Yuan X, Peng L, Zeng W, et al. DNMT3A R882 Mutations Predict a Poor Prognosis in AML. Medicine. 2016;95(18):e3519. doi: 10.1097/md.0000000000003519.
  14. Marcucci G, Maharry K, Wu Y, et al. IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2010;28(14):2348–55. doi: 10.1200/JCO.2009.27.3730.
  15. Schnittger S, Eder C, Jeromin S, et al. ASXL1 exon 12 mutations frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia. 2013;27(1):82–91. doi: 1038/leu.2012.262.
  16. Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012;97(3):388. doi: 10.3324/haematol.2011.051532.
  17. Wagner K, Damm F, Gohring G, et al. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol. 2010;28(14):2356–64. doi: 10.1200/jco.2009.27.6899.
  18. Dinardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732–6. doi: 10.1002/ajh.24072.
  19. Brunetti L, Gundry MC, Goodell MA. DNMT3A in Leukemia. Cold Spring Harb Perspect Med. 2017;7(2):a030320. doi: 10.1101/cshperspect.a030320.
  20. Park SH, Choi JC, Kim SY, et al. Incidence and Prognostic Impact of DNMT3A Mutations in Korean Normal Karyotype Acute Myeloid Leukemia Patients. BioMed Res Int. 2015;2015:1–11. doi: 10.1155/2015/723682.
  21. Chotirat S, Thongnoppakhun W, Promsuwicha O, et al. Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. J Hematol Oncol. 2012;5(1):5. doi: 10.1186/1756-8722-5-5.
  22. Petrova L, Vrbacky F, Lanska M, et al. IDH1 and IDH2 mutations in patients with acute myeloid leukemia: Suitable targets for minimal residual disease monitoring? Clin Biochem. 2018;61:34–9. doi: 10.1016/j.clinbiochem.2018.08.012.
  23. Waitkus MS, Diplas BH, Yan H. Biological Role and Therapeutic Potential of IDH Mutations in Cancer. Cancer Cell. 2018;34(2):186–95. doi: 10.1016/j.ccell.2018.04.011.
  24. Clark O, Yen K, Mellinghoff IK. Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer. Clin Cancer Res. 2016;22(8):1837–42. doi: 1158/1078-0432.CCR-13-1333.
  25. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 Mutations in Gliomas. N Engl J Med 2009;360(8):765–73. doi: 10.1056/NEJMoa0808710.
  26. Parsons DW, Jones S, Zhang X, et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. 2008;321(5897):1807–12. doi: 10.1126/science.1164382.
  27. Whitehall VLJ, Dumenil TD, McKeone DM, et al. Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype. Epigenetics. 2014;9(11):1454–60. doi: 10.4161/15592294.2014.971624.
  28. Mardis ER, Ding L, Dooling DJ, et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. N Engl J Med. 2009;361(11):1058–66. doi: 10.1056/NEJMoa0903840.
  29. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409–12. doi: 10.1182/blood-2010-12-322479.
  30. Berenstein R, Blau IW, Kar A, et al. Comparative examination of various PCR-based methods for DNMT3A and IDH1/2 mutations identification in acute myeloid leukemia. J Exp Clin Cancer Res. 2014;33(1):44. doi: 10.1186/1756-9966-33-44.
  31. Mizuta S, Yamane N, Komai T, et al. Investigation of screening method for DNMT3A mutations by high‐resolution melting analysis in acute myeloid leukemia. Int J Lab Hematol. 2019;41(5):593–600. doi: 10.1111/ijlh.13056.
  32. МотыкоЕ.В., Блау О.В., Полушкина Л.Б. и др. Прогностическое значение генетических мутаций у больных острыми миелоидными лейкозами: результаты совместного исследования гематологических клиник Санкт-Петербурга (Россия) и клиники Шарите (Германия). Клиническая онкогематология. 2019;12(2):211–9. doi: 10.21320/2500-2139-2019-12-2-211-219.
    [Motyko EV, Blau OV, Polushkina LB, et al. Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany). Clinical oncohematology. 2019;12(2):211–9. doi: 10.21320/2500-2139-2019-12-2-211-219. (In Russ)]
  33. ElNahass YH, Badawy RH, ElRefaey FA, et al. IDH Mutations in AML Patients; A higher Association with Intermediate Risk Cytogenetics. Asian Pacif J Cancer Prev. 2020;21(3):721–5. doi: 10.31557/APJCP.2020.21.3.721.
  34. Ferret Y, Boissel N, Helevaut N, et al. Clinical Relevance Of IDH1/2 Mutant Allele Burden During Follow-Up In Acute Myeloid Leukemia. A Study By The French ALFA Group. Haematologica. 2018;103(5):822–9. doi: 10.3324/haematol.2017.183525.
  35. Brambati C, Galbiati S, Xue E, et al. Droplet digital polymerase chain reaction for DNMT3A and IDH1/2 mutations to improve early detection of acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation. Haematologica. 2016;101(4):e157–e161. doi: 10.3324/haematol.2015.135467.
  36. Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135(1):35–45. doi: 10.1309/AJCPD7NR2RMNQDVF.
  37. Zou Y, Bai HX, Wang Z, Yang L. Comparison of immunohistochemistry and DNA sequencing for the detection of IDH1 mutations in gliomas. Neuro Oncol. 2015;17(3):477–8. doi: 10.1093/neuonc/nou351.
  38. Petiti J, Rosso V, Croce E, et al. Highly Sensitive Detection of IDH2 Mutations in Acute Myeloid Leukemia. J Clin Med. 2020;9(1):271. doi: 10.3390/jcm9010271.
  39. Aref S, Kamel AS, Abdel AMF, et al. Prevalence and clinical effect of IDH1 and IDH2 mutations among cytogenetically normal acute myeloid leukemia patients. Clin Lymphoma Myel Leuk. 2015;15(9):550–5. doi: 10.1016/j.clml.2015.05.009.
  40. Boissel N, Nibourel O, Renneville A, et al. Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group. J Clin Oncol. 2010;28(23):3717–23. doi: 10.1200/jco.2010.28.2285.
  41. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: A systematic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511–22. doi: 10.1158/1078-0432.ccr-16-2628.
  42. Montalban-Bravo G, DiNardo CD. The role of IDH mutations in acute myeloid leukemia. Future Oncol. 2018;10(14):979–93. doi: 10.2217/fon-2017-0523.
  43. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732–42. doi: 10.1182/blood-2017-04-779447.
  44. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998;19(3):219–20. doi: 10.1038/890.
  45. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi: 10.1056/NEJMoa1005143.
  46. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. doi: 1056/NEJMoa1301689.
  47. Блау О.В. Мутации генов при острых миелоидных лейкозах. Клиническая онкогематология. 2016;9(3):245–56. doi: 10.21320/2500-2139-2016-9-3-245-256.
    [Blau OV. Genetic Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2016;9(3):245–56. doi: 10.21320/2500-2139-2016-9-3-245-256. (In Russ)]
  48. Guryanova OA, Shank K, Spitzer B, et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22(12):1488–95. doi: 10.1038/nm.4210.
  49. Hou HA, Kuo YY, Liu CY, et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2012;119(2):559–68. doi: 10.1182/blood-2011-07-369934.
  50. Ploen GG, Nederby L, Guldberg P, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167(4):478–86. doi: 10.1111/bjh.13062.
  51. Rothenberg-Thurley M, Amler S, Goerlich D, et al. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. Leukemia. 2018;32(7):1598–608. doi: 10.1038/s41375-018-0034-z.
  52. Gale RE, Lamb K, Allen C, et al. Simpson’s Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia. J Clin Oncol. 2015;33(18):2072–83. doi: 10.1200/jco.2014.59.2022.
  53. Gaidzik VI, Schlenk RF, Paschka P, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: Results of the AML Study Group (AMLSG). Blood. 2013;121(23):4769–77. doi: 10.1182/blood-2012-10-461624.
  54. Elsayed GM, Fahmi AEA, Shafiket NF, et al. Study of DNA methyl transferase 3A mutation in acute myeloid leukemic patients. Egypt J Med Hum Genet. 2018;19(4):315–9. doi: 10.1016/j.ejmhg.2018.05.005.
  55. Berenstein R, Blau IW, Suckert N, et al. Quantitative detection of DNMT3A R882H mutation in acute myeloid leukemia. J Exp Clin Cancer Res. 2015;34(1):55. doi: 10.1186/s13046-015-0173-2.
  56. Young AL, Challen GA, Birmann BM, et al. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7(1):12484. doi: 10.1038/ncomms12484.
  57. Asada S, Fujino T, Goyama S, et al. The role of ASXL1 in hematopoiesis and myeloid malignancies. Cell Mol Life Sci. 2019;76(13):2511–23 doi: 10.1007/s00018-019-03084-7.
  58. Chou WC, Huang HH, Hou HA, et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood. 2010;116(20):4086–94. doi: 10.1182/blood-2010-05-283291.
  59. Molenaar RJ, Thota S, Nagata Y, et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia. 2015;29(11):2134–42. doi: 10.1038/leu.2015.91.
  60. Asada S, Kitamura T. Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms. Int J Hematol. 2019;110(2):179–86. doi: 10.1007/s12185-018-2563-7.
  61. Shivarov V, Ivanova M, Naumova E. Rapid Detection of DNMT3A R882 Mutations in Hematologic Malignancies Using a Novel Bead-Based Suspension Assay with BNA(NC) Probes. PLoS ONE. 2014;9(6):e99769. doi: 10.1371/journal.pone.0099769.
  62. Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145(6):788–800. doi: 10.1111/j.1365-2141.2009.07697.x.
  63. Abbas S, Lugthart S, Kavelaars F, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6. doi: 10.1182/blood-2009-11-250878.
  64. Dunlap JB, Leonard J, Rosenberg M, et al. The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML. Am J Hematol. 2019;94(8):913–20. doi: 10.1002/ajh.25517.
  65. Virijevic M, Karan-Djurasevic T, Marjanovic I, et al. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype. Radiol Oncol. 2016;50(4):385–93. doi: 10.1515/raon-2016-0044.
  66. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. doi: 10.1056/NEJMoa1516192.
  67. Boddu P, Takahashi K, Pemmaraju N, et al. Influence of IDH on FLT3ITD status in newly diagnosed AML. Leukemia. 2017;31(11):2526– doi: 10.1038/leu.2017.244.
  68. Yan X-J, Xu J, Gu Z-H, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43(4):309–15. doi: 10.1038/ng.788.
  69. Abdel-Wahab O, Adli M, Saunders L, et al. ASXL1 Mutations Promote Myeloid Transformation Through Inhibition of PRC2-Mediated Gene Repression. Blood. 2011;118(21):405. doi: 10.1182/blood.v118.21.405.405.
  70. Inoue D, Matsumoto M, Nagase R. Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. Exp Hematol. 2016;44(3):172–6.e1. doi: 10.1016/j.exphem.2015.11.011.
  71. Gelsi-Boyer V, Brecqueville M, Devillier R, et al. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012;5(1):12. doi: 10.1186/1756-8722-5-12.
  72. Paschka P, Schlenk RF, Gaidzik VI. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German Austrian Acute Myeloid Leukemia Study Group. Haematologica. 2015;100(3):324–30. doi: 10.3324/haematol.2014.114157.

Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany)

MYELOID TUMORS , , , ,

EV Motyko1, OV Blau2, LB Polushkina1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, YuS Ruzhenkova1, EV Kleina1, NB Pavlenko1, AM Radzhabova1, EV Karyagina3, OS Uspenskaya4, SV Voloshin1, AV Chechetkin1, IS Martynkevich1

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

2 Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

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

4 Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Ekaterina Vadimovna Motyko, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)925-05-62; e-mail: genetics.spb@mail.ru

For citation: Motyko EV, Blau OV, Polushkina LB, et al. Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany). Clinical oncohematology. 2019;12(2):211–9.

DOI: 10.21320/2500-2139-2019-12-2-211-219

ABSTRACT

Aim. To analyze the effect on prognosis of mutations that are typical of acute myeloid leukemia (AML) patients.

Materials & Methods. The study included 620 AML patients surveyed at Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Berlin, Germany). G-banding of chromosomes was employed for cytogenetic testing. Aberration screening in DNMT3A, IDH1/2 genes was based on real-time polymerase chain reaction (PCR) with subsequent analysis of melting and sequencing profiles. Mutations in FLT3, NPM1 genes were revealed by PCR.

Results. Mutations were identified in 343 (55.3 %) out of 620 patients. Significantly more often mutations were discovered in patients with normal karyotype (NK) (p = 0.001). FLT3-ITD mutation was associated with reduced medians of overall survival (OS) and disease-free (DFS) survival: 11.3 vs. 15.8 months with FLT3-ITD– (p = 0.005) and 10.0 vs. 13.3 months with FLT3-ITD+ (p = 0.009), respectively. The relation of FLT3-ITD allele burden to OS duration was also assessed. In the ITDlow/ITD– group the OS median was considerably longer than in the ITDhigh group (p = 0.028). In the group of patients with 1 mutation in NPM1 gene OS and DFS were much better in comparison with other patients (medians of 27.4 and 13.9 months, respectively, p = 0.040; 19.3 and 12.0 months, p = 0.049). Negative impact of mutations in DNMT3A gene was noticed while assessing OS median: 12 (DNMT3A+) and 15 months (DNMT3A–), respectively (p = 0.112). Mutations in IDH1 gene correlated with a better OS than in the group without mutations (p = 0.092). The rs11554137 polymorphism in IDH1 gene was associated with worse OS in the group of patients with NK (p = 0.186). In 144 patients various mutation combinations (from 2 to 5) were identified. It was demonstrated that mutations in FLT3 (FLT3-ITD), NPM1, DNMT3A, and IDH2 were identified significantly more often in combinations with other mutations (p = 0.001): NPM1+/FLT3-ITD+ (20.8 %), NPM1+/FLT3-ITD+/DNMT3A+ (8.3 %), and FLT3-ITD+/DNMT3A+ (8.3 %). Patients with 1 mutation had a noticeably longer OS median compared with patients with 2 mutations (18.1 and 12.2 months; p = 0.003). In patients with NPM1+ according to their OS the most unfavorable additional mutation was FLT3-ITD (median 27.4 vs. 9.2 months; p = 0.019) and the combination of NPM1+/FLT3-ITD+/DNMT3A+ (median 27.4 vs. 14.6 months; p = 0.141). OS of patients with DNMT3A+ showed a downward trend if FLT3-ITD additional mutation was identified (17.3 vs. 7.1 months; p = 0.074).

Conclusion. Mutations in FLT3, DNMT3A, IDH1/2, NPM1 genes frequently occur in AML intermediate-risk patients, i.e. they determine the intermediate prognosis group in AML. The studied mutations considerably impact prognosis. It is important to take into consideration mutation type, its allele burden, and the presence of additional mutations. A patient with 2 mutations has a considerably worse OS compared with a patient with 1 mutation. The studied group of patients with the combination of NPM1+/FLT3-ITD+, NPM1+/FLT3-ITD+/DNMT3A+, DNMT3A+/FLT3-ITD+ mutations has the poorest prognosis. Comprehensive analysis of genetic damages in AML patients allows to most accurately predict the course and prognosis of the disease and to plan targeted therapy.

Keywords: acute myeloid leukemias, mutations in FLT3, NPM1, DNMT3A, IDH1/2 genes, karyotype, prognosis.

Received: July 13, 2018

Accepted: January 16, 2019

Read in PDF 

REFERENCES

  1. Schlenk RF, Dohner H. Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2013;2013(1):324–30. doi: 10.1182/asheducation-2013.1.324.

  2. Sanders MA, Valk PJ. The evolving molecular genetic landscape in acute myeloid leukaemia. Curr Opin Hematol. 2013;20(2):79–85. doi: 10.1097/MOH.0b013e32835d821c.

  3. Preisler H, Davis RB, Kirshner J, et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a cancer and leukemic group B study. Blood. 1987;69(5):1441–9.

  4. Wiernik PH, Banks PLC, Case DC, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. 1992;79(2):313–9.

  5. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2018. Т. 1. 1008 с.

    [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols for blood system diseases.) Moscow: Praktika Publ.; 2018. Vol. 1. 1008 p. (In Russ)]

  6. Bennett JM, Catovsky D, Daniel MT, 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.

  7. Heim S, Mitelman F. Cancer Cytogenetics: chromosomal and molecular genetic aberrations of tumor cells. 4th ed. Wiley-Blackwell: 2015. рр. 632. doi: 10.1002/9781118795569.

  8. Jordan CT. Unique molecular and cellular features of acute myelogenous leukemia stem cells. 2002;16(4):559–62. doi: 10.1038/sj.leu.2402446.

  9. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506– doi: 10.1038/nature10738.

  10. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. doi: 10.1056/NEJMoa1113205.

  11. Campbell PJ, Pleasance ED, Stephens PJ, et al. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci USA. 2008;105(35):13081–6. doi: 10.1073/pnas.0801523105.

  12. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752– doi: 10.1182/blood.v98.6.1752.

  13. Santos FP, Jones D, Qiao W, et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer. 2011;117(10):2145–55. doi: 10.1002/cncr.25670.

  14. Sallman DA, Lancet JE. What are the most promising new agents in acute myeloid leukemia? Curr Opin Hematol. 2017;24(2):99–107. doi: 10.1097/MOH.0000000000000319.

  15. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). 2006;107(10):4011–20. doi: 10.1182/blood-2005-08-3167.

  16. Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–6. doi: 10.1182/blood-2005-05-2164.

  17. Тилова Л.Р., Савинкова А.В., Жидкова Е.М. и др. Молекулярно-генетические нарушения в патогенезе опухолей системы крови и соответствующие им изменения сигнальных систем клетки. Клиническая онкогематология. 2017;10(2):235– doi: 10.21320/2500-2139-2017-10-2-235-249.

    [Tilova LR, Savinkova AV, Zhidkova EM, et al. Molecular Genetic Abnormalities in the Pathogenesis of Hematologic Malignancies and Corresponding Changes in Cell Signaling Systems. Clinical oncohematology. 2017;10(2):235–49. doi: 10.21320/2500-2139-2017-10-2-235-249. (In Russ)]

  18. Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase mutations may predict acute myeloid leukemia. Am J Hematol. 2015;90(5):E77–9. doi: 10.1002/ajh.23965.

  19. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. doi: 10.1056/NEJMoa1112304.

  20. Renneville A, Boissel N, Nibourel O, et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia. 2012;26(6):1247–54. doi: 10.1038/leu.2011.382.

  21. Marcucci G, Maharry K, Wu Y-Z, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28(14):2348–55. doi: 10.1200/JCO.2009.27.3730.

  22. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636–43. doi: 10.1200/JCO.2010.28.3762.

  23. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6. doi: 10.1182/blood-2009-11-250878.

  24. Thol F, Damm F, Ludeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889– doi: 10.1200/JCO.2011.35.4894.

  25. Ley TJ, Miller C, Ding L, Raphael BJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059– doi: 10.1056/NEJMoa1301689.

  26. Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014;28(8):1586– doi: 10.1038/leu.2014.55.

  27. Ravandi F, Kantarjian H, Faderl S, et al. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34(6):752– doi: 10.1016/j.leukres.2009.10.001.

  28. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML study group Ulm. Blood. 2002;100(13):4372– doi: 10.1182/blood-2002-05-1440.

  29. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441– doi: 10.1182/blood-2014-05-578070.

  30. Kim Y, Lee GD, Park J, et al. Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length. Blood Cancer J. 2015;5(8):e336. doi: 10.1038/bcj.2015.61.

  31. Linch DC, Hills RK, Burnett AK, et al. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124(2):273– doi: 10.1182/blood-2014-02-554667.

  32. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30(7):735– doi: 10.1200/JCO.2011.36.9868.

  33. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. 2011;17(9):1404– doi: 10.1016/j.bbmt.2011.02.003.

  34. Islam M, Mohamed Z, Assenov Y. Differential analysis of genetic, epigenetic, and cytogenetic abnormalities in AML. Int J Genom. 2017;2017:2913648. doi: 10.1155/2017/2913648.

  35. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;375(9):900– doi: 10.1056/NEJMc1608739.

  36. Dohner H, Estey E, Amadori S, et al. Diagnosis and Management of Acute Myeloid Leukemia in Adults: Recommendations from an International Expert Panel, on Behalf of the European LeukemiaNet. Blood. 2010;115(3):453– doi: 10.1182/blood-2009-07-235358.

  37. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776– doi: 10.1182/blood-2007-08-109090.

  38. Pratcorona M, Brunet S, Nomdedeu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: Relevance to post-remission therapy. Blood. 2013;121(14):2734– doi: 10.1182/blood-2012-06-431122.

  39. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18–60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double- Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126(23): 6, abstract.

  40. Ibrahem L, Mahfouz R, Elhelw L, et al. Prognostic significance of DNMT3A mutations in patients with acute myeloid leukemia. Blood Cells Mol Dis. 2015;54(1):84– doi: 10.1016/j.bcmd.2014.07.015.

  41. Ley T, Ding L, Walter M, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424– doi: 10.1056/NEJMoa1005143.

  42. Willander K, Falk I, Chaireti R, et al. Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia. Biomark Res. 2014;2(1):18. doi: 10.1186/2050-7771-2-18.

  43. Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511– doi: 10.1158/1078-0432.CCR-16-2628.

  44. Wagner K, Damm F, Gohring G, et al. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol. 2010;28(14):2356– doi: 10.1200/JCO.2009.27.6899.

  45. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood. 2016;127(1):71– doi: 10.1182/blood-2015-07-604538.

  46. Ploen GG, Nederby L, Guldberg P, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167(4):478– doi: 10.1111/bjh.13062.

  47. Gaidzik V, Weber D, Paschka P, et al. Monitoring of minimal residual disease (MRD) of DNMT3A mutations (DNMT3Amut) in acute myeloid leukemia (AML): a study of the AML Study Group (AMLSG). Blood. 2015;126(23):226, abstract.

Hypomethylating Agents in Oncohematology

REVIEWS , , , ,

AD Shirin, OYu Baranova

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

For correspondence: Anton Dmitrievich Shirin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-24; e-mail: shirin-anton@mail.ru

For citation: Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-369-382

ABSTRACT

The review describes epigenetic processes, including methylation of nuclear and mitochondrial DNA, as well as RNA. It dwells on mechanisms of demethylation and corresponding medicinal products. It presents detailed information on results of numerous large randomized studies intended to evaluate hypomethylating agents (azanucleosides). Special attention is paid to outcomes of azanucleoside therapy in patients with acute myeloid leukemias. The article describes several prognostic systems and treatment algorithms for myelodysplastic syndromes. Two azanucleosides have been approved in Russia to date: azacitidine (for SQ administration) and decitabine (for IV administration). International authors analyze the experience in oral and subcutaneous administration of decitabine. However, the problem of off-label use of hypomethylating agents is still open. The review gives a brief description of ongoing clinical trials with azanucleosides.

Keywords: epigenetics, acute myeloid leukemias, myelodysplastic syndromes, azacitidine, decitabine, hypomethylating agents, azanucleosides.

Received: May 10, 2016

Accepted: May 20, 2016

Read in PDF (RUS)pdficon

REFERENCES

  1. Уоддингтон К.Х. Основные биологические концепции. В кн.: На пути к теоретической биологии. Часть I. Пролегомены. М.: Мир, 1970. С. 11–38.
    [Waddington CH. Basic Ideas of Biology. In: Waddington CH, ed. Towards a Theoretical Biology. Vol. 1. Edinburgh: Edinburgh University Press. 1968–72. (Russ. ed.: Waddington CH. Osnovnye biologicheskie kontseptsii. In: Waddington CH, ed. Na puti k teoreticheskoi biologii. Chast’ I. Prolegomeny. Moscow: Mir Publ.; 1970. pp. 11–38.)]
  2. Huntly BJP, Johnson PWM. Targeting Epigenetic Readers in Hematologic Malignancies: A Good BET? The Hematologist. 2012;9(2):5–7.
  3. Daser A, Rabbitts TH. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes & Dev. 2004;18:965–74. doi: 10.1101/gad.1195504.
  4. Ansorge WJ. Next-generation DNA sequencing techniques. New Biotechnol. 2009;25(4):195–203. doi: 10.1016/j.nbt.2008.12.009.
  5. Foley SB, Rios JJ, Mgbemena V. Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. EBioMedicine. 2014;2(1):74–81. doi: 10.1016/j.ebiom.2014.12.003.
  6. Wojdacz TK, Moller TH, Thestrup BB, et al. Limitations and advantages of MS-HRM and bisulfite sequencing for single locus methylation studies. Exp Rev Mol Diagn. 2010;10(5):575–80. doi: 10.1586/erm.10.46.
  7. Reinders J, Paszkowski J. Bisulfite methylation profiling of large genomes. Epigenomics. 2010;2(2):209–20. doi: 10.2217/epi.10.6.
  8. Thompson CB. Targeting Metabolic Inputs into Epigenetic Regulations of Acute Leukemia. Blood. 2013;122(21):SCI-26.
  9. Зиновкина Л.А., Зиновкин Р.А. Метилирование ДНК, митохондрии и программируемое старение. Биохимия. 2015;80(12):1830–7.
    [Zinovkina LA, Zinovkin RA. DNA methylation, mitochondria, and programmed aging. Biokhimiya. 2015;80(12):1830–7. (In Russ)]
  10. Vanyushin BF, Kiryanov GI, Kudryashova IB, Belozersky AN. DNA & methylase in loach embryos (Misgurnus fossilis). FEBS Lett. 1971;15(4):313–6. doi: 10.1016/0014-5793(71)80646-4.
  11. Vanyushin BF, Kirnos MD. The nucleotide composition and pyrimidine clusters in DNA from beef heart mitochondria. FEBS Lett. 1974;39(2):195–9. doi: 10.1016/0014-5793(74)80049-99.
  12. Vanyushin BF, Kirnos MD. The structure of animal mitochondrial DNA (base composition, pyrimidine clusters, character of methylation). Mol Cell Biochem. 1977;14(1–3):31–6. doi: 10.1007/bf01734162.
  13. Byun HM, Panni T, Motta V, et al. Effects of airborne pollutants on mitochondrial DNA methylation. Part Fibre Toxicol. 2013;10(1):18. doi: 10.1186/1743-8977-10-18.
  14. Sun C, Reimers LL, Burk RD. Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer. Gynecol Oncol. 2011;121(1):59–63. doi: 10.1016/j.ygyno.2011.01.013.
  15. Vanyushin BF, Nemirovsky LE, Klimenko VV, et al. The 5-methylcytosine in DNA of rats. Gerontologia. 1973;19(3):138–52. doi: 10.1159/000211967.
  16. Биология и медицина. Метилирование РНК. [Электронный документ] Доступно по: http://medbiol.ru/medbiol/epigenetica/001a1613.htm. Ссылка активна на 14.05.2013.
    [Biologiya i meditsina. Metilirovanie RNK. (Biology and Medicine. RNA Methylation) [Internet]. Available from: http://medbiol.ru/medbiol/epigenetica/001a1613.htm. (accessed 14.05.2013) (In Russ)]
  17. Yu B, Yang Z, Li J, et al. Methylation as a crucial step in plant microRNA biogenesis. Science. 2005;307(5711):932–5. doi: 10.1126/science.1107130.
  18. Goll MG, Kirpekar E, Maggert KA, et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science. 2006;311(5759):395–8. doi: 10.1126/science.1120976.
  19. Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, et al. The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016;530(7591):441–6. doi: 10.1038/nature16998.
  20. Christman J. 5-Azacytidine and 5-aza-2¢-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21(35):5483–95. doi: 10.1038/sj.onc.1205699.
  21. Kumar A, List A. F, Hozo I, et al. Decitabine versus 5-azacitidine for the treatment of myelodysplastic syndrome: adjusted indirect meta-analysis. Haematologica. 2010;95(2):340–2. doi: 10.3324/haematol.2009.017764.
  22. Phase II Decitabine (DAC) Versus Azacitidine (AZA) in Myelodysplastic Syndrome (MDS). [Internet] Available from: http://www.druglib.com/trial/80/NCT02269280.html. (accessed 15.05.2016).
  23. Fenaux P, Gattermann N, Seymour JF, et al. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol. 2010;149(2):244–9. doi: 10.1111/j.1365-2141.2010.08082.x.
  24. Al-Ali HK, Jaekel N, Niederwieser D. The role of hypomethylating agents in the treatment of elderly patients with AML. J Geriatr Oncol. 2014;5(1):89–105. doi: 10.1016/j.jgo.2013.08.004.
  25. Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–24. doi: 10.1002/cncr.22496.
  26. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670–7. doi: 10.1200/jco.2011.38.9429.
  27. European Medicines Agency: assessment report on Dacogen 19 July 2012. [Internet] Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002221/WC500133571.pdf2012. (accessed 17.05.2016).
  28. Minutes for the February 9 2012 meeting of the FDA Oncologic Drugs Advisory Committee. [Internet] Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM293710.pdf2012. (accessed 19.05.2016).
  29. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65. doi: 10.1182/blood-2012-03-420489.
  30. Schanz J, Tuchler H, Sole F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820–9. doi: 10.1200/jco.2011.35.6394.
  31. Kantarjian H, O’Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer. 2008;113(6):1351–61. doi: 10.1002/cncr.23697.
  32. Garcia-Manero G. Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management. Am J Hematol. 2015;90(9):831–41. doi: 10.1002/ajh.24102.
  33. Garcia-Manero G, Fenaux P. Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol. 2011;29(10):516–23. doi: 10.1200/jco.2010.31.0854.
  34. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27(11):1850–6. doi: 10.1200/jco.2008.17.1058.
  35. Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011;29(18):2521–7. doi: 10.1200/jco.2010.34.4226.
  36. Garcia-Manero G, Jabbour E, Borthakur G, et al. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. J Clin Oncol. 2013;31(20):2548–53. doi: 10.1200/jco.2012.44.6823.
  37. Wei Y, Dimicoli S, Bueso-Ramos C, et al. Toll-like receptor alterations in myelodysplastic syndrome. Leukemia. 2013;27(9):1832–40. doi: 10.1038/leu.2013.180.
  38. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–32. doi: 10.1016/s1470-2045(09)70003-8.
  39. Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA. 2010;107(16):7473–8. doi: 10.1073/pnas.1002650107.
  40. Itzykson R, Thepot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117(2):403–11. doi: 10.1182/blood-2010-06-289280.
  41. Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116(16):3830–4. doi: 10.1002/cncr.25247.
  42. Montalban-Bravo G, Garcia-Manero G. Novel drugs for older patients with acute myeloid leukemia. Leukemia. 2015;29(4):760–9. doi: 10.1038/leu.2014.244.
  43. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood. 2015;126(3):291–9. doi: 10.1182/blood-2015-01-621664.
  44. Pleyer L, Burgstaller S, Girschikofsky M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol. 2014;93(11):1825–38. doi: 10.1007/s00277-014-2126-9.
  45. Radujkovic A, Dietrich S, Bochtler T, et al. Azacitidine and low-dose cytarabine in palliative patients with acute myeloid leukemia and high bone marrow blast counts – a retrospective single-center experience. Eur J Haematol. 2014;93(2):112–7. doi: 10.1111/ejh.12308.
  46. Field T, Perkins J, Huang Y, et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2010;45(2):255–60. doi: 10.1038/bmt.2009.134.
  47. Gerds AT, Gooley TA, Estey EH, et al. Pretransplantation Therapy with Azacitidine vs Induction Chemotherapy and Posttransplantation Outcome in Patients with MDS. Biol Blood Marrow Transplant. 2012;18(8):1211–8. doi: 10.1016/j.bbmt.2012.01.009.
  48. Damaj G, Duhamel A, Robin M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies. J Clin Oncol. 2012;30(36):4533–40. doi: 10.1200/jco.2012.44.3499.
  49. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogeneous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010;116(23):5420–31. doi: 10.1002/cncr.25500.
  50. Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115(9):1899–905. doi: 10.1002/cncr.24198.
  51. Schroeder T, Czibere A, Platzbecker U, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013 27(6), 1229–35. doi: 10.1038/leu.2013.7.
  52. Lubbert M, Bertz H, Wasch R, et al. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant. 2010;45:627–32. doi: 10.1038/bmt.2009.222.
  53. Sanchez-Abarca LI, Gutierrez-Cosio S, Santamaria C, et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood. 2010;115(1):107–21. doi: 10.1182/blood-2009-03-210393.
  54. Goodyear О, Agathanggelou A, Novitzky-Basso, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116(11):1908–18. doi: 10.1182/blood-2009-11-249474.
  55. Atanackovich D, Luetkens T, Kloth B, et al. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol. 2011;86(11):918–22. doi: 10.1002/ajh.22141.
  56. Kroger N, Bacher U, Bader P, et al. NCI first international workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: report from the committee on disease-specific methods and strategies for monitoring relapse following allogeneic stem cell transplantation: II. Chronic leukemias, myeloproliferative neoplasms, and lymphoid malignancies. Biol Blood Marrow Transplant. 2010;16(10):1325–46. doi: 10.1016/j.bbmt.2010.06.008.
  57. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26(3):381–9. doi: 10.1038/leu.2011.234.
  58. Sockel K, Wermke M, Radke J, et al. Minimal Residual Disease-Directed Preemptive Treatment With Azacitidine In Patients With NPM1-Mutant Acute Myeloid Leukemia And Molecular Relapse. Haematologica. 2011;96(10):1568–70. doi: 10.3324/haematol.2011.044388.
  59. The MDS Foundation. New MDS Clinical Trials. [Internet] Available from: http://www.mds-foundation.org/clinical-trial-announcements/#New-MDS-Clinical-Trials. (accessed 17.05.2016).