MV Solovev, MV Soloveva, LP Mendeleeva

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

For correspondence: Maksim Valerevich Solovev, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: maxsolovej@mail.ru

For citation: Solovev MV, Soloveva MV, Mendeleeva LP. Supportive Therapy in Multiple Myeloma: Practical Recommendations. Clinical oncohematology. 2023;16(4):426–48. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-426-448

ABSTRACT

Supportive therapy is becoming increasingly important for the state-of-the-art algorithm of multiple myeloma (MM) treatment. The introduction of innovative drugs and transplantation methods into clinical practice considerably improved the disease-free and overall survival rates. However, in the vast majority of cases, MM still remains an incurable malignant plasma cell tumor. It is often treated on a continuous basis with a succession of targeted drugs and integration of glucocorticosteroids and conventional cytostatic agents into the program therapy. All of these together with immunodeficiency, bone lesions, and myeloma nephropathy lead to a high risk of adverse events and cumulative toxicity of treatment. At the same time, one of the main goals at all MM therapy stages is to maintain quality of life. The characteristics of clinical symptoms, the nuances of targeted therapy and chemotherapy-associated adverse events justify the need for further development of supportive MM therapy algorithms which remain to be a matter of current concern. They should be mainly aimed at preventing the therapy complications, reducing the rate of adverse events and clinical manifestations of side effects as well as developing a treatment strategy for cumulative toxicity. In the state-of-the-art algorithm of program MM treatment, supportive therapy-related knowledge is of no less value than the information on antitumor drugs and their efficacy. This paper reports the personal experience and provides recommendations mostly based on the results of clinical studies or views of expert panels. It also offers practical recommendations for supportive therapy in symptomatic MM which include prevention of skeletal complications, thromboses, and infections, nausea and vomiting management, vaccination, pre-medication and the algorithm of monoclonal antibody administration, anesthesia, peripheral polyneuropathy treatment, correction of secondary immunodeficiency, nutritional support, fatigue assessment and countermeasures.

Keywords: multiple myeloma, supportive therapy.

Received: June 22, 2023

Accepted: September 8, 2023

Read in PDF

REFERENCES

1. Костина И.Э., Гитис М.К., Менделеева Л.П. и др. Рентгеновская компьютерная томография в диагностике и мониторинге поражения костей при множественной миеломе с использованием низкодозового и стандартного протоколов сканирования. Гематология и трансфузиология. 2018;63(2):113–23. doi: 10.25837/HAT.2018.13..2..002.
   [Kostina IE, Gitis MK, Mendeleeva LP, et al. Computed tomography in the diagnosis and monitoring of bone lesions in multiple myeloma using low-dose and standard scanning protocols. Russian journal of hematology and transfusiology. 2018;63(2):113–23. doi: 10.25837/HAT.2018.13..2..002. (In Russ)]
2. Terpos E, Zamagni E, Lentzsch S, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncol. 2021;22(3):e119–e130. doi: 10.1016/S1470-2045(20)30559-3.
3. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370–81. doi: 10.1016/S1470-2045(18)30072-X.
4. Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in Osteoporosis and Oncology New Drug Developments. Ann Pharmacother I. 2009;43(9):1445–55. doi: 10.1345/aph.1M102.
5. Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc. 2006;81(8):1047–53. doi: 10.4065/81.8.1047.
6. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: Recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20(8):1303–17. doi: 10.1093/annonc/mdn796.
7. Anderson K, Ismaila N, Flynn PJ, et al. Role of bone-modifying agents in multiple myeloma: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2018;36(8):812–8. doi: 10.1200/JCO.2017.76.6402.
8. Terpos E, Morgan G, Dimopoulos MA, et al. International myeloma working group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31(18):2347–57. doi: 10.1200/JCO.2012.47.7901.
9. Бессмельцев С.С. Лечение костной болезни при множественной миеломе. Вестник гематологии. 2016;12(1):4–22.
   [Bessmeltsev The treatment of bone disease in multiple myeloma. Vestnik gematologii. 2016;12(1):4–22. (In Russ)]
10. Crockett JC, Mellis DJ, Scott DI, Helfrich MH. New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: Focus on the RANK/RANKL axis. Osteoporos Int. 2011;22(1):1–20. doi: 10.1007/s00198-010-1272-8.
11. Mikami S, Oya M, Mizuno R, et al. Invasion and metastasis of renal cell carcinoma. Med Mol Morphol. 2014;47(2):63–7. doi: 10.1007/s00795-013-0064-6.
12. Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: The Medical Research Council Myeloma IX Trial. Blood. 2012;119(23):5374–83. doi: 10.1182/blood-2011-11-392522.
13. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma. N Engl J Med. 1996;334(8):488–93. doi: 10.1056/nejm199602223340802.
14. Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial. Lancet. 2010;376(9757):1989–99. doi: 10.1016/S0140-6736(10)62051-X.
15. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98(8):1735–44. doi: 10.1002/cncr.11701.
16. Anastasilakis AD, Toulis KA, Polyzos SA, Terpos E. RANKL inhibition for the management of patients with benign metabolic bone disorders. Expert Opin Investig Drugs. 2009;18(8):1085–102. doi: 10.1517/13543780903048929.
17. Santini D, Perrone G, Roato I, et al. Expression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol. 2011;226(3):780–4. doi: 10.1002/jcp.22402.
18. Casimiro S, Mohammad KS, Pires R, et al. RANKL/RANK/MMP-1 Molecular Triad Contributes to the Metastatic Phenotype of Breast and Prostate Cancer Cells In Vitro. PLoS One. 2013;8(5):e63153. doi: 10.1371/journal.pone.0063153.
19. Delmas PD. Clinical Potential of RANKL Inhibition for the Management of Postmenopausal Osteoporosis and Other Metabolic Bone Diseases. J Clin Densitom. 2008;11(2):325–38. doi: 10.1016/j.jocd.2008.02.002.
20. Sattler AM, Schoppet M, Schaefer JR, Hofbauer LC. Novel Aspects on RANK Ligand and Osteoprotegerin in Osteoporosis and Vascular Disease. Calcif Tissue Int. 2004;74(1):103–6. doi: 10.1007/s00223-003-0011-y.
21. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139–46. doi: 10.1016/j.abb.2008.03.018.
22. Timotheadou E, Kalogeras KT, Koliou GA, et al. Evaluation of the Prognostic Value of RANK, OPG, and RANKL mRNA Expression in Early Breast Cancer Patients Treated with Anthracycline-Based Adjuvant Chemotherapy. Transl Oncol. 2017;10(4):589–98. doi: 10.1016/j.tranon.2017.05.006.
23. Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation of denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017;105:11–7. doi: 10.1016/J.BONE.2017.08.003.
24. Popp AW, Varathan N, Buffat H, et al. Bone Mineral Density Changes After 1 Year of Denosumab Discontinuation in Postmenopausal Women with Long-Term Denosumab Treatment for Osteoporosis. Calcif Tissue Int. 2018;103(1):50–4. doi: 10.1007/S00223-018-0394-4.
25. Kristinsson SY, Pfeiffer RM, Bjorkholm M, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood. 2010;115(24):4991–8. doi: 10.1182/BLOOD-2009-11-252072.
26. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–23. doi: 10.1182/blood-2013-04-460121.
27. Schoen MW, Luo S, Gage B, et al. Association of venous thromboembolism with increased mortality in patients with multiple myeloma. J Clin Oncol. 2018;36(15_suppl):8051. doi: 10.1200/JCO.2018.36.15_SUPPL.8051.
28. Huang H, Li H, Li D. Effect of serum monoclonal protein concentration on haemostasis in patients with multiple myeloma. Blood Coagul Fibrinolysis. 2015;26(5):556–9. doi: 10.1097/MBC.0000000000000296.
29. De Stefano V, Larocca A, Carpenedo M, et al. Thrombosis in multiple myeloma: risk stratification, antithrombotic prophylaxis, and management of acute events. A consensus-based position paper from an ad hoc expert panel. Haematologica. 2022;107(11):2536. doi: 10.3324/HAEMATOL.2022.280893.
30. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. doi: 10.1038/sj.leu.2405062.
31. Li A, Wu Q, Luo S, et al. Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug-Associated Thrombosis Among Patients With Multiple Myeloma. J Natl Compr Canc Netw. 2019;17(7):840–7. doi: 10.6004/JNCCN.2018.7273.
32. Covut F, Ahmed R, Chawla S, et al. Validation of the IMPEDE VTE score for prediction of venous thromboembolism in multiple myeloma: a retrospective cohort study. Br J Haematol. 2021;193(6):1213–9. doi: 10.1111/BJH.17505.
33. Miceli TS, Gonsalves WI, Buadi FK. Supportive Care in Multiple Myeloma: Current Practices and Advances. Cancer Treat Res Commun. 2021;29:100476. doi: 10.1016/J.CTARC.2021.100476.
34. Sanfilippo KM, Luo S, Wang TF, et al. Predicting Venous Thromboembolism in Multiple Myeloma: Development and Validation of the IMPEDE VTE Score. Am J Hematol. 2019;94(11):1176. doi: 10.1002/AJH.25603.
35. Piedra K, Peterson T, Tan C, et al. Comparison of Venous Thromboembolism Incidence in Newly Diagnosed Multiple Myeloma Patients Receiving Bortezomib, Lenalidomide, Dexamethasone (RVD) or Carfilzomib, Lenalidomide, Dexamethasone (KRD) with Aspirin or Rivaroxaban Thromboprophylaxis HHS Public Access. Br J Haematol. 2022;196(1):105–9. doi: 10.1111/bjh.17772.
36. Callander NS, Baljevic M, Adekola K, et al. NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022. J Natl Compr Canc Netw. 2022;20(1):8–19. doi: 10.6004/JNCCN.2022.0002.
37. Terpos E, Kleber M, Engelhardt M, et al. European myeloma network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100(10):1254–66. doi: 10.3324/haematol.2014.117176.
38. Leclerc V, Karlin L, Herledan C, et al. Thromboembolic events and thromboprophylaxis associated with immunomodulators in multiple myeloma patients: a real-life study. J Cancer Res Clin Oncol. 2022;148(3):975–84. doi: 10.1007/s00432-021-03693-5.
39. Anderson SM, Beck B, Sterud S, et al. Evaluating the use of appropriate anticoagulation with lenalidomide and pomalidomide in patients with multiple myeloma. J Oncol Pharm Pract. 2019;25(4):806–12. doi: 10.1177/1078155218758500.
40. Takaishi K, Tsukamoto S, Ohwada C, et al. Low incidence of thromboembolism in multiple myeloma patients receiving immunomodulatory drugs; a retrospective single-institution analysis. J Thromb Thrombolysis. 2019;48(1):141–8. doi: 10.1007/S11239-019-01809-W.
41. Dede RJ, Pruemer JM. Comparing venous thromboembolism prophylactic strategies for ambulatory multiple myeloma patients on immunomodulatory drug therapy. J Oncol Pharm Pract. 2015;22(2):248–55. doi: 10.1177/1078155215569555.
42. Piedra K, Peterson T, Tan C, et al. Comparison of Venous Thromboembolism Incidence in Newly Diagnosed Multiple Myeloma Patients Receiving Bortezomib, Lenalidomide, Dexamethasone (RVD) or Carfilzomib, Lenalidomide, Dexamethasone (KRD) with Aspirin or Rivaroxaban Thromboprophylaxis. Br J Haematol. 2022;196(1):105. doi: 10.1111/BJH.17772.
43. Mizrahi T, Leclerc J-M, David M, et al. ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2015;37(5):e328–e332. doi: 10.1097/MPH.0000000000000333.
44. Merlen C, Bonnefoy A, Wagner E, et al. L-Asparaginase lowers plasma antithrombin and mannan-binding-lectin levels: Impact on thrombotic and infectious events in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62(8):1381–7. doi: 10.1002/pbc.25515.
45. Kristinsson SY, Tang M, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012;97(6):854–8. doi: 10.3324/HAEMATOL.2011.054015.
46. Blimark C, Holmberg E, Mellqvist UH, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100(1):107–13. doi: 10.3324/HAEMATOL.2014.107714.
47. Lim C, Sinha P, Harrison SJ, et al. Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Clin Lymphoma Myeloma Leuk. 2021;21(7):444–450.e3. doi: 10.1016/J.CLML.2021.02.002.
48. Drayson MT, Bowcock S, Planche T, et al. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Oncol. 2019;20(12):1760. doi: 10.1016/S1470-2045(19)30506-6.
49. Raje NS, Anaissie E, Kumar SK, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol. 2022;9(2):e143–e161. doi: 10.1016/S2352-3026(21)00283-0.
50. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: Updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259–66. doi: 10.1200/JCO.2009.26.0638.
51. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124(20):4032–43. doi: 10.1002/cncr.31680.
52. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018;379(19):1811–22. doi: 10.1056/NEJMoa1805762.
53. George LL, Malik MN, Miller EJ, et al. Special Considerations for Supportive Care and Management of Complications in Elderly Patients With Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2021;21(12):812–22. doi: 10.1016/J.CLML.2021.07.013.
54. Karlsson J, Andreasson B, Kondori N, et al. Comparative study of immune status to infectious agents in elderly patients with multiple myeloma, Waldenstrom’s macroglobulinemia, and monoclonal gammopathy of undetermined significance. Clin Vaccine Immunol. 2011;18(6):969–77. doi: 10.1128/CVI.00021-11.
55. Ludwig H, Kumar S. Prevention of infections including vaccination strategies in multiple myeloma. Am J Hematol. 2023;98(S2):S46–S62. doi: 10.1002/AJH.26766.
56. Ведение пациентов онкогематологического профиля в период пандемии COVID-19. Под ред. И.В. Поддубной. М.: Экон-Информ, 2022. 140 с.
    [Poddubnaya IV, ed. Vedenie patsientov onkogematologicheskogo profilya v period pandemii COVID-19. (The management of oncohematological patients during COVID-19 pandemics.) Moscow: Ekon-Inform ; 2022. 140 p. (In Russ)]
57. Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309–22. doi: 10.1016/J.ANNONC.2020.11.014.
58. Hua Q, Zhu Y, Liu H. Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin’s lymphoma (B-NHL) chemotherapy: A meta-analysis. J Chemother. 2015;27(6):365–70. doi: 10.1179/1973947815Y.0000000025.
59. Ren YR, Jin YD, Zhang ZH, et al. Rituximab treatment strategy for patients with diffuse large B‑cell lymphoma after first‑line therapy: A systematic review and meta‑ Chin Med J (Engl). 2015;128(3):378–83. doi: 10.4103/0366-6999.150111.
60. Taniwaki M, Yoshida M, Matsumoto Y, et al. Elotuzumab for the treatment of relapsed or refractory multiple myeloma, with special reference to its modes of action and SLAMF7 signaling. Mediterr J Hematol Infect Dis. 2018;10(1):2018014. doi: 10.4084/mjhid.2018.014.
61. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9. doi: 10.1200/JCO.2011.37.2649.
62. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207–19. doi: 10.1056/NEJMoa1506348.
63. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. J Clin Oncol. 2023;41(3):568. doi: 10.1200/JCO.21.02815.
64. Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol. 2016;9(1):51. doi: 10.1186/S13045-016-0283-0.
65. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319–31. doi: 10.1056/nejmoa1607751.
66. Boyle EM, Leleu X, Petillon MO, et al. Daratumumab and dexamethasone is safe and effective for triple refractory myeloma patients: final results of the IFM 2014-04 (Etoile du Nord) trial. Br J Haematol. 2019;187(3):319–27. doi: 10.1111/bjh.16059.
67. Baldo BA. Monoclonal Antibodies Approved for Cancer Therapy. In: Safety of Biologics Therapy. Springer International Publishing; 2016:57–140. doi: 10.1007/978-3-319-30472-4_3.
68. Van De Donk NWCJ, Moreau P, Plesner T, et al. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood. 2016;127(6):681–95. doi: 10.1182/blood-2015-10-646810.
69. Nooka AK, Gleason C, Sargeant MO, et al. Managing infusion reactions to new monoclonal antibodies in multiple myeloma: Daratumumab and elotuzumab. J Oncol Pract. 2018;14(7):414–22. doi: 1200/JOP.18.00143.
70. Головкина Л.Н., Минеева Н.В., Менделеева Л.П. и др. Модификация преаналитического этапа непрямой пробы Кумбса у больных множественной миеломой при лечении даратумумабом. Гематология и трансфузиология. 2018;63(1):44–54. doi: 10.25837/HAT.2018.45..1..004.
    [Golovkina LL, Mineeva NV, Mendeleeva LP, et al. A modification of the pre-analytical phase of the indirect coombs test for multiple myeloma patients treated with daratumumab. Russian journal of hematology and transfusiology. 2018;63(1):44–54. doi: 10.25837/HAT.2018.45..1..004. (In Russ)]
71. De Vooght KMK, Oostendorp M, Van Solinge WW. New mAb therapies in multiple myeloma: interference with blood transfusion compatibility testing. Curr Opin Hematol. 2016;23(6):557–62. doi: 10.1097/MOH.0000000000000276.
72. Li Y, Li C, Zhang L, et al. Long-term storage protocol of reagent red blood cells treated with 0.01M dithiothreitol (DTT) for pre-transfusion testing of patients receiving anti-CD38 therapy, daratumumab. Hematology. 2023;28(1):2186037. doi: 10.1080/16078454.2023.2186037.
73. Van De Donk NWCJ, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13–29. doi: 10.1182/blood-2017-06-740944.
74. Zhu C, Song Z, Wang A, et al. Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells. Front Immunol. 2020;11:1771. doi: 10.3389/fimmu.2020.01771.
75. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096–107. doi: 10.1016/S0140-6736(19)32556-5.
76. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–71. doi: 10.1016/S0140-6736(21)00592-4.
77. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482–94. doi: 10.1056/NEJMra0706547.
78. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68(21):8643–53. doi: 10.1158/0008-5472.CAN-07-6611.
79. Navari RM, Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016;374(14):1356–67. doi: 10.1056/NEJMra1515442.
80. Snowden JA, Ahmedzai SH, Ashcroft J, et al. Guidelines for supportive care in multiple myeloma 2011. Br J Haematol. 2011;154(1):76–103. doi: 10.1111/J.1365-2141.2011.08574.X.
81. Bountra C, Gale JD, Gardner CJ, et al. Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs. Oncology. 1996;53(Suppl 1):102–9. doi: 10.1159/000227649.
82. Mitchelson F. Pharmacological agents affecting emesis. A review (Part I). Drugs. 1992;43(3):295–315. doi: 10.2165/00003495-199243030-00002.
83. Berger MJ, Ettinger DS, Aston J, et al. Antiemesis, version 2.2017 featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2017;15(7):883–93. doi: 10.6004/jnccn.2017.0117.
84. Leslie RA. Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus. Neurochem Int. 1985;7(2):191–211. doi: 10.1016/0197-0186(85)90106-8.
85. Снеговой А.В., Абрамов М.Е., Бяхов М.Ю. и др. Практические рекомендации по профилактике и лечению тошноты и рвоты у онкологических больных. Злокачественные опухоли. 2016;4(2):378–89. doi: 10.18027/2224-5057-2016-4s2-378-389.
    [Snegovoi AV, Abramov ME, Byakhov MYu, et al. Practical recommendations for nausea and vomiting prevention and treatment in oncological patients. Malignant tumors. 2016;4(2):378–89. doi: 10.18027/2224-5057-2016-4s2-378-389. (In Russ)]
86. Einhorn LH, Rapoport B, Navari RM, et al. 2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting. Support Care Cancer. 2017;25(1):303–8. doi: 10.1007/S00520-016-3449-y.
87. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(28):3240–61. doi: 10.1200/JCO.2017.74.4789.
88. Loteta B, Paviglianiti A, Naso V, et al. Netupitant/palonosetron without dexamethasone for preventing nausea and vomiting in patients with multiple myeloma receiving high-dose melphalan for autologous stem cell transplantation: a single-center experience. Support Care Cancer. 2022;30(1):585. doi: 10.1007/S00520-021-06472-7.
89. Tendas A, Marchesi F, Mengarelli A, et al. Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions. Support Care Cancer. 2019;27(3):793–803. doi: 10.1007/S00520-018-4594-2.
90. Ye P, Pei R, Wang T, et al. Multiple-day administration of fosaprepitant combined with tropisetron and olanzapine improves the prevention of nausea and vomiting in patients receiving chemotherapy prior to autologous hematopoietic stem cell transplant: a retrospective study. Ann Hematol. 2022;101(8):1835–41. doi: 10.1007/S00277-022-04877-w.
91. Patel P, Leeder JS, Piquette-Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol. 2017;83(10):2148–62. doi: 10.1111/bcp.13322.
92. Roila F, Aapro M, Ballatori E, et al. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol. 2006;17(1):20–8. doi: 10.1093/annonc/mdj078.
93. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189–98. doi: 10.1200/JCO.2010.34.4614.
94. Razvi Y, Chan S, McFarlane T, et al. ASCO, NCCN, MASCC/ESMO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in adult patients. Support Care Cancer. 2019;27(1):87–95. doi: 10.1007/s00520-018-4464-y.
95. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(28):3240–61. doi: 10.1200/JCO.2017.74.4789.
96. Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppression for healing of duodenal ulcers?. A model of the relationship between ulcer healing and acid suppression. 1990;99(2):345–51. doi: 10.1016/0016-5085(90)91015-X.
97. Ивашкин В.Т., Маев И.В., Царьков П.В. и др. Диагностика и лечение язвенной болезни у взрослых (клинические рекомендации Российской гастроэнтерологической ассоциации, Российского общества колоректальных хирургов и Российского эндоскопического общества). Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2020;30(1):49–70.
    [Ivashkin VT, Maev IV, Tsarkov PV, et al. Diagnosis and treatment of peptic ulcer in adults (clinical guidelines of the Russian Gastroenterological Association, the Russian Society of Colorectal Surgeons, and the Russian Endoscopic Society). Rossiiskii zhurnal gastroenterologii, gepatologii, koloproktologii. 2020;30(1):49–70. (In Russ)]
98. Hu Z-H, Shi A-M, Hu D-M, Bao J-J. Efficacy of proton pump inhibitors for patients with duodenal ulcers: A pairwise and network meta-analysis of randomized controlled trials. Saudi J Gastroenterol. 2017;23(1):11–9. doi: 10.4103/1319-3767.199117.
99. Poynard T, Lemmaire M, Agostini H. Meta-analysis of randomized clinical trials comparing lansoprazole raitidine or famotidine in the treatment of acute duodenal ulcer. Eur J Gastroenterol Hepatol. 1995;7(7):661–5.
100. Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017;390(10094):613–24. doi: 10.1016/S0140-6736(16)32404-7.
101. Семочкин С.В., Соловьев М.В., Менделеева Л.П. Профилактика и лечение бортезомибиндуцированной нейропатии у пациентов с множественной миеломой. Онкогематология. 2022;17(2):141–50. doi: 10.17650/1818-8346-2022-17-2-141-150.
     [Semochkin SV, Solovyev MV, Mendeleeva LP. Prevention and management of bortezomib-induced peripheral neuropathy in patients with multiple myeloma. Oncohematology. 2022;17(2):141–50. doi: 10.17650/1818-8346-2022-17-2-141-150. (In Russ)]
102. Miceli TS, Gonsalves WI, Buadi FK. Supportive Care in Multiple Myeloma: Current Practices and Advances. Cancer Treat Res Commun. 2021;29:100476. doi: 10.1016/J.CTARC.2021.100476.
103. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. Под ред. В.Г. Савченко М.: Практика, 2018. 1008 с.
     [Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols in hematological diseases.) Moscow: Praktika; 2018. 1008 p. (In Russ)]
104. Morawska M, Grzasko N, Kostyra M, et al. Therapy-related peripheral neuropathy in multiple myeloma patients. Hematol Oncol. 2015;33(4):113–9. doi: 10.1002/HON.2149.
105. Guzdar A, Costello C. Supportive Care in Multiple Myeloma. Curr Hematol Malig Rep. 2020;15(2):56–61. doi: 10.1007/S11899-020-00570-9.
106. Zhi WI, Ingram E, Li SQ, et al. Acupuncture for Bortezomib-Induced Peripheral Neuropathy: Not Just for Pain. Integr Cancer Ther. 2018;17(4):1079. doi: 10.1177/1534735418788667.
107. Shah N, Mustafa SS, Vinh DC. Management of secondary immunodeficiency in hematological malignancies in the era of modern oncology. Crit Rev Oncol Hematol. 2023;181:103896. doi: 10.1016/J.CRITREVONC.2022.103896.
108. Girmenia C, Cavo M, Offidani M, et al. Management of infectious complications in multiple myeloma patients: Expert panel consensus-based recommendations. Blood Rev. 2019;34:84–94. doi: 10.1016/J.BLRE.2019.01.001.
109. Compagno N, Malipiero G, Cinetto F, Agostini C. Immunoglobulin replacement therapy in secondary hypogammaglobulinemia. Front Immunol. 2014;5:626. doi: 10.3389/fimmu.2014.00626.
110. Coluzzi F, Rolke R, Mercadante S. Pain Management in Patients with Multiple Myeloma: An Update. Cancers. 2019;11(12):2037. doi: 10.3390/CANCERS11122037.
111. Davies MP, Fingas S, Chantry A. Mechanisms and treatment of bone pain in multiple myeloma. Curr Opin Support Palliat Care. 2019;13(4):408–16. doi: 10.1097/SPC.0000000000000467.
112. Бесова Н.С., Борисова Т.Н., Ларионова В.Б. и др. Клинические рекомендации по нутритивной поддержке при химиотерапии и/или лучевой терапии (электронный документ). М., 2014. Доступно по: https://oncology.ru/association/clinical-guidelines/2014/29.pdf?ysclid=ljftefrlc4177015966. Ссылка активна на06.2023.
     [Besova NS, Borisova TN, Larionova VB, et al. Clinical guidelines for nutritional support on chemo- and/or radiotherapy. (Internet) Moscow; 2014. Available from: https://oncology.ru/association/clinical-guidelines/2014/29.pdf?ysclid=ljftefrlc4177015966. Accessed 28.06.2023. (In Russ)]
113. Virizuela JA, Camblor-Alvarez M, Luengo-Perez LM, et al. Nutritional support and parenteral nutrition in cancer patients: an expert consensus report. Clin Transl Oncol. 2018;20(5):619–29. doi: 10.1007/s12094-017-1757-4.
114. Arends J, Bachmann P, Baracos V, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11–48. doi: 10.1016/j.clnu.2016.07.015.
115. Сытов А.В., Лейдерман И.Н., Ломидзе С.В. и др. Практические рекомендации по нутритивной поддержке онкологических больных. Злокачественные опухоли. 2017;7(352):524–32. doi: 10.18027/2224-5057-2017-7-3s2-524-532.
     [Sytov AV, Leiderman IN, Lomidze SV, et al. Practical recommendations on nutritive support for cancer patients. Malignant tumors. 2017;7(352):524–32. doi: 10.18027/2224-5057-2017-7-3s2-524-532. (In Russ)]
116. Isenring E, Elia M. Which screening method is appropriate for older cancer patients at risk for malnutrition? Nutrition. 2015;31(4):594–7. doi: 10.1016/J.NUT.2014.12.027.
117. Camblor-Alvarez M, Ocon-Breton MJ, Luengo-Perez LM, et al. Soporte nutricional y nutricion parenteral en el paciente oncologico: informe de consenso de un grupo de expertos. Nutr Hosp. 2018;35(1):224–33. doi: 10.20960/nh.1361.
118. Bower JE. Cancer-related fatigue: Mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014;11(10):597. doi: 10.1038/NRCLINONC.2014.127.
119. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Lancet. 2003;362(9384):640–50. doi: 10.1016/S0140-6736(03)14186-4.
120. Miller AH, Ancoli-Israel S, Bower JE, et al. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. 2008;26(6):971–82. doi: 10.1200/JCO.2007.10.7805.
121. Tariman JD, Dhorajiwala S. Genomic Variants Associated With Cancer-Related Fatigue: A Systematic Review. Clin J Oncol Nurs. 2016;20(5):537–46. doi: 10.1188/16.CJON.537-546.
122. Bower JE. The role of neuro-immune interactions in cancer-related fatigue: Biobehavioral risk factors and mechanisms. Cancer. 2019;125(3):353–64. doi: 10.1002/CNCR.31790.
123. Berger AM, Wielgus K, Hertzog M, et al. Patterns of circadian activity rhythms and their relationships with fatigue and anxiety/depression in women treated with breast cancer adjuvant chemotherapy. Support Care Cancer. 2010;18(1):105–14. doi: 10.1007/S00520-009-0636-0.
124. Al-Majid S, Mccarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs. 2001;2(3):186–97. doi: 10.1177/109980040100200304.
125. O’Higgins CM, Brady B, O’Connor B, et al. The pathophysiology of cancer-related fatigue: current controversies. Support Care Cancer. 2018;26(10):3353–64. doi: 10.1007/S00520-018-4318-7.
126. Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cancer-Related Fatigue; 2023. Available from: https://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. (accessed 07.07.2023).
127. Minton O, Stone P. A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol Off J Eur Soc Med Oncol. 2009;20(1):17–25. doi: 10.1093/annonc/mdn537.
128. Ramsenthaler C, Kane P, Gao W, et al. Prevalence of symptoms in patients with multiple myeloma: a systematic review and meta-analysis. Eur J Haematol. 2016;97(5):416–29. doi: 10.1111/EJH.12790.
129. Suzuki K, Kobayashi N, Ogasawara Y, et al. Clinical significance of cancer-related fatigue in multiple myeloma patients. Int J Hematol. 2018;108(6):580–7. doi: 10.1007/S12185-018-2516-1.
130. Mendoza TR, Wang XS, Cleeland CS, et al. The Rapid Assessment of Fatigue Severity in Cancer Patients Use of the Brief Fatigue Inventory. 1999;85(5):1186–96. doi: 10.1002/(sici)1097-0142(19990301)85:5<1186::aid-cncr24>3.0.co;2-n.

OYu Vinogradova^1,2,3, MM Pankrashkina¹, AL Neverova¹, MV Chernikov¹, LA Mukha¹, DI Shikhbabaeva¹, VV Ptushkin^1,2,3,4

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

² Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela ul., Moscow, Russian Federation, 117997

³ NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

⁴ Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya ul., Moscow, Russian Federation, 125993

For correspondence: Anna Leonidovna Neverova, PhD in Biology, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)015-65-49; e-mail: anyuta6549@yandex.ru

For citation: Vinogradova OYu, Pankrashkina MM, Neverova AL, et al. Primary Immune Thrombocytopenia and Thrombopoietin Receptor Agonists: Feasibilities of Treatment Discontinuation upon Achieving Stable Complete Platelet Response. Clinical oncohematology. 2023;16(4):413–25. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-413-425

ABSTRACT

Aim. To assess the stability of clinical remission in patients with primary immune thrombocytopenia (ITP) after withdrawal of thrombopoietin receptor agonists (TPO-RAs).

Materials & Methods. The study enrolled 456 patients with primary ITP who received second- and subsequent-line TPO-RA treatment. Complete platelet response (PR) was achieved in 338 patients, the therapy was discontinued in 116 of them. The present prospective clinical study started in 2014 and focused on the data of these 116 patients. Among them, there were 27 (23 %) men and 89 (77 %) women. By the time of TPO-RA therapy onset, the median age of the patients was 60 years (range 13–87 years), on ITP diagnosis date it was 52 years (range 1–80 years).

Results. By the time of data analysis, 59 % of patients sustained PR after TPO-RA withdrawal. The median PR duration after TPO-RA withdrawal was 230 weeks. Romiplostim and eltrombopag recipients showed no significant differences in the survival rates without PR-loss after TPO-RA withdrawal. In the present study, the maximum PR duration achieved 9.5 years. The mid-term assessment of PR status was carried out in 3, 6, 12, 24, and 30 months after TPO-RA withdrawal and showed 99 %, 94 %, 83 %, 72 %, and 70 %, respectively. The number of previous therapy lines significantly affected the survival rates without PR-loss (p = 0.011). The age of patients, prior splenectomy, TPO-RA treatment duration, time to different PR levels on therapy, PR duration on TPO-RA therapy, and platelet count upon TPO-RA withdrawal showed no significant effect on this parameter. After PR-loss, TPO-RAs were administered again to 31 (27 %) patients. Repeated PR was achieved in 26 (84 %) of them.

Conclusion. TPO-RA administration yields multi-year off-treatment remission in some patients with primary ITP. Upon therapy discontinuation, 59 % of patients with complete PR sustained PR for 3 months to 9.5 years. Stable PR after TPO-RA withdrawal significantly correlated with only one of the studied prognostic parameters, i.e., the number of previous therapy lines.

Keywords: primary immune thrombocytopenia, ITP, thrombopoietin receptor agonists, romiplostim, eltrombopag.

Received: June 30, 2023

Accepted: September 15, 2023

Read in PDF

REFERENCES

1. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386–93. doi: 10.1182/blood-2008-07-162503.
2. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–86. doi: 10.1182/blood-2009-06-225565.
3. Ионова Т.И., Виноградова О.Ю., Шелехова Т.В. и др. Изменения качества жизни у пациентов с хронической иммунной тромбоцитопенией в процессе терапии ромиплостимом, его эффективность и безопасность в условиях реальной клинической практики: результаты многоцентрового наблюдательного исследования. Клиническая онкогематология. 2023;16(2):154–65. doi: 10.21320/2500-2139-2023-16-2-154-165.
   [Ionova TI, Vinogradova OYu, Shelekhova TV, et al. Quality of Life Changes in Patients with Chronic Immune Thrombocytopenia in the Process of Romiplostim Therapy, its Efficacy and Safety in the Real-World Setting: Results of a Multi-Center Observational Study. Clinical oncohematology. 2023;16(2):154–65. doi: 10.21320/2500-2139-2023-16-2-154-165. (In Russ)]
4. Perera M, Garrido T. Advances in the pathophysiology of primary immune thrombocytopenia Hematology. 2017;22(1):41–53. doi: 10.1080/10245332.2016.1219497.
5. Ogawara H, Handa H, Morita K, et al. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2003;71(4):283–8. doi: 10.1034/j.1600-0609.2003.00138.x.
6. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103(2):500–6. doi: 10.1182/blood-2003-01-0275.
7. Российские клинические рекомендации. Идиопатическая тромбоцитопеническая пурпура (ИТП) у взрослых (электронный документ). Доступно по: https://npngo.ru/uploads/media_document/631/4a7a26c4-0f1b-4588-b2db-4b99d54d72epdf. Ссылка активна на 30.06.2023.
   [Russian clinical guidelines. Idiopathic thrombocytopenic purpura (ITP) in adults. (Internet) Available from: https://npngo.ru/uploads/media_document/631/4a7a26c4-0f1b-4588-b2db-4b99d54d72e5.pdf. Accessed 30.06.2023. (In Russ)]
8. Bussel J, Cooper N, Boccia R, et al. Immune thrombocytopenia. Expert Rev Hematol. 2021;14(11):1013–25. doi: 10.1080/17474086.2021.1995347.
9. Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene. 2002;21(21):3359–67. doi: 10.1038/sj.onc.1205323.
10. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98(1):10–23. doi: 10.1007/s12185-013-1382-0.
11. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87(10):4068–71.
12. Ballem PJ, Segal GM, Stratton JR, et al. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80(1):33–40. doi: 10.1172/JCI113060.
13. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76(6):628–38. doi: 10.1016/j.clpt.2004.08.010.
14. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116(22):4639–45. doi: 10.1182/blood-2010-04-281717.
15. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371(9610):395–403. doi: 10.1016/S0140-6736(08)60203-2.
16. Kuter DJ. The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag. Blood Rev. 2022;53:100909. doi: 10.1016/j.blre.2021.100909.
17. Масчан А.А., Румянцев А.Г., Ковалева Л.Г. и др. Рекомендации российского совета экспертов по диагностике и лечению больных первичной иммунной тромбоцитопенией. Онкогематология. 2010;5(3):36–45.
    [Maschan AA, Rumyantsev AG, Kovaleva LG, et al. Recommendations of the Russian Expert Panel on diagnosis and treatment of primary immune Onkogematologiya. 2010;5(3):36–45. (In Russ)]
18. Neunert C, Terrell DR, Arnold DM, et al. American society of hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829–66. doi: 10.1182/bloodadvances.2019000966.
19. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780–817. doi: 10.1182/bloodadvances.2019000812.
20. Wang L, Gao Z, Chen XP, et al. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. Sci Rep. 2016;6:39003. doi: 10.1038/srep39003.
21. Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol. 2018;181(2):183–95. doi: 10.1111/bjh.15090.
22. Cheng G, Saleh MN, Marcher C, et al. Lancet. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377(9763):393–402. doi: 10.1016/S0140-6736(10)60959-2.
23. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161–71. doi: 10.1182/blood-2008-04-150078.
24. Зотова И.И., Грицаев С.В., Шилова Е.Р. и др. Агонисты рецептора тромбопоэтина в лечении идиопатической тромбоцитопенической пурпуры (первичной иммунной тромбоцитопении): эффективность и безопасность в повседневной клинической практике. Клиническая онкогематология. 2017;10(1):93–100. doi: 10.21320/2500-2139-2017-10-1-93-100.
    [Zotova II, Gritsaev SV, Shilova ER, et al. Thrombopoietin Receptor Agonists in Treatment of Idiopathic Thrompocytopenic Purpura (Primary Immune Thrombocytopenia): Efficacy and Safety in Everyday Clinical Practice. Clinical oncohematology. 2017;10(1):93–100. doi: 10.21320/2500-2139-2017-10-1-93-100. (In Russ)]
25. Птушкин В.В., Виноградова О.Ю., Панкрашкина М.М. и др. Агонисты рецептора тромбопоэтина в лечении хронической резистентной первичной иммунной тромбоцитопении: эффективность и безопасность в повседневной клинической практике. Терапевтический архив. 2018;90(7):70–6. doi: 10.26442/terarkh201890770-76.
    [Ptushkin VV, Vinogradova OY, Pankrashkina MM, et al. Thrombopoietin Receptor Agonists in the Treatment of Chronic Resistant Primary Immune Thrombocytopenia: Efficacy and Safety Data in Real Clinical Practice. Terapevticheskii arkhiv. 2018;90(7):70–6. doi: 10.26442/terarkh201890770-76. (In Russ)]
26. Newland A, Bussel JM, Arnold DM, et al. Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim. Blood. 2018;132(Suppl 1):735. doi: 10.1182/blood-2018-99-109791.
27. Lucchini E, Palandri F, Volpetti S, et al. Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study. Br J Haematol. 2021;193(2):386–96. doi: 10.1111/bjh.17334.
28. Newland A, Cervinek L, Eggermann J, et al. Sustained hemostatic platelet counts in adult patients with primary immune thrombocytopenia (ITP) following cessation of romiplostim – four European case studies. Haematologica. 2011;96(Suppl 2):98, abstract 237.
29. Bussel J, Rodeghiero F, Lyons R, et al. Sustained hemostatic platelet counts in adults with immune thrombocytopenia (ITP) following cessation of treatment with the TPO receptor agonist romoiplostim: report of 9 cases. Blood (ASH Annual Meeting Abstracts). 2011;118(21): Abstract 3281.
30. Leven E, Miller A, Boulad N, et al. Successful Discontinuation of Eltrombopag Treatment in Patients with Chronic ITP. 2012;120(21):1085 doi: 10.1182/blood.V120.21.1085.1085.
31. Bussel J, Wang X, Lopez A, Eisen M. Case study of remission in adults with immune thrombocytopenia following cessation of treatment with the thrombopoietin mimetic romiplostim. Hematology. 2016;21(4):257–62. doi: 10.1179/1607845415Y.0000000041.
32. Stasi R, Newland A, Godeau B, et al. An interim analysis of a phase 2, single-arm study of platelet responses and remission rates in patients with immune thrombocytopenia (ITP) receiving romiplostim. Blood. 2013;122(21):1074.
33. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013;121(3):537–45. doi: 10.1182/blood-2012-04-425512.
34. Gonzalez-Lopez TJ, Gonzalez-Porras JR, Arefi M, et al. Sustained response after short-medium-term treatment with eltrombopag in patients with ITP. Blood. 2013;122(21):2323. doi: 10.1182/blood.V122.21.2323.2323.
35. Ghadaki B, Nazi I, Kelton G, Donald MA. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoetin receptor agonist. Transfusion. 2013;53(11):2807–12. doi: 10.1111/trf.12139.
36. Gonzalez-Lopez TJ, Sanchez-Gonzalez B, Pascual C, et al. Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia. Platelets. 2015;26(1):83–6. doi: 10.3109/09537104.2013.870987.
37. Gonzalez-Lopez TJ, Pascual C, Alvarez-Roman MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol. 2015;90(3):E40–Е43. doi: 10.1002/ajh.23900.
38. Mahevas M, Fain O, Ebbo M, et al. The temporary use of thrombopoietin-receptor agonists may induce a prolonged remission in adult chronic immune thrombocytopenia. Results of a French observational study. Br J Haematol. 2014;165(6):865–9. doi: 10.1111/bjh.12888.
39. Cervinek L, Mayer J, Doubek M. Sustained remission of chronic immune thrombocytopenia after discontinuation of treatment with thrombopoietin-receptor agonists in adults. Int J Hematol. 2015;102(1):7–11. doi: 10.1007/s12185-015-1793-1.
40. Provan D, Taylor L, Nandigham R, et al. Sustained responses following treatment with romiplostim in immune thrombocytopenia: a single-centre experience. J Hematol Thrombo Dis. 2014;2(4):147–9. doi: 10.4172/2329-8790.1000147.
41. Newland A, Godeau B, Priego V, et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 2016;172(2):262–73. doi: 10.1111/bjh.13827.
42. Iino M, Sakamoto Y, Sato T. Treatment-free remission after thrombopoietin receptor agonist discontinuation in patients with newly diagnosed immune thrombocytopenia: an observational retrospective analysis in real-world clinical practice. Int J Hematol. 2020;112(2):159–68. doi: 10.1007/s12185-020-02893-y.
43. Mahevas M, Guillet S, Viallard J-F, et al. Rate of Prolonged Response after Stopping Thrombopoietin-Receptor Agonists Treatment in Primary Immune Thrombocytopenia (ITP): Results from a Nationwide Prospective Multicenter Interventional Study (STOPAGO). 2021;138(Suppl 1):583. doi: 10.1182/blood-2021-152767.
44. Doobaree IU, Newland A, McDonald V, et al. Primary immune thrombocytopenia (ITP) treated with romiplostim in routine clinical practice: retrospective study from the United Kingdom ITP Registry. Eur J Haematol. 2019;102(5):416–23. doi: 10.1111/ejh.13221.
45. Forsythe A, Schneider J, Pham T, et al. Real-world evidence on clinical outcomes in immune thrombocytopenia treated with thrombopoietin receptor agonists. J Comp Eff Res. 2020;9(7):447–57. doi: 10.2217/cer-2019-0177.
46. Виноградова О.Ю., Бобкова М.М., Черников М.В. и др. Сохранение ремиссии без лечения у больных иммунной тромбоцитопенией (ИТП) с полным стойким ответом на терапию агонистами тромбопоэтиновых рецепторов (аТПОр). Гематология и трансфузиология. 2020;65(S1):22.
    [Vinogradova OYu, Bobkova MM, Chernikov MV, et al. Sustaining off-treatment remission in immune thrombocytopenia (ITP) patients with complete stable response to thrombopoietin receptor agonists (TPO-RAs). Gematologiya i transfuziologiya. 2020;65(S1):22. (In Russ)]
47. Barlassina A, Gonzalez-Lopez TJ, Cooper N, Zaja F. European Delphi panel to build consensus on tapering and discontinuing thrombopoietin receptor agonists in immune thrombocytopenia. Platelets. 2023:2170999. doi: 10.1080/09537104.2023.2170999. Epub ahead of print.

GR Gimatdinova¹, OE Danilova², VP Kuzmin¹, GI Davydkin¹, YuV Kostalanova³, DA Kudlai⁴, IL Davydkin²

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

² SamGMU Research Institute of Hematology, Transfusiology and Intensive Care, 165Б K. Marksa pr-t, Samara, Russian Federation, 443086

³ Samara Regional Clinical Oncology Dispensary, 50 Solnechnaya ul., Samara, Russian Federation, 443031

⁴ NRC Institute of Immunology FMBA of Russia, 24 Kashirskoye sh., Moscow, Russian Federation, 115522

For correspondence: Geliya Rifkatovna Gimatdinova, 89 Chapaevskaya ul., Samara, Russian Federation, 443099; Tel.: +7(919)809-68-56; e-mail: gimatdinova1995@icloud.com

For citation: Gimatdinova GR, Danilova OE, Kuzmin VP, et al. Cardiovascular Complications of the Immunotherapy of Hematological Malignancies: A Literature Review. Clinical oncohematology. 2023;16(4):407–12. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-407-412

ABSTRACT

In clinical oncology in general, tumor treatment is closely related to a highly relevant issue of chemotherapy-induced adverse events. Among side effects, cardiovascular toxicity occupies the foremost place. The strategy of controlling the cardiovascular complications associated with antitumor drug and cell therapies presupposes an early diagnosis of changes in the heart muscle and blood vessels at the stage of subclinical manifestations of adverse events. The present literature review provides the analysis of data on immunotherapy side effects in hematological malignancies with a focus on cardiovascular complications. The review comprehensively discusses the characteristics of cardiovascular complications associated with immune checkpoint inhibitors, CAR-T cell products, bispecific antibodies as well as immunomodulatory and antiangiogenic drugs.

Keywords: cardiotoxicity, immunotherapy, oncology, hematology.

Received: April 3, 2023

Accepted: September 30, 2023

Read in PDF

REFERENCES

1. Totzeck M, Michel L, Lin Y, et al. Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. Eur Heart J. 2022;43(20):1928–40. doi: 10.1093/eurheartj/ehac106.
2. Asnani A. Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management. Curr Oncol Rep. 2018;20(6):44. doi: 10.1007/s11912-018-0690-1.
3. Yasukawa M. Immunotherapy for hematological neoplasms. Rinsho Ketsueki. 2012;53(10):1759–67. doi: 10.11406/rinketsu.53.1759.
4. Totzeck M, Schuler M, Stuschke M, et al. Cardio-oncology – strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol. 2019;280:163–75. doi: 10.1016/j.ijcard.2019.01.038.
5. Moslehi JJ. Cardiovascular Toxic Effects of Targeted Cancer Therapies. N Engl J Med. 2016;375(15):1457–67. doi: 10.1056/NEJMra1100265.
6. Rassaf T, Totzeck M, Backs J, et al. Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology. Clin Res Cardiol. 2020;109(10):1197–222. doi: 10.1007/s00392-020-01636-7.
7. Michel L, Helfrich I, Hendgen-Cotta UB, et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J. 2022;43(4):316–29. doi: 10.1093/eurheartj/ehab430.
8. Шубникова Е.В., Букатина Т.М., Вельц Н.Ю. и др. Ингибиторы контрольных точек иммунного ответа: новые риски нового класса противоопухолевых средств. Безопасность и риск фармакотерапии. 2020;8(1):9–22. doi: 10.30895/2312-7821-2020-8-1-9-22.
   [Shubnikova EV, Bukatina TM, Velts NYu, et al. Immune checkpoint inhibitors: new risks of a new class of antitumour agents. Safety and Risk of Pharmacotherapy. 2020;8(1):9–22. doi: 10.30895/2312-7821-2020-8-1-9-22. (In Russ)]
9. Лепик К.В. Ингибиторы иммунных контрольных точек в терапии лимфом. Клиническая онкогематология. 2018;11(4):303–12. doi: 10.21320/2500-2139-2018-11-4-303-312.
   [Lepik KV. Immune Checkpoint Inhibitors in the Treatment of Lymphomas. Clinical oncohematology. 2018;11(4):303–12. doi: 10.21320/2500-2139-2018-11-4-303-312. (In Russ)]
10. Zarifa A, Lopez-Mattei J, Palaskas N, et al. Immune Checkpoint Inhibitor (ICI)-Related Cardiotoxicity. Adv Exp Med Biol. 2021;1342:377–87. doi: 10.1007/978-3-030-79308-1_15.
11. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated with Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. doi: 10.1016/j.jacc.2018.02.037.
12. Michel L, Totzeck M, Lehmann L, et al. Emerging role of immune checkpoint inhibitors and their relevance for the cardiovascular system. Herz. 2020;45(7):645–51. doi: 10.1007/s00059-020-04954-8.
13. Patel R, Parikh R, Gunturu K, et al. Cardiotoxicity of Immune Checkpoint Inhibitors. Curr Oncol Rep. 2021;23(7):79. doi: 10.1007/s11912-021-01070-6.
14. Dong M, Yu T, Zhang Z, et al. ICIs-Related Cardiotoxicity in Different Types of Cancer. J Cardiovasc Dev Dis. 2022;9(7):203. doi: 10.3390/jcdd9070203.
15. Palaskas N, Lopez-Mattei J, Durand JB, et al. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc. 2020;9(2):e013757. doi: 10.1161/JAHA.119.013757.
16. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68. doi: 10.1200/JCO.2017.77.6385
17. Rassaf T, Totzeck M, Backs J, et al. Onkologische Kardiologie. Der Kardiologie. 2020;14:267–93. doi: 10.1007/s12181-020-00395-z.
18. Bonaca MP, Olenchock BA, Salem JE, et al. Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology. Circulation. 2019;140(2):80–91. doi: 10.1161/CIRCULATIONAHA.118.034497.
19. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289–367. doi: 10.1093/eurheartj/ehaa575.
20. Michel L, Rassaf T, Totzeck M. Biomarkers for the detection of apparent and subclinical cancer therapy-related cardiotoxicity. J Thorac Dis. 2018;10(Suppl 35):S4282–S4295. doi: 10.21037/jtd.2018.08.15.
21. Thavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients with Immune Checkpoint Inhibitor-Associated Myocarditis. J Am Coll Cardiol. 2021;77(12):1503–16. doi: 10.1016/j.jacc.2021.01.050.
22. Khunger A, Battel L, Wadhawan A, et al. New Insights into Mechanisms of Immune Checkpoint Inhibitor-Induced Cardiovascular Toxicity. Curr Oncol Rep. 2020;22(7):65. doi: 10.1007/s11912-020-00925-8.
23. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(38):3599–726. doi: 10.1093/eurheartj/ehab368.
24. Castrillon J, Eng C, Cheng F. Pharmacogenomics for immunotherapy and immune-related cardiotoxicity. Hum Mol Genet. 2020;29(R2):R186–R196. doi: 10.1093/hmg/ddaa137.
25. Safi M, Ahmed H, Al-Azab M, et al. PD-1/PDL-1 Inhibitors and Cardiotoxicity; Molecular, Etiological and Management Outlines. J Adv Res. 2020;29:45–54. doi: 10.1016/j.jare.2020.09.006.
26. Brumberger Z, Branch M, Klein M, et al. Cardiotoxicity risk factors with immune checkpoint inhibitors. Cardiooncology. 2022;8(1):3. doi: 10.1186/s40959-022-00130-5.
27. Burns EA, Gentille C, Trachtenberg B, et al. Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management. Diseases. 2021;9(1):20. doi: 10.3390/diseases9010020.
28. Lefebvre B, Kang Y, Smith AM, et al. Cardiovascular effects of CAR T cell therapy. A retrospective study. JACC CardioOncol. 2020;2(2):193–203. doi: 10.1016/j.jaccao.2020.04.012.
29. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943–7. doi: 10.1634/theoncologist.2018-0028.
30. Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323–35. doi: 10.2147/TCRM.S150524.
31. Alvi R, Frigault M, Fradley M, et al. Cardiovascular Events Among Adults Treated with Chimeric Antigen Receptor T-Cells (CAR-T). J Am Coll Cardiol. 2019;74(25):3099–108. doi: 10.1016/j.jacc.2019.10.038.
32. Dal’bo N, Patel R, Parikh R, et al. Cardiotoxicity of Contemporary Anticancer Immunotherapy. Curr Treat Options Cardiovasc Med. 2020;22(12):62. doi: 10.1007/s11936-020-00867-1.
33. Gutierrez C, Rajendram P, Pastores S. Toxicities Associated with Immunotherapy and Approach to Cardiotoxicity with Novel Cancer Therapies. Crit Care Clin. 2021;37(1):47–67. doi: 10.1016/j.ccc.2020.08.003.
34. Oved J, Barrett D, Teachey D. Cellular therapy: Immune-related complications. Immunol Rev. 2019;290(1):114–26. doi: 10.1111/imr.12768.
35. Gardner R, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134(24):2149–58. doi: 10.1182/blood.2019001463.
36. Thakur A, Huang M, Lum L. Bispecific antibody-based therapeutics: Strengths and challenges. Blood Rev. 2018;32(4):339–47. doi: 10.1016/j.blre.2018.02.004.
37. Jung J, Lee S, Yang D, et al. Efficacy and safety of blinatumomab treatment in adult Korean patients with relapsed/refractory acute lymphoblastic leukemia on behalf of the Korean Society of Hematology ALL Working Party. Ann Hematol. 2019;98(1):151–8. doi: 10.1007/s00277-018-3495-2.
38. Tian Z, Liu M, Zhang Y, Wang X. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J Hematol Oncol. 2021;14(1):75. doi: 10.1186/s13045-021-01084-4.
39. Stein-Merlob A, Ganatra S, Yang E. T-cell Immunotherapy and Cardiovascular Disease: Chimeric Antigen Receptor T-cell and Bispecific T-cell Engager Therapies. Heart Fail Clin. 2022;18(3):443–54. doi: 10.1016/j.hfc.2022.02.008.
40. Darvishi B, Farahmand L, Jalili N, Majidzadeh-A K. Blinatumomab provoked fatal heart failure. Int Immunopharmacol. 2016;41:42–6. doi: 10.1016/j.intimp.2016.10.017.
41. Piccolomo A, Schifone C, Strafella V, et al. Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment. Cancers (Basel). 2020;12(9):2528. doi: 10.3390/cancers12092528.
42. Chanan-Khan A, Miller K, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006;24(34):5343–9. doi: 10.1200/JCO.2005.05.0401.
43. Jacob R, Strati P, Palaskas N, et al. Lenalidomide-Induced Myocarditis, Rare But Possibly Fatal Toxicity of a Commonly Used Immunotherapy. JACC Case Rep. 2020;2(13):2095–100. doi: 10.1016/j.jaccas.2020.07.033.
44. Bringhen S, Milan A, Ferri C, et al. Cardiovascular adverse events in modern myeloma therapy – Incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA). Haematologica. 2018;103(9):1422–32. doi: 10.3324/haematol.2018.191288.
45. Das A, Dasgupta S, Gong Y, et al. Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: A network meta-analysis of randomized clinical trials. Hematol Oncol. 2022;40(2):233–42. doi: 10.1002/hon.2959.
46. Bojan A, Torok-Vistai T, Parvu A. Assessment and Management of Cardiotoxicity in Hematologic Malignancies. Dis Markers. 2021;2021:6616265. doi: 10.1155/2021/6616265.

EG Khamaganova, SP Khizhinskii, EP Kuzminova, AR Abdrakhimova, EA Leonov, TV Gaponova, EN Parovichnikova

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

For correspondence: Ekaterina Georgievna Khamaganova, PhD in Biology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)613-24-76; e-mail: ekhamag@mail.ru

For citation: Khamaganova EG, Khizhinskii SP, Kuzminova EP, et al. An Optimal Multi-Locus HLA-Typing in Potential Donors of Allogeneic Hematopoietic Stem Cells. Clinical oncohematology. 2023;16(4):399–406. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-399-406

ABSTRACT

Background. HLA-typing and matched donor selection as well as the detection of donor-specific anti-HLA antibodies are essential for allogeneic hematopoietic cell transplantation (allo-HSCT). In accordance with the guidelines of the Center for International Blood and Marrow Transplant Research (CIBMTR) optimal HLA-typing is performed on 11 HLA genes (-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1) with an adequate coverage aiming to obtain the values at the two-field level.

Aim. To assess the results of multi-locus HLA-typing in bone marrow/hematopoietic cell donors from the database at the National Research Center for Hematology in terms of their conformance with the CIBMTR guidelines for allo-HSCT and to analyze the frequency and distribution of HLA alleles and multi-locus HLA haplotypes.

Materials & Methods. The study enrolled 3485 donors who were HLA-typed by next-generation sequencing.

Results. In all donors, the alleles of HLA class I genes were identified at the fourth-field level (nucleotide sequence). When the results were reduced to the second-field level (amino acid sequence), 61 HLA-A, 92 HLA-B, and 49 HLA-C alleles were detected. The alleles of class II genes were discovered either at the two-field or high-resolution levels. Among the HLA-DRB locus genes, 57 DRB1, 11 DRB3, 6 DRB4, and 5 DRB5 alleles were identified. Also, 23 HLA-DQA1, 30 HLA-DQB1, 14 HLA-DPA1, and 33 HLA-DPB1 alleles were detected. There were reported 3289 different HLA haplotypes of A-B-C-DRB1-DQA1-DQB1-DPA1-DPB1 genes.

Conclusion. The database created at the National Research Center for Hematology includes potential bone marrow/hematopoietic stem cell donors typed for 11 classical polymorphic genes HLA-A, ‐B, ‐C, ‐DRB1, ‐DRB3/4/5, ‐DQA1, ‐DQB1, ‐DPA1, and -DPB1, which is in line with the guidelines of CIBMTR. The frequency and distribution of HLA alleles and multi-locus HLA haplotypes in our donors correspond to those in populations of European origin. HLA-typing and donor selection with regard to 11 HLA genes will contribute to improving the outcomes of both unrelated and haploidentical HSCTs.

Keywords: allo-HSCT, HLA-typing, HLA alleles, HLA haplotypes, bone marrow/hematopoietic stem cell donors.

Received: June 14, 2023

Accepted: September 18, 2023

Read in PDF

REFERENCES

1. Протоколы трансплантации аллогенных гемопоэтических стволовых клеток. Под ред. В.Г. Савченко. М.: Практика, 2020. 320 с.
   [Savchenko VG, ed. Protokoly transplantatsii allogennykh gemopoeticheskikh stvolovykh kletok. (Allogeneic hematopoietic stem cell transplantation protocols.) Moscow: Praktika Publ.; 2020. 320 p. (In Russ)]
2. Standards for Histocompatibility and Immunogenetics Testing. Version 8.0. [Internet] Available from: https://efi-web.org/committees/standards-committee (accessed06.2023).
3. Приказ Министерства здравоохранения Российской Федерации № 519-н от 29.07.2022 г. «Об утверждении Порядка проведения медицинского обследования донора, давшего письменное информированное добровольное согласие на изъятие своих органов и (или) тканей для трансплантации». М., 2022.
   [Decree No. 519-n of the Ministry of Health of the Russian Federation dated July 29, 2022, On the approval of the Procedure of conducting a medical examination of a donor who has given written informed voluntary consent to the removal of his organs and/or tissues for transplantation. Moscow; 2022. (In Russ)]
4. Организация работы «типирующей лаборатории» в Федеральном регистре доноров костного мозга и гемопоэтических стволовых клеток, донорского костного мозга и гемопоэтических стволовых клеток, реципиентов костного мозга и гемопоэтических стволовых клеток: методические рекомендации ФМБА России. М., 2022. 6 с.
   [“Typing laboratory” management in the Federal Registry of Bone Marrow and Hematopoietic Stem Cell Donors, Donor Bone Marrow and Hematopoietic Stem Cells, Bone Marrow and Hematopoietic Stem Cell Recipients: methodological guidelines of the FMBA of Russia. Moscow; 2022. 6 p. (In Russ)]
5. Yu N, Askar M, Wadsworth K, et al. Current donor selection strategies for allogeneic hematopoietic cell transplantation. Hum Immunol. 2022;83(10):665–73. doi: 10.1016/j.humimm.2022.04.008.
6. Timofeeva OA, Philogene MC, Zhang QJ. Current donor selection strategies for allogeneic hematopoietic cell transplantation. Hum Immunol. 2022;83(10):674–86. doi: 10.1016/j.humimm.2022.08.007.
7. Хамаганова Е.Г., Дроков М.Ю., Хижинский С.П. и др. Антитела к антигенам лейкоцитов (HLA) у больных с запланированной трансплантацией аллогенных гемопоэтических стволовых клеток. Трансфузиология. 2022;23(2):156–69.
   [Khamaganova EG, Drokov MYu, Khizhinskii SP, et al. Antibodies to human leukocyte antigens (HLA) in patients with planned transplantation of allogeneic hematopoietic stem cells. 2022;23(2):156–69. (In Russ)]
8. Fleischhauer K, Shaw BE, Gooley T, et al. International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol. 2012;13(4):366–74. doi: 10.1016/S1470-2045(12)70004-9.
9. Pidala J, Lee SJ, Ahn KW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014;124(16):2596–606. doi: 10.1182/blood-2014-05-576041.
10. Fleischhauer K, Shaw BE. HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities. Blood. 2017;130(9):1089–96. doi: 10.1182/blood-2017-03-742346.
11. Fuchs EJ, McCurdy SR, Solomon SR, et al. HLA informs risk predictions after haploidentical stem cell transplantation with posttransplantation cyclophosphamide. Blood. 2022;139(10):1452–68. doi: 10.1182/blood.2021013443.
12. Nunes E, Heslop H, Fernandez-Vina M, et al. Definitions of histocompatibility typing terms: Harmonization of Histocompatibility Typing Terms Working Group. Hum Immunol. 2011;72(12):1014–16. doi: 10.1016/j.humimm.2011.06.002.
13. Nomenclature for Factors of the HLA System. [Internet] Available from: http://hla.alleles.org/nomenclature/naming.html (accessed 08.06.2023).
14. QIAamp DNA Mini and Blood Mini Handbook. 5th edition. [Internet] Available from: https://www.qiagen.com/cn/resources/download.aspx?id=62a200d6-faf4-469b-b50f-2b59cf738962&lang=en (accessed 08.06.2023).
15. Excoffier L, Lischer H. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10(3):564–7. doi: 10.1111/j.1755-0998.2010.02847.x.
16. Null and Alternatively Expressed Alleles. [Internet] Available from: https://hla.alleles.org/alleles/nulls.html (accessed 08.06.2023).
17. Hurley CK, Kempenich J, Wadsworth K, et al. Common, intermediate and well-documented HLA alleles in world populations: CIWD version 3.0.0. HLA. 2020;95(6):1–16. doi: 10.1111/tan.13811.
18. IMGT/HLA. Release Documentation. [Internet] Available from: https://www.ebi.ac.uk/ipd/imgt/hla/release/ (accessed 08.06.2023).
19. Dawkins RL, Lloyd SS. MHC Genomics and Disease: Looking Back to Go Forward. Cells. 2019;8(9):1–10. doi: 10.3390/cells8090944.
20. Kauppi L, Stumpf MP, Jeffreys AJ. Localized breakdown in linkage disequilibrium does not always predict sperm crossover hot spots in the human MHC class II region. Genomics. 2005;86(1):13–24. doi: 10.1016/j.ygeno.2005.03.011.
21. Fernandez-Vina MA, Klein JP, Haagenson M, et al. Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood. 2013;121(22):4603–10. doi: 10.1182/blood-2013-02-481945.
22. Yamamoto H, Uchida N, Naofumi MN, et al. Anti-HLA Antibodies Other than Against HLA-A, -B, -DRB1 Adversely Affect Engraftment and Nonrelapse Mortality in HLA-Mismatched Single Cord Blood Transplantation: Possible Implications of Unrecognized Donor-specific Antibodies. Biol Blood Marrow Transplant. 2014;20(10):1634–40. doi: 10.1016/j.bbmt.2014.06.024.
23. Tsamadou C, Engelhardt D, Platzbecker U, et al. HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation. Front Immunol. 2021;12:771449. doi: 10.3389/fimmu.2021.771449.
24. Ducreux S, Dubois V, Amokrane K, et al. HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell Am J Hematol. 2018;93(8):994–1001. doi: 10.1002/ajh.25133.
25. Хамаганова Е.Г., Леонов Е.А., Абдрахимова А.Р. и др. HLA-генетическое разнообразие русской популяции, выявленное методом секвенирования следующего поколения. Медицинская иммунология. 2021;23(3):509–22. doi: 10.15789/1563-0625-HDI-2182.
    [Khamaganova EG, Leonov EA, Abdrakhimova AR, et al. HLA diversity in the Russian population assessed by next generation sequencing. Medical Immunology. 2021;23(3):509–22. doi: 10.15789/1563-0625-HDI-2182. (In Russ)]
26. Smirnova D, Loginova M, Druzhinina S, et al. Distributions of HLA-A, -B, -C, -DRB1 and -DQB1 alleles typed by next generation sequencing in Russian volunteer donors. HLA. 2023;101(6):623‐ doi: 10.1111/tan.15007.
27. Creary LE, Gangavarapu S, Mallempati KC, et al. Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population. Hum Immunol. 2019;80(10):807–22. doi: 10.1016/j.humimm.2019.07.27.
28. Begovich AB, Moonsamy PV, Mack SJ, et al. Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations. Tissue Antigens. 2001;57(5):424–39. doi: 10.1034/j.1399-0039.2001.057005424.x.
29. Hollenbach JA, Madbouly A, Gragert L, et al. A combined DPA1~DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer. Immunogenetics. 2012;64(8):559–69. doi: 10.1007/s00251-012-0615-3.
30. Grundschober C, Sanchez-Mazas A, Excoffier L, et al. HLA-DPB1 DNA polymorphism in the Swiss population: linkage disequilibrium with other HLA loci and population genetic affinities. Eur J Immunogenet. 1994;21(3):143–57. doi: 10.1111/j.1744-313x.1994.tb00186.x.
31. Scibola СF, Akers NK, Conde L, et al. Multi-locus HLA class I and II allele and haplotype associations with follicular lymphoma. Tissue Antigens. 2012;79(4):279–86. doi: 10.1111/j.1399-0039.2012.01845.
32. Linjama T, Rather C, Ritari J, et al. Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors. Biol Blood Marrow Transplant. 2019;25(10):1956–64. doi: 10.1016/j.bbmt.2019.07.008.
33. Allele Frequency Net Database. [Internet] Available from: http://www.allelefrequencies.net/. (accessed 08.06.2023).
34. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339–48. doi: 10.1056/NEJMsa1311707.
35. Dehn J, Setterholm M, Buck K, et al. HapLogic: A Predictive Human Leukocyte Antigen-Matching Algorithm to Enhance Rapid Identification of the Optimal Unrelated Hematopoietic Stem Cell Sources for Transplantation. Biol Blood Marrow Transplant. 2016;22(11):2038–46. doi: 10.1016/j.bbmt.2016.07.022.

MM Kanunnikov, NN Mamaev, TL Gindina, AI Shakirova, AM Sadykov, SV Razumova, SN Bondarenko, LS Zubarovskaya

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

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; e-mail: nikmamaev524@gmail.com

For citation: Kanunnikov MM, Mamaev NN, Gindina TL, et al. BAALC-Expressing Leukemia Hematopoietic Stem Cells and Their Place in the Study of CBF-Positive Acute Myeloid Leukemias in Children and Adults. Clinical oncohematology. 2023;16(4):387–98. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-387-398

ABSTRACT

Background. Due to changing views on pathogenesis, risk factors and therapy strategies in prognostically favorable CBF-positive acute myeloid leukemias^[1] (AML), the expression monitoring of RUNX1/RUNX1T1 or CBFB/MYH11 fusion genes, as an additional evaluation of treatment outcomes, appears to be insufficient. This indicates the need to improve the monitoring of the CBF+ AML course by means of parallel measurements of BAALC expression levels which roughly correlate with the mass of BAALC-expressing leukemia hematopoietic stem cells (BAALC-e LHSC).

Aim. To improve the quality of assessing treatment outcomes with due account for expression levels of RUNX1/RUNX1T1 or CBFB/MYH11 fusion genes and the mass of BAALC-e LHSC and on this basis to pave the way for personalized CBF+ AML treatment.

Materials & Methods. This study enrolled 39 adult patients aged 20–81 years (median 32 years) and 8 children aged 2–18 years (median 12 years). Among them there were 20 females and 27 males. AML with inv(16)(p13;q22)/t(16;16) was identified in 19 patients, t(8;21)(q22;q22) was detected in 28 patients. BAALC, WT1, RUNX1/RUNX1T1, CBFB/MYH11 expression levels were measured by quantitative real-time PCR and related to the expression of the ABL1 expert gene.

Results. In 23 patients, inv(16) and t(8;21) appeared to be isolated. Additional multidirectional chromosomal changes were observed in 24 patients with inv(16) and in 18 patients with t(8;21). All enrolled patients showed increased BAALC expression. In the course of therapy, it was decreasing to the threshold value in 16/18 (89 %) patients. The evaluation of the mean BAALC expression levels in the pooled groups of children and adults with isolated findings of either inv(16) or t(8;21) showed the decrease of the BAALC-e LHSC mass only in children (p = 0.049). The comparison of the mean WT1 expression levels in the pooled groups of children and adults with isolated and additional chromosomal abnormalities revealed their significant decrease in patients with complicated variants (p = 0.023).

Conclusion. The case reports provided in this paper show that the molecular monitoring with serial measurements of fusion genes and BAALC gene expression levels in CBF+ AML patients can lay the basis for further improvement of personalized treatment strategies for these patients. In all likelihood, parallel measurements of the above gene expression levels will allow to establish the framework for decision-making concerning treatment extent and timely HSC transplantation.

[1] NOTE. CBF-positive acute myeloid leukemias are characterized by the presence of inv(16)(p13;q22)/t(16;16) or t(8;21)(q22;q22) in blast cells, incidence of 12–15 %, and favorable prognosis. (Scientific editor.)

Keywords: CBF+ AML, BAALC, WT1, RUNX1/RUNX1T1, and CBFB/MYH11 genes, molecular monitoring, chemotherapy, HSCT.

Received: March 15, 2023

Accepted: September 7, 2023

Read in PDF

REFERENCES

1. Sangle NA, Perkins S. Core-Binding Factor Acute Myeloid Leukemia. Arch Pathol. Lab Med. 2011;135(11):1504–9. doi: 10.5868/arpa.2010-0482-RS.
2. Byrd JC, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol. 1999;17(12):3767–75. doi: 1200/jco.1999.17.12.3767.
3. Byrd JC, Ruppert AS, Mrozek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13;q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol. 2004;22(6):1087–94. doi: 10.1200/JCO.2004.07.012.
4. Begna KH, Xu X, Gangatet N, et al. Core-binding factor acute myeloid leukemia: Long-term outcome of 70 patients uniformly treated with “7+3”. Blood Cancer J. 2022;12(4):55. doi: 10.1038/s41408-022-00654-0.
5. Schlenk RF, Benner A, Krauter J, et al. Individual Patient Data-Based Meta Analysis of Patients aged 16 to 60 Years with Core Binding Factor Acute Myeloid Leukemia: A Survey the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22(18):3741–50. doi: 10.1200/JCO.2004.03.012.
6. Reikvam H, Hatfield KJ, Kittang AO, et al. Acute myeloid leukemia with the t(8;21) translocation: Clinical consequences and biological implications. J Biomed Biotechnol. 2011;2011:104631. doi: 10.1155/2011/104631.
7. Goyama S, Mulloy JC. Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol. 2011;94(2):126–33. doi: 10.1007/s12185-011-0858-z.
8. Lam K, Zhang D-E. RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci. 2012;17(3):1120–39. doi: 10.2741/3977.
9. Han C, Gao X, Li Y, et al. Characteristics of Cohesin Mutation in Acute Myeloid Leukemia and Its Clinical Significance. Front Oncol. 2021;11:579881. doi: 10.3389/fonc.2021.579881.
10. Solh M, Yohe S, Weisdorf D, et al. Core-binding factor acute myeloid leukemia: Heterogeneity, monitoring, and therapy. Am J Hematol. 2014;89(12):1121–9. doi: 10.1002/ajh.23821.
11. Paschka p, Du J, Schlenk RF, et al. Secondary Genetic Lesions in Acute Myeloid Leukemia with Inv(16) or t(16;16): A study of the German-Austrian AML Study Group (AMLSG). Blood. 2013;121(1):170–7. doi: 10.1182/blood-2012-05-431486.
12. Krauth MT, Eder C, Alpermann T, et al. High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome. Leukemia. 2014;28(7):1449–58. doi: 10.1038/leu.2014.4.
13. Гиндина Т.Л., Мамаев Н.Н., Бондаренко С.Н. и др. Результаты аллогенной трансплантации гемопоэтических стволовых клеток у больных острым миелоидным лейкозом c t(8;21)(q22;q22)/RUNX1-RUNX1T1 и дополнительными цитогенетическими аномалиями. Клиническая онкогематология. 2016;9(2):148–54. doi: 10.21320/2500-2139-2016-9-2-148-154.
    [Gindina TL, Mamaev NN, Bondarenko SN, et al. Results of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia with t(8;21)(q22;q22)/RUNX1-RUNX1T1 and Additional Cytogenetic Abnormalities. Clinical oncohematology. 2016;9(2):148–54. doi: 10.21320/2500-2139-2016-9-2-148-154. (In Russ)]
14. Christen F, Hoyer K, Yoshida K, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019;133(10):1140–51. doi: 10.1182/blood-2018-05-852822.
15. Allen C, Hills RK, Lamb R, et al. The importance of Relative Mutant Level for Evaluation Impact on Outcome of KIT, FLT3 and CBL Mutations in Core-Binding Factor Acute Myeloid Leukemia. 2013;27(9):1891–901. doi: 10.1038/leu.2013.186.
16. Sood R, Hansen NF, Donovan FX, et al. Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia. Leukemia. 2016;30(2):501–4. doi: 10.1038/leu.2015.141.
17. Ishikawa Y, Kawashima N, Atsuta Y, et al. Prospective Evaluation of Prognostic Impact of Kit Mutations on Acute Myeloid Leukemia with RUNX1-RUNX1T1 and CBFB-MYH11. Blood Adv. 2020;4(1):66–75. doi: 10.1182/bloodadvances.2019000709.
18. Jahn N, Terzer T, Strang Str E. et al. Genomic Heterogeneity in Core-Binding Factor Acute Myeloid Leukemia and its Clinical Implications. Blood Adv. 2020;4(21):6342–52. doi: 10.1182/bloodadvances.2020002673.
19. Opatz S, Bamopoulos SA, Metzeler KH, et al. The Clinical Mutatome of Core Binding Factor Leukemia. 2020;34(6):1553–62. doi: 10.1038/s41375-019-0697-0.
20. Zhen T, Cao Y, Ren G. et al. RUNX1 and CBFβ-SMMHC transactive target genes together in abnormal myeloid progenitors for leukemia development. Blood. 2020;136(21):2373–85. doi: 10.1182/blood.2020007747.
21. Al-Harbi S, Aljurf M, Mothy M, et al. An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1. Blood Adv. 2020;4(1):229–38. doi: 10.1182/bloodadvances.2019000168.
22. Mao X, Yin R, Liu L, et al. Clinical impact of c-KIT and CEBPA mutations in 33 patients with corebinding factor (Non-M3) acute myeloid leukemia. Pediatr Neonatol. 2022;64(4):435–41. doi: 10.1016/j.pedneo.2022.05.020.
23. Kayser S, Kramer M, Martinez-Cuadron D, et al. Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Haematologica. 2022;107(4):836–43. doi: 10.3324/haematol.2021.278645.
24. Rege K, Swansbury GJ, Atra AA, et al. Disease features in acute myeloid leukemia with t(8;21)(q22;q22). Influence of age, secondary karyotype abnormalities, CD19 status, and extramedullary leukemia on survival. Leuk Lymphoma. 2000;40(1–2):67–77. doi: 10.3109/10428190009054882.
25. Marcucci G, Mrozek K, Ruppert AS, et al. Prognostic factors and Outcome of Core Binding Factor Acute Myeloid Leukemia Patients with t(8;21) Differ from those of Patients with inv(16): A Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23(24):5705–17. doi: 10.1200/JCO.2005.15.610.
26. Mosna F, Papayannidis C, Martinelli G, et al. Complex karyotype, older age, and reduced first-line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long-term follow-up. Am J Hematol. 2015;90(6):515–23. doi: 10.1002/ajh.24000.
27. Ustun C, Morgan EA, Ritz EM, et al. Core-binding factor acute myeloid leukemia with inv(16): Older age and high white blood cell count are risk factors for treatment failure. Int J Lab Hematol. 2021;43(1):e19-e25. doi: 10.1111/ijlh.13338.
28. Marcault C, Boissel N, Haferlach C, et al. Prognostic of Core Binding Factor (CBF) Acute myeloid Leukemia with Complex Karyotype. Clin Lymphoma Myeloma Leuk. 2021;22(3):e199–e205. doi: 10.1016/j.clml.2021.09.007.
29. Wei H, Wang Y, Gale RB, et al. Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia. Clin Cancer Res. 2020;26(13):3154–61. doi: 10.1158/1078-0432.CCR-19-3433.
30. Chen G, Yang J, Cao F, et al. The prognostic benefit from intermediate-dose cytarabine as consolidation therapy varies by cytogenetic subtype in t(8;21) acute myeloid leukemia: a retrospective cohort study. Ann Transl Med. 2022;10(16):858. doi: 10.21037/atm-22-2965.
31. Shen Y, Zhang Y, Chang J, et al. CAG (cytarabine, aclarubicine and granulocytic colony-stimulating factor) regimen for core binding acute myeloid leukemia with measurable residual disease. Res Square. 2022; doi: 10.21203/rs.3.rs-2234776/v1.
32. Yoon JH, Kim HJ, Kim JW, et al. Identification of Molecular and Cytogenetic Risk Factors for Unfavorable Core-Binding-Factor- Positive Adult AML with Post-Remission Treatment Outcome Analysis Including Transplantation. Bone Marrow Transplant. 2014;49(12):1466–74. doi: 10.1038/bmt.2014.180.
33. Xiaosu Z, Leqing C, Yazhen Q, et al. Classifying AML Patients with inv(16) into high-risk and low-risk relapsed patients based on peritransplantation minimal residual disease determined by CBFβ/MYH11 gene expression. Ann Hematol. 2019;98(1):73–81. doi: 10.1007/s00277-018-3480-9.
34. Kuwatsuka S, Miyamura K, Suzuki R, et al, Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia t(8;21) and inv(16) represent different clinical outcomes. 2009;113(9):2096–103. doi: 10.1182/blood-2008-03-145862.
35. Mizutani M, Hara M, Fujita H, et al. Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR. Bone Marrow Transplant. 2016;51(5):645–53. doi: 10.1038/bmt.2015.349.
36. Byun JM, Shin D-Y, Koh Y, et al. Survival disparities in patients with relapsed core-binding factor acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation. Int J Clin Exp Med. 2016;9(12):23285–93.
37. Beyar-Katz O, Lavi N, Ringelstein-Harlev S, et al. Superior outcome of patients with favorable-risk acute myeloid leukemia using consolidation with autologous stem cell transplantation. Leuk Lymphoma. 2019;60(10):2449–56. doi: 10.1080/10428194.2019.1594214.
38. Hu GH, Chemg YE, Lu AD, et al. Allogeneic hematopoietic stem cell transplantation can improve the prognosis of high-risk pediatric t(8;21) acute myeloid leukemia in first remission based on MRD-guided treatment. BMC Cancer. 2020;20(1):553. doi: 10.1186/s12885-020-07043-5.
39. Choi EJ, Lee JH, Kim H, et al. Autologous hematopoietic cell transplantation following high-dose cytarabine consolidation for core-binding factor acute myeloid leukemia in first complete remission: a phase 2 prospective trial. Int J Hematol. 2021;113(6):851–60. doi: 10.1007/s12185-021-03099-6.
40. Capria S, Trisolini SM, Diverio D, et al. Autologous stem cell transplantation in favorable-risk acute myeloid leukemia: single-center experience and current challenges. Int J Hematol. 2022;116(4):586–93. doi: 10.1007/s12185-022-03370-4.
41. Sula M, Bacher U, Leibundgut EO, et al. Excellent outcome after consolidation with autologous transplantation in patients with core binding factor acute myeloid leukemia. Bone Marrow Transplant. 2020;55(8):1690–3. doi: 10.1038/s41409-019-0762-3.
42. Halaburda K, Labopin M, Mailhol A, et al. Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020;105(6):1723–30. doi: 10.3324/haematol.2019.222810.
43. Wang T, Chen S, Chen J, et al. Allogeneic Hematopoietic Stem Cell Transplantation Improved Survival for Adult Core Binding Factor Acute Myelogenous Leukemia Patients with Intermediate- and Adverse-Risk Genetics in the 2017 European LeukemiaNet. Transplant Cell Ther. 2021;27(2):173.e1–173.e9. doi: 10.1016/j.jtct.2020.10.010.
44. Ustun C, Morgan E, Moodie EEM, et al. Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit). Cancer Med. 2018;7(9):4447–55. doi: 10.1002/cam4.1733.
45. Martin G, Barragan E, Bolufer P, et al. Relevance of Presenting White Blood Cells Count and Kinetic of Molecular Remission in the Prognosis of Acute Myeloid Leukemia with CBFbeta/MYH11 Rearrangements. Haematologica. 2000;85(7):699–703.
46. Delaunay J, Vey N, Leblanc T, et al. Prognosis of inv(16)/t(16;16) Acute Myeloid Leukemia (AML): A Survey of 110 Cases from the French AML Intergroup. Blood. 2003;102(2):462–9. doi: 10.1182/blood-2002-11-3527.
47. Appelbaum FR, Kopecky KI, Tallman MS, et al. The clinical spectrum of adult acute myeloid leukemia associated with core binding factor translocations. Br J Haematol. 2006;135(2):165–73. doi: 10.1111/j.1365-2141.2006.06276.x
48. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213–23. doi: 10.1182/blood-2012-10-462879.
49. Hoyos M, Nomdedeu JF, Esteve J, et al. Core Binding Factor Acute Myeloid Leukemia: The impact of Age, Leukocyte Count, Molecular Findings and Minimal Residual Disease. Eur J Haematol. 2013;91(3):209–18. doi: 10.1111/ejh.12130.
50. Brunner AM, Blonquist TM, Sadrzadeh H, et al. Population-Based Disparities in Survival Among Patients with Core-Binding Factor Acute Myeloid Leukemia: A SEEP Database Analyze. Leuk Res. 2014:38(7):773–80. doi: 10.1016/j.leukres. 2014.04.001.
51. Jung HAE, Maeng CH, Park S, et al. Prognostic Factor Analysis in Core-Binding Factor-positive Acute Myeloid Leukemia. Anticancer Res. 2014;34(2):1037–45.
52. Duployez N, Willekens C, Marceau-Renout A, et al. Prognosis and monitoring of core-binding factor acute myeloid leukemia: current and emerging factors. Exp Rev Hematol. 2015;8(1):43–56. doi: 10.1586/17474086.2014.976551.
53. Talami A, Bettelli F, Pioli V, et al. How to improve Prognostification in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring. 2021;9(8):958. doi: 10.3390/biomedicines9089953.
54. Tobal K, Newton J, Macheta M, et al. Molecular quantitation of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse. Blood. 2000;95(3):815–9.
55. Corbaciouglu A, Scholl C, Schlenk RF, et al. Prognostic impact of minimal residual disease in CBF-MYH11-positive acute myeloid leukemia. J Clin Oncol. 2010;28(23):3724–9. doi: 10.1200/JCO.2010.28.6468.
56. Wang Y, Wu DP, Liu QF, et al. In adults with t(8;21)AML posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood. 2014;124(12):1880–6. doi: 10.1182/blood-2014-03-563403.
57. Wang T, Zhou B, Zhang J, et al. Allogeneic hematopoietic stem cell transplantation could improve survival for pure CBF-AML patients with minimal residual disease positive after the second consolidation. Leuk Lymphoma. 2021;62(4):995–8. doi: 10.1080/10428194.2020.1846736.
58. Konuma T, Kondo T, Masuko M, et al. Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission. Bone Marrow Transplant. 2021;56(11):2779–87. doi: 10.1038/s41409-021-01409-4.
59. Duan W, Liu X, Jia J, et al. The loss of absence of minimal residual disease of < 0.1% at any time after two cycles of consolidation chemotherapy in CBFB-MYH11-positive acute myeloid leukemia indicates poor prognosis. Br J Haematol. 2021;192(2):265–71. doi: 10.1111/bjh.16745.
60. Duan W, Liu X, Zhao X, et al. Both the Subtypes of KIT Mutation and Minimal Residual Disease Are Associated with Prognosis in Core Binding Factor Acute Myeloid Leukemia: A Retrospective Clinical Cohort Study in Single Center. Ann Hematol. 2021;100(5):1203–12. doi: 10.1007/s00277-021-04432-z.
61. Kurosawa S, Miyawaki S, Yamaguchi T, et al. Prognosis of patients with core and minimal residual disease. Eur J Haematol. 2013;91(3):209–18. doi: 10.1111/ejh.12130.
62. Rucker F, Agrawal M, Corbaciouglu A, et al. Measurable Residual Disease Monitoring in Acute Myeloid Leukemia with t(8;21)(q22;q22.1): Results of the AML Study Group. Blood. 2019;134(19):1608–18. doi: 10.1182/blood.2019001425.
63. Yalniz FE, Patel KP, Bashir Q, et al. Significance of Minimal Residual Disease Monitoring by Real-Time Quantitative Polymerase Chain Reaction in Core Binding Factor Acute Myeloid Leukemia for Transplantation Outcomes. Cancer. 2020;126(10):2183–92. doi: 10.1002/cncr.32769.
64. Rotchanapanya W, Hokland P, Tunsing P, et al. Clinical Outcomes Based on Measurable Residual Disease Status in Patients with Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis. J Pers Med. 2020;10(4):250. doi: 10.3390/jpm.10040250.
65. Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21) AML-ETO translocations in childhood acute myeloid leukemia. B 2002;99(10):3801–5. doi: 10.1182/blood.v99.10.3801.
66. Nicifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. 1993;82(3):712–5.
67. Yoon J-H, Kim H-J, Shin S-H, et al. BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML. Eur J Haematol. 2013;91(2):112–21. doi: 10.1111/ejh.12142.
68. Mamaev NN, Shakirova AI, Barkhatov IM, et al. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Hematol Transfus Int J. 2020;8(6):127–31. doi: 10.15406/htij.2020.08.00240.
69. Mamaev NN, Shakirova AI, Kanunnikov MM. BAALC-expressing Cells in Acute Leukemia and Myelodysplastic Syndromes: Present and Future. Generis Publishing; 2022. 98 p.
70. McGowan-Jordan J, Hastings RJ, Moore S, eds. An International System for Human Cytogenomic Nomenclature (2020). Basel; 2020. 170 p. doi: 10.1159/isbn.978-3-318-06867-2.
71. Shakirova AI, Mamaev NN, Barkhatov IM, et al. Clinical significance of BAALC overexpression for prediction post-transplant relapses in acute myeloid leukemia. Cell Ther Transplant. 2019;8(2):45–57. doi: 10.18620/ctt-1866-8836-02019-8-2-45-57.
72. Гудожникова Я.В., Мамаев Н.Н., Бархатов И.М. и др. Результаты молекулярного мониторинга в посттрансплантационный период с помощью серийного исследования уровня экспрессии гена WT1 у больных острыми миелоидными лейкозами. Клиническая онкогематология. 2018;11(3):241–51. doi: 10.21320/2500-2139-2018-11-3-241-251.
    [Gudozhnikova YaV, Mamaev NN, Barkhatov IM, et al. Results of Molecular Monitoring in Posttransplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2018;11(3):241–51. doi: 10.21320/2500-2139-2018-11-3-241-251. (In Russ)]
73. Gottardi M, Mosna F, De Angeli S, et al. Clinical and Experimental Efficacy of Gemtuzumab Ozogamicin in Core Binding Factor Acute Myeloid Leukemia. Hematol Rep. 2017;9(3):87–90. doi: 10.4081/hr.2017.7028.
74. Mansoor N, Jabbar N, Arshed U, et al. Outcome of Core Binding Factor Acute Leukemia in Children: A Single-Center Experience. J Pediatr Hematol Oncol. 2020;42(6):e423–e427. doi: 10.1097/MPH.0000000000001853.
75. Baul SN, Baveja A, Kumar P, et al. A glimpse into translocation (8;21) in acute myeloid leukemia: Profile and therapeutic outcomes from a tertiary care hematology center from East India. J Hematol Allied Sci. 2022;2(3):85–90. doi: 10.25259/JHAS_1_2022.
76. Borthakur G, Kantarjian H. Core binding factor acute myelogenous leukemia-2021 treatment algorithm. Blood Cancer. 2021;11(6):114. doi: 10.1038/s31408-021-00503-06.
77. Surapally S, Tanen DG, Pullkan AA. Emerging therapies for inv(16) AML. Blood. 2021;137(9):2579–84. doi: 10.1182/blood.2020008971.
78. Fan S, Shen MZ, Zhang XH, et al. Preemptive Immunotherapy for Minimal Residual Disease in Patients With t(8;21) Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation. Front Oncol. 2022;11(10):773394. doi: 3389/fonc.2021.773394.
79. Cooperrider JH, Shukla N, Nawas MT, Patel AA. The Cup Runneth Over: Treatment Strategies for Newly Diagnosed Acute Myeloid Leukemia. JCO Oncol Pract. 2023;19(2):74–85. doi: 10.1200/OP.22.00342.

VV Lozovaya¹, OA Malikhova^1,2, AO Tumanyan¹

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

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

For correspondence: Valeriya Vitalevna Lozovaya, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)136-12-78; e-mail: lera.lozovaya@bk.ru

For citation: Lozovaya VV, Malikhova OA, Tumanyan AO. Endoscopic Semiotics of the Gastritis-Like Form of primary Gastric Non-Hodgkin Lymphomas. Clinical oncohematology. 2023;16(4):380–6. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-380-386

ABSTRACT

Aim. To characterize the main differentially significant endoscopic features specific to the gastritis-like form of primary gastric non-Hodgkin lymphomas (NHL).

Materials & Methods. This prospective study analyzes the results of complex endoscopic diagnosis in 43 patients with primary gastric NHL. They were examined and treated at the NN Blokhin National Medical Cancer Research Center from 2019 to 2023. The patients were 30–70 years of age, those over the age of 50 predominated and accounted for 79 % (n = 34). There were 33 women and 10 men. The control group included 45 patients with gastritis-like malignant gastric tumors: adenocarcinoma and signet-ring cell cancer.

Results. The morphological analysis yielded a diagnosis of MALT-lymphoma in 90.7 % (n = 39) and diffuse large B-cell lymphoma in 9.3 % (n = 4) of cases. Sensitivity, specificity, and accuracy of the clarification methods of complex endoscopic diagnosis were considerably higher compared to white-light mode examination. According to the results of complex endoscopic analysis, all patients were stratified into 4 groups with different types of H. pylori-induced atrophic gastritis (n = 10; 23.25 %), erosive gastritis (n = 10; 23.25 %), hyperplastic gastritis (n = 8; 18.6 %), and combined gastritis (n = 15; 34.9 %). The focus was laid on identifying the main differentially significant endoscopic features specific to the gastritis-like form of primary gastric NHL which distinguish it from the lesions in other malignant tumors.

Conclusion. The complex examination using 4 concrete clarification methods of endoscopic diagnosis is indispensable to properly interpret the detected changes and timely diagnose the gastritis-like form of primary gastric NHL. These include narrow-band imaging (NBI/BLI and LCI), close-focus and magnification examinations, combined narrow-band imaging and magnification examination, as well as endosonography.

Keywords: primary gastric non-Hodgkin lymphomas, MALT-lymphoma, gastritis-like form of primary gastric NHLs, endoscopic diagnosis.

Received: April 25, 2023

Accepted: September 5, 2023

Read in PDF

REFERENCES

1. Ghimire P, Wu GY, Zhu L. Primary gastrointestinal lymphoma. World J Gastroenterol. 2011;17(6):697–707. doi: 10.3748/wjg.v17.i6.697.
2. Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 2012;380(9844):848–57. doi: 10.1016/S0140-6736(12)60605-9.
3. Takigawa H, Masaki S, Naito T, et al. Helicobacter suis infection is associated with nodular gastritis‐like appearance of gastric mucosa‐associated lymphoid tissue lymphoma. Cancer Med. 2019;8(10):4370–9. doi: 10.1002/cam4.2314.
4. Isomoto H, Matsushima K, Hayashi T, et al. Endocytoscopic findings of lymphomas of the stomach. BMC Gastroenterol. 2013;13:174. doi: 10.1186/1471-230X-13-174.
5. Park BS, Lee SH. Endoscopic features aiding the diagnosis of gastric mucosa-associated lymphoid tissue lymphoma. J Yeungnam Med Sci. 2019;36(2):85–91. doi: 10.12701/yujm.2019.00136.
6. Peng T, Deng L, Wang Y, et al. Establishing an endoscopic diagnostic process system (M-system) for gastric MALT lymphoma of superficial-spreading type. Jpn J Clin Oncol. 2021;51(4):560–8. doi: 10.1093/jjco/hyaa242.
7. Janssen J. The impact of EUS in primary gastric lymphoma. Best Pract Res Clin Gastroenterol. 2009;23(5):671–8. doi: 10.1016/j.bpg.2009.05.008.
8. Zullo A, Hassan C, Andriani A, et al. Primary low-grade and high-grade gastric MALT-lymphoma presentation. J Clin Gastroenterol. 2010;44(5):340–4. doi: 10.1097/MCG.0b013e3181b4b1ab.
9. Малихова О.А. Современная стратегия комплексной эндоскопической диагностики и мониторинг неходжкинских лимфом желудка: Дис.… д-ра мед. наук. М., 2010. 291 с.
   [Malikhova OA. Sovremennaya strategiya kompleksnoi endoskopicheskoi diagnostiki i monitoring nekhodzhkinskikh limfom zheludka. (Modern strategy of complex endoscopic diagnosis and monitoring of gastric non-Hodgkin lymphomas.) [dissertation] Moscow; 2010. 291 p. (In Russ)]
10. Suwa T, Uotani T, Inui W, et al. A case of signet ring cell carcinoma and mucosa-associated lymphoid tissue lymphoma of the stomach diagnosed simultaneously via magnifying endoscopy with narrow-band imaging. Clin J Gastroenterol. 2021;14(2):453–9. doi: 10.1007/s12328-020-01325-y.
11. Iwamuro M, Tanaka T, Nishida K, et al. Two cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma masquerading as follicular gastritis. Ecancermedicalscience. 2019;13:933. doi: 10.3332/ecancer.2019.933.

AA Spornik, NS Vasilev, AA Samoilova, AA Mamedova, VS Bogatyrev, EG Smirnova, AA Bannikova, AA Rukavitsyn, NS Shorokhov, NE Mochkin, VO Sarzhevskii, EA Demina, VYa Melnichenko

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

For correspondence: Anna Anatolevna Spornik, 70 Nizhnyaya Pervomaiskaya ul., Moscow, Russian Federation, 105203; Tel.: +7(962)390-38-45; e-mail: anna_spornik@mail.ru; Prof. Elena Andreevna Demina, MD, PhD, 70 Nizhnyaya Pervomaiskaya ul., Moscow, Russian Federation, 105203; Tel.: +7(903)678-72-67; e-mail: drdemina@yandex.ru

For citation: Spornik AA, Vasilev NS, Samoilova AA, et al. Primary Prevention of Neutropenia by Empegfilgrastim in Patients with Advanced Stages of Classical Hodgkin Lymphoma Treated with Intensive First-Line Chemotherapy with a Modified 6-Cycle Program EACODD-14 Under the Protocol “LKh-Rossiya-1”. Clinical oncohematology. 2023;16(4):370–9. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-370-379

ABSTRACT

Aim. To assess the efficacy of a long-acting form of the granulocyte colony-stimulating factor (G-CSF) empegfilgrastim in primary prevention of neutropenia in patients with advanced stages of classical Hodgkin lymphoma (cHL) who received intensive chemotherapy with reduced inter-cycle interval under the protocol “LKh-Rossiya-1”.

Materials & Methods. The study enrolled 35 patients with newly diagnosed cHL. All patients had advanced stages (IIB X/Е and III/IV) of the disease. They were treated at the NI Pirogov National Medical and Surgical Center from March 2013 to August 2022. The primary prevention of neutropenia by long-acting G-CSF (empegfilgrastim) was administered to 21 patients under the protocol “LKh-Rossiya-1”. They received 6 chemotherapy cycles of modified EACODD-14, in total 126 cycles. The control group consisted of 14 patients who received 6 ЕАСОРР-14 chemotherapy cycles (in total 84 cycles) with dacarbazine as substitution for procarbazine. In the control group, the primary prevention of neutropenia was carried out using discrete G-CSF (filgrastim). The median (range) follow-up in the main (n = 21) and control (n = 14) groups was 18 (5–36) and 39 (29–116) months, respectively. The treatment efficacy was assessed based on PET-CT in 31 patients and on CT in 4 patients.

Results. By the end of chemotherapy, complete metabolic response was achieved in 28 (80 %) out of 35 patients (95 % in the EACODD-14 and 73 % in ЕАСОРР-14 groups). In 6 (17 %) patients, partial remission was confirmed only by CT scan, and in 1 (3 %) patient, PET/CT showed stabilization. After consolidation radiotherapy, complete remission was reported in all 35 patients. Both groups received the full chemotherapy program per protocol. Without a violation of G-CSF regimen, the EACODD-14 group received 121 (96 %) cycles out of those 126 planned, whereas the ЕАСОРР-14 group received all 84 cycles per protocol. Full implementation of 107 (88.4 %) cycles in the first group and 24 (29 %) cycles in the second group was achieved in 12 (57 %) and 5 (36 %) patients, respectively (p < 0.001). Neutropenia grade 4 was more often identified in filgrastim than in empegfilgrastim recipients (57 % vs. 19 %; p < 0.05) and in a larger number of cycles (15 % vs. 3 %; p < 0.01). The rate of infection episodes in the ЕАСОРР-14 group was higher (50 % vs. 28 %) and in more cycles (15 % vs. 5 %; p < 0.05). Due to the use of long-acting G-CSF (empegfilgrastim) the number of inpatient days could be reduced from 9 to 5.

Conclusion. The results of this study demonstrate the advantage of long-acting G-CSF (empegfilgrastim) as compared with its discrete form (filgrastim) in intensified programs with a reduced inter-cycle interval and high risk of febrile neutropenia (EACODD-14 and EACOРР-14). The use of empegfilgrastim allowed to administer three times as many chemotherapy cycles adhering to the principle of dose intensity in a larger number of patients with advanced cHL stages.

Keywords: classical Hodgkin lymphoma, EACODD-14, EACOРР-14, empegfilgrastim, treatment outcomes.

Received: June 26, 2023

Accepted: September 10, 2023

Read in PDF

REFERENCES

1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. 439 p.
2. Злокачественные новообразования в России в 2019 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2020. С. 25–40.
   [Kaprin AD, Starinskii VV, Shakhzadova AO, eds. Zlokachestvennye novoobrazovaniya v Rossii v 2019 godu (zabolevaemost’ i smertnost’). (Malignant neoplasms in Russia in 2019 (incidence and mortality.) Moscow: MNIOI im. P.A. Gertsena — filial FGBU “NMITs radiologii” Publ.; 2020. pp. 25–40. (In Russ)]
3. Eichenauer DA, Engert A, Andre M, et al. Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):70–5. doi: 10.1093/annonc/mdu181.
4. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2018. С. 9–27.
   [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines on diagnosis and treatment of lymphoproliferative disorders.) Moscow: Buki Vedi Publ.; 2018. рp. 9–27. (In Russ)]
5. Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(6):755–81. doi: 10.6004/jnccn.2020.0026.
6. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258–66. doi: 10.1002/cncr.21847.
7. Абрамов М.Е. Аспекты применения пегфилграстима при проведении химиотерапии пациентов с солидными опухолями. Фарматека. 2013;8(261):31–4.
   [Abramov ME. Aspects of the use of pegfilgrastim during chemotherapy in patients with solid tumors. 2013;8(261):31–4. (In Russ)]
8. Bosly A, Bron D, Van Hoof A, et al. Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann Hematol. 2008;87(4):277–83. doi: 10.1007/s00277-007-0399-y.
9. Багрова С.Г. Гранулоцитарные колониестимулирующие факторы в профилактике фебрильной нейтропении. Эффективная фармакотерапия. 2015;31:6–15.
   [Bagrova SG. Granulocyte colony-stimulating factors in the prevention of febrile neutropenia. Effektivnaya farmakoterapiya. 2015;31:6–15. (In Russ)]
10. Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006;354(19):2034–45. doi: 10.1056/NEJMra052706.
11. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32. doi: 10.1016/j.ejca.2010.10.013.
12. Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21(5):248–51. doi: 10.1093/annonc/mdq195.
13. Криворотько П.В., Бурдаева О.Н., Ничаева М.Н. и др. Эффективность и безопасность препарата Экстимия® (эмпэгфилграстим) у пациентов с диагнозом «рак молочной железы», получающих миелосупрессивную химиотерапию: результаты двойного слепого сравнительного клинического исследования III фазы. Современная онкология. 2015;17(2):45–52.
    [Krivorotko PV, Burdaeva ON, Nichaeva MN, et al. Efficacy and safety of Extimia® (empegfilgrastim) in patients with diagnosed breast cancer receiving myelosuppressive chemotherapy: results of a double-blind controlled phase III clinical study. Sovremennaya onkologiya. 2015;17(2):45–52. (In Russ)]
14. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14(1):29–35. doi: 10.1093/annonc/mdg019.
15. Yang B-B, Kido A. Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet. 2011;50(5):295–306. doi: 2165/11586040-000000000-00000.
16. Weycker D, Malin J, Kim J, et al. Risk of hospitalization for neutropenic complications of chemotherapy in patients with primary solid tumors receiving pegfilgrastim or filgrastim prophylaxis: a retrospective cohort study. Clin Ther. 2009;31(5):1069–81. doi: 10.1016/j.clinthera.2009.05.019.
17. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20(3):727–31. doi: 10.1200/JCO.2002.20.3.727.
18. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178–84. doi: 10.1200/JCO.2005.09.102.
19. Engert A, Bredenfeld H, Dohner H, et al. Pegfilgrastim support for full delivery of BEACOPP-14 chemotherapy for patients with high-risk Hodgkin’s lymphoma: results of a phase II study. Haematologica. 2006;91(4):546–9.
20. Демина Е.А., ЛеонтьеваА.А., Тумян Г.С. и др. Оптимизация терапии первой линии у пациентов с распространенными стадиями лимфомы Ходжкина: эффективность и токсичность интенсивной схемы ЕАСОРР-14 (опыт ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России). Клиническая онкогематология. 2017;10(4):443–52. doi: 10.21320/2500-2139-2017-10-4-443-452.
    [Demina EA, Leont’eva AA, Tumyan GS, et al. First-Line Therapy for Patients with Advanced Hodgkin’s Lymphoma: Efficacy and Toxicity of Intensive ЕАСОРР-14 Program (NN Blokhin National Medical Cancer Research Center Data). Clinical oncohematology. 2017;10(4):443–52. doi: 10.21320/2500-2139-2017-10-4-443-452. (In Russ)]
21. Демина Е.А., Шорохов Н.С., Шпирко В.О. и др. Многоцентровой протокол по лечению первичных больных классической лимфомой Ходжкина, ЛХ-Россия-1. Первые предварительные результаты. Злокачественные лимфомы. Сборник тезисов постерной сессии XIX Российской конференции с международным участием. М., 2022. С. 25.
    [Demina EA, Shorokhov NS, Shpirko VO, et al. Multicenter protocol for the treatment of primary patients with classical Hodgkin lymphoma, “LKh-Rossiya-1”. First preliminary results. Zlokachestvennye limfomy. Sbornik tezisov posternoi sessii XIX Rossiiskoi konferentsii s mezhdunarodnym uchastiem (Malignant lymphomas. Collection of abstracts of the poster session of the XIX Russian Conference with international participation). Moscow; pp. 25. (In Russ)]
22. Демина Е.А., Тумян Г.С., Моисеева Т.Н. и др. Лимфома Ходжкина. Клинические рекомендации. Современная онкология. 2020;22(2):6–33. doi: 10.26442/18151434.2020.2.200132.
    [Demina EA, Tumyan GS, Moiseeva TN, et al. Hodgkin Lymphoma. Clinical recommendations. Journal of Modern Oncology. 2020;22(2):6–33. doi: 10.26442/18151434.2020.2.200132. (In Russ)]
23. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–68. doi: 10.1200/JCO.2013.54.8800.
24. Novotny JR, Muller-Beissenhirtz H, Herget-Rosenthal S, et al. Grading of symptoms in hyperleukocytic leukaemia: A clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome. Eur J Haematol. 2005;74(6):501–10. doi: 10.1111/j.1600-0609.2005.00421.x.
25. Aapro M, Boccia R, Leonard R, et al. Refining the role of pegfilgrastim (a long-acting G-CSF) for prevention of chemotherapy-induced febrile neutropenia: consensus guidance recommendations. Support Care Cancer. 2017;25(11):3295–304. doi: 10.1007/s00520-017-3842-1.
26. Cornes P, Gascon P, Chan S, et al. Systematic Review and Meta-analysis of Short- versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia. Adv Ther. 2018;35(11):1816–29. doi: 10.1007/s12325-018-0798-6.

ES Nesterova, EE Zvonkov, AM Kovrigina, TN Obukhova, BV Biderman, AB Sudarikov, YaK Mangasarova, AU Magomedova, AK Smolyaninova, SM Kulikov, EN Parovichnikova

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

For correspondence: Ekaterina Sergeevna Nesterova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-23-61, +7(910)429-62-26; e-mail: nest.ek@yandex.ru

For citation: Nesterova ES, Zvonkov EE, Kovrigina AM, et al. Follicular Lymphoma of Grades 1–3А With and Without t(14;18)(q32;q21): A Prognosis, Choice of Chemotherapy and Its Outcomes. Clinical oncohematology. 2023;16(4):361–9. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-361-369

ABSTRACT

Aim. To determine the prognostic value of t(14;18)(q32;q21) in follicular lymphoma (FL) of grades 1–3А, to assess the chemotherapy efficacy in “t(14;18)+ FL” and “t(14;18)– FL” patients, and to analyze the cases of ineffective therapy.

Materials & Methods. The retrospective/prospective study carried out at the National Research Center for Hematology in the period of 2001–2022 enrolled 362 patients with newly diagnosed FL of grades 1–3А. Their risk stratification was based on predictive models FLIPI and PPI3 (Personalized Predictive Index[1]). The patients were 30–81 years of age (median 52 years). There were 225 women and 137 men. They received the following regimens: R-B (n = 80), R-CHOP (n = 189), R-CHOP (4 cycles) + R-DHAP (2 cycles) (n = 28), and R-CHOP (4 cycles) + R-DHAP (2 cycles) + auto-HSCT in the first-line therapy (n = 65). For 2 years, maintenance rituximab therapy was administered to all the enrolled patients, whichever drug chemotherapy they received. Standard cytogenetic analysis and FISH were carried out in 265/362 (73 %) patients.

Results. Patients were divided into two comparable groups: “t(14;18)+ FL” (n = 196) and “t(14;18)– FL” (n = 69). Patients without cytogenetics/FISH (n = 97) were excluded from the analysis. In patients without t(14;18), poor prognostic factors, such as grade 3А (p = 0.003) and Ki-67 > 35 % (p = 0.001), were identified significantly more often, and also high PPI3 risk was reported (p = 0.008). No differences (p = 0.84) were detected during FLIPI risk stratification of patients. Bone marrow lesions were observed significantly more often in “t(14;18)+ FL” compared to “t(14;18)– FL” (p = 0.002). The chemotherapy outcomes, such as 2-year EFS and OS, appeared to be considerably worse in “t(14;18)– FL” compared to “t(14;18)+ FL” patients.

Conclusion. The group of FL patients with t(14;18) appeared to be most numerous and more prognostically favorable. Immunochemotherapy regimens R-B and R-CHOP are more justified in the first-line therapy of FL with low PPI3 risk. Therapy outcomes were comparable in efficacy. In intermediate and high PPI3 risk FL patients with t(14;18), the most effective first-line therapy was the one with consistent administration of R-CHOP, R-DHAP, and auto-HSCT. Based on the results of this study, FL of grades 1–3А without t(14;18) can well be considered to be a prognostically unfavorable variant of this malignant lymphoid tumor. The rate of early relapses/progression after the standard immunochemotherapy (R-B and R-CHOP), according to our data, is 60 %. In patients with newly diagnosed FL who received consistent administration of R-CHOP, R-DHAP, and auto-HSCT in the first-line therapy, this rate drops to 30 %. Our results clearly indicate the need for new FL treatment approaches.

[1] Personalized Predictive Index (PPI3) is an original predictive model specially developed for follicular lymphoma at the National Research Center for Hematology.

Keywords: follicular lymphoma, prognosis, t(14;18)(q32;q21).

Received: March 15, 2023

Accepted: September 6, 2023

Read in PDF

REFERENCES

1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. 2016;127(20):2375–90. doi: 10.1182/blood-2016-01-643569.
2. Casulo C, Byrtek M, Dawson KL, et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516–22. doi: 10.1200/JCO.2014.59.7534.
3. Jurinovic V, Kridel R, Staiger AM, et al. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood. 2016;128(8):1112–20. doi: 10.1182/blood-2016-05-717355.
4. Maurer MJ, Bachy E, Ghesquieres H, et al. Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol. 2016;91(11):1096–101. doi: 10.1002/ajh.24492.
5. Zhu Z, Li T, Zhang X, et al. Molecular and clinical progress in follicular lymphoma lacking the t(14;18) translocation (Review). Int J Oncol. 2020;56(1):7–17. doi: 10.3892/ijo.2019.4917.
6. Katzenberger T, Kalla J, Leich E, et al. A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood. 2009;113(5):1053–61. doi: 10.1182/blood-2008-07-168682.
7. Ott G, Katzenberger T, Lohr A, et al. Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood. 2002;99(10):3806–12. doi: 10.1182/blood.v99.10.3806.
8. Weinberg OK, Ai WZ, Mariappan MR, et al. “Minor” BCL2 breakpoints in follicular lymphoma: frequency and correlation with grade and disease presentation in 236 cases. J Mol Diagn. 2007;9(4):530–7. doi: 10.2353/jmoldx.2007.070038.
9. Horsman DE, Okamoto I, Ludkovski O, et al. Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes. Br J Haematol. 2003;120(3):424–33. doi: 10.1046/j.1365-2141.2003.04086.x.
10. Leich E, Zamo A, Horn H, et al. MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype. Blood. 2011;118(20):5550–8. doi: 10.1182/blood-2011-06-361972.
11. Ohno H. Pathogenetic and clinical implications of non-immunoglobulin; BCL6 translocations in B-cell non-Hodgkin’s lymphoma. J Clin Exp Hematop. 2006;46(2):43–53. doi: 10.3960/jslrt.46.43.
12. Horn H, Schmelter C, Leich E, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96(9):1327–34. doi: 10.3324/haematol.2011.042531.
13. Gu K, Fu K, Jain S, et al. t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the alternative breakpoint region. Mod Pathol. 2009;22(9):1251–7. doi: 10.1038/modpathol.2009.81.
14. Leich E, Salaverria I, Bea S, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114(4):826–34. doi: 10.1182/blood-2009-01-198580.
15. Nann D, Ramis-Zaldivar JE, Muller I, et al. Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease. Blood Adv. 2020;4(22):5652–65. doi: 10.1182/bloodadvances.2020002944.
16. Leich E, Maier C, Bomben R, et al. Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage. Blood Adv. 2021;5(23):4890–900. doi: 10.1182/bloodadvances.2021005081.
17. Kridel R, Xerri L, Gelas-Dore B, et al. The Prognostic Impact of CD163-Positive Macrophages in Follicular Lymphoma: A Study from the BC Cancer Agency and the Lymphoma Study Association. Clin Cancer Res. 2015;21(15):3428–35. doi: 10.1158/1078-0432.
18. Linley A, Krysov S, Ponzoni M, et al. Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells. Blood. 2015;126(16):1902–10. doi: 10.1182/blood-2015-04-640805.
19. Vitolo U, Ferreri AJ, Montoto S. Follicular lymphomas. Crit Rev Oncol Hematol. 2008;66(3):248–61. doi: 10.1016/j.critrevonc.2008.01.014.
20. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122(10):3424–31. doi: 10.1172/JCI63186.
21. Нестерова Е.С., Кравченко С.К., Гемджян Э.Г. и др. Лечение фолликулярной лимфомы: 10-летний опыт. Гематология и трансфузиология. 2012;57(S3):65–6.
    [Nesterova ES, Kravchenko SK, Gemdzhian EG, et al. Treatment of follicular lymphoma: 10-year experience. Gematologiya i transfuziologiya. 2012;57(S3):65–6. (In Russ)]
22. Нестерова Е.С., Кравченко С.К., Мангасарова Я.К. и др. Фолликулярная лимфома. Высокодозная иммунохимиотерапия с трансплантацией аутологичных стволовых клеток крови: результаты первого проспективного исследования в России. Терапевтический архив. 2016;88(7):62–71. doi: 10.17116/terarkh201688762-71.
    [Nesterova ES, Kravchenko SK, Mangasarova IaK, et al. Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia. Terapevticheskii Arkhiv. 2016;88(7):62– doi: 10.17116/terarkh201688762-71. (In Russ)]
23. Абрамова А.В., Абдуллаев А.О., Азимова М.Х. и др. Алгоритмы диагностики и протоколы лечения заболеваний системы крови. В 2 томах. М.: Практика, 2018. Том 2.
    [Abramova AV, Abdullaev AO, Azimova MKh, et al. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. V 2 tomakh. (Diagnostic algorithms and treatment protocols in hematological diseases. In 2 volumes.) Moscow: Praktika Publ.; 2018. Vol. 2. (In Russ)]
24. Беляева А.В., Габеева Н.Г., Смольянинова А.К. и др. Опыт применения высокодозной полихимиотерапии в первой линии лечения у больных фолликулярной лимфомой с факторами неблагоприятного прогноза. Гематология и трансфузиология. 2020;65(S1):61.
    [Belyaeva AV, Gabeeva NG, Smol’yaninova AK, et al. Experience of using high-dose polychemotherapy in the first line of treatment in patients with follicular lymphoma and unfavorable prognosis factors. Gematologiya i transfuziologiya. 2020;65(S1):61. (In Russ)]
25. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5):1258–65. doi: 10.1182/blood-2003-12-4434.
26. Nesterova ES, Severina NA, Biderman BV, et al. А new combination of prognostic markers in follicular lymphoma that influences the choice of therapy. Blood. 2021;138(Suppl 1):4520. doi: 10.1182/blood-2021-145104.
27. Nesterova E, Severina N, Biderman B, et al. Combination of EZH2 gene mutation and BCL2 gene rearrangement as an indicator of favorable prognosis of follicular lymphoma. Hemasphere. 2021;5(Suppl 2):368. doi: 10.1097/HS9.0000000000000566.
28. Нестерова Е.С., Северина Н.А., Бидерман Б.В. и др. Новое сочетание клинических и молекулярно-биологических маркеров прогнозирования при фолликулярной лимфоме 1–2 и 3А цитологического типа как основа риск-адаптивной терапии. Гематология и трансфузиология. 2022;67(S2):129–30.
    [Nesterova ES, Severina NA, Biderman BV, et al. A new combination of clinical and molecular biological markers of prognosis in follicular lymphoma grades 1–2 and 3A as the basis of risk-adaptive therapy. Gematologiya i transfuziologiya. 2022;67(S2):129–30. (In Russ)]
29. Leonard JP. POD24 in follicular lymphoma: time to be “wise”. Blood. 2022;139(11):1609–10. doi: 10.1182/blood.2021013437.
30. Casulo C, Dixon JG, Le-Rademacher J, et al. Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials. Blood. 2022;139(11):1684–93. doi: 10.1182/blood.2020010263.
31. Sortais C, Lok A, Tessoulin B, et al. Progression of disease within 2 years (POD24) is a clinically relevant endpoint to identify high-risk follicular lymphoma patients in real life. Ann Hematol. 2020;99(7):1595–604. doi: 10.1007/s00277-020-04025-2.
32. Casulo C, Dixon JG, Ou FS, et al. Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials. Blood Adv. 2021;5(6):1737–45. doi: 10.1182/bloodadvances.2020002724.
33. Jurinovic V, Metzner B, Pfreundschuh M, et al. Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group. Biol Blood Marrow Transplant. 2018;24(6):1172–9. doi: 10.1016/j.bbmt.2018.03.022.
34. Huet S, Tesson B, Jais J-P, et al. A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts. Lancet Oncol. 2018;19(4):549–61. doi: 10.1016/S1470-2045(18)30102-5.
35. Luminari S, Manni M, Galimberti S, at al. Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study. J Clin Oncol. 2022;40(7):729–39. doi: 10.1200/JCO.21.01234.
36. Dreyling M, Ghielmini M, Rule S, et al.; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):298–308. doi: 10.1016/j.annonc.2020.11.008.
37. Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica. 2013;98(7):1014–21. doi: 10.3324/haematol.2013.084723.
38. Lenz G, Dreyling M, Schiegnitz E, et al.; German Low-Grade Lymphoma Study Group. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood. 2004;104(9):2667–74. doi: 10.1182/blood-2004-03-0982.
39. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006;108(8):2540–4. doi: 10.1182/blood-2006-03-013193.
40. Gyan E, Foussard C, Bertrand P, et al.; Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang (GOELAMS). High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood. 2009;113(5):995–1001. doi: 10.1182/blood-2008-05-160200.
41. Ladetto M, De Marco F, Benedetti F, et al.; Gruppo Italiano Trapianto di Midollo Osseo (GITMO); Intergruppo Italiano Linfomi (IIL). Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood. 2008;111(8):4004–13. doi: 10.1182/blood-2007-10-116749.
42. Bruna R, Benedetti F, Boccomini C, et al. Prolonged survival in the absence of disease-recurrence in advanced-stage follicular lymphoma following chemo-immunotherapy: 13-year update of the prospective, multicenter randomized GITMO-IIL trial. Haematologica. 2019;104(11):2241–8. doi: 10.3324/haematol.2018.209932.
43. Alig S, Jurinovic V, Shahrokh Esfahani M, et al. Evaluating upfront high-dose consolidation after R-CHOP for follicular lymphoma by clinical and genetic risk models. Blood Adv. 2020;4(18):4451–62. doi: 10.1182/bloodadvances.2020002546.

AA Danilenko, NA Falaleeva, SV Shakhtarina

AF Tsyb Medical Radiological Research Centre, branch of the NMRC of Radiology, 4 Koroleva ul., Obninsk, Kaluga Region, Russian Federation, 249036

For correspondence: Anatolii Aleksandrovich Danilenko, MD, PhD, 4 Koroleva ul., Obninsk, Kaluga Region, Russian Federation, 249036; Tel.: +7(909)250-18-10; e-mail: danilenkoanatol@mail.ru

For citation: Danilenko AA, Falaleeva NA, Shakhtarina SV. Historical Background of the Role of Bone Marrow Core Biopsy in the Staging System for Classical Hodgkin Lymphoma and the Current View in the Era of PET-CT: A Literature Review. Clinical oncohematology. 2023;16(4):351–60. (In Russ).

DOI: 10.21320/2500-2139-2023-16-4-351-360

ABSTRACT

The staging of Hodgkin lymphoma lays the groundwork for optimal treatment decision making. For a long time, bone marrow assessment has been an integral part of staging. The study of bone marrow involvement in tumor progression includes radiological method and morphological analysis of its core biopsy samples. During the last five decades of using bone marrow core biopsy, the attitude of oncologists and hematologists to this invasive and painful procedure remained ambivalent between denying and affirming the need to carry it out in all or most Hodgkin lymphoma cases. The present review provides the historical background of bone marrow core biopsy and considers its appropriateness for patients with classical Hodgkin lymphoma.

Keywords: Hodgkin lymphoma, bone marrow, core biopsy.

Received: March 26, 2023

Accepted: September 2, 2023

Read in PDF

REFERENCES

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. doi: 10.3322/caac.21708.
2. Sasse S, Brockelmann PJ, Goergen H, et al. Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8, HD10, and HD11 Trials. J Clin Oncol. 2017;35:1999–2007. doi: 10.1200/JCO.2016.70.9410.
3. Subramanian G, Basu D, Badhe B, Dutta TK. Role of bone marrow trephine biopsy in the diagnosis of marrow involvement in Hodgkin’s disease. Indian J Pathol Microbiol. 2007;50(3):640–3.
4. Weiler-Sagie M, Kagna O, Dann EJ, et al. Characterizing bone marrow involvement in Hodgkin’s lymphoma by FDG-PET/CT. Eur J Nucl Med Mol Imaging. 2014;41(6):1133–40. doi: 10.1007/s00259-014-2706-x
5. Ghedini G. Per la patogenesi e per la diagnosi delle malattie del sangue e degli organi emopoietici, punture esplorativa del midollo osseo. Clinic Medica Italiana. 1908;47:724–36.
6. Seyfarth C. Eine einfache Methode zur diagnostichen Entnahme von Knochenmark beim Lebenden. Arch fur Schiffs-und Tropen-Hygiene, Pathologie und Therapie exotischer Krankheiten. 1922;26:337–41.
7. Arinkin MI. Die Intravitale Untersuchungsmethodik des Knochenmarks. Folia Haematologica. 1929;38:233–40.
8. Arjeff MJ. Zur Methodik der Diagnostischen Punktion des Brustbeines. Folia Haematologica. 1931;45:55.
9. Воробьев А.И. И.А. Кассирский и его вклад в медицину. М.: Медицина, 1988.
   [Vorob’ev AI. I.A. Kassirskii i ego vklad v meditsinu. (I.A. Kassirskii and his contribution to medicine.) Moscow: Meditsina; 1988. (In Russ)]
10. Rubinstein MA. The technic and diagnostic value of aspiration of bone marrow from the iliac crest. Ann Intern Med. 1950;32:1905–8.
11. Bierman HR. Bone marrow aspiration of the posterior iliac crest, an additional safe site. California Med. 1952;77:138–9.
12. Jamshidi K, Swaim WR. Bone marrow biopsy with unaltered architecture: a new biopsy device. J Lab Clin Med. 1971;77(2):335–42.
13. Hernandez-Garcia MT, Hernandez-Nieto L, Perez-Gonzalez E, Brito-Barroso ML. Bone marrow trephine biopsy: anterior superior iliac spine versus posterior superior iliac spine. Clin Lab Haematol. 1993;15(1):15–9. doi: 10.1111/j.1365-2257.1993.tb00117.x.
14. Tomasian A, Jennings JW. Bone marrow aspiration and biopsy: techniques and practice implications. Skeletal Radiol. 2022;51(1):81–8. doi: 10.1007/s00256-021-03882-w.
15. Draganski E, Deason T, Craig FE. Bone Marrow Aspiration and Biopsy Performed by RNs: A Review of Clinical Practice. Am J Nurs. 2019;119(9):47–53. doi: 10.1097/01.NAJ.0000580260.18537.ca.
16. Криволапов Ю.А. Биопсия костного мозга: научно-практическое издание. М.: Практическая медицина, 2014. 528 с.
    [Krivolapov YuA. Biopsiya kostnogo mozga: nauchno-prakticheskoe izdanie. (Bone marrow biopsy: research and practice edition.) Moscow: Prakticheskaya meditsina Publ.; 2014. 528 p. (In Russ)]
17. Howell SJ, Grey M, Changet L, et al. The value of bone marrow examination in the staging of Hodgkin’s lymphoma: a review of 955 cases seen in a regional cancer centre. Br J Haematol. 2002;119(2):408–11. doi: 10.1046/j.1365-2141.2002.03842.x.
18. Fend F, Kremer M. Diagnosis and classification of malignant lymphoma and related entities in the bone marrow trephine biopsy. Pathobiology. 2007;74(2):133–43. doi: 10.1159/000101712.
19. Brunning RD, Bloomfield CD, McKenna RW, Peterson LA. Bilateral trephine bone marrow biopsies in lymphoma and other neoplastic diseases. Ann Intern Med. 1975;82(3):365–6. doi: 10.7326/0003-4819-82-3-365.
20. Levis A, Pietrasanta D, Godio L, et al. A large-scale study of bone marrow involvement in patients with Hodgkin’s lymphoma. Clin Lymphoma. 2004;5(1):50–5. doi: 10.3816/clm.2004.n.010.
21. Wang J, Weiss LM, Chang KL, et al. Diagnostic utility of bilateral bone marrow examination: significance of morphologic and ancillary technique study in malignancy. Cancer. 2002;94(5):1522–31. doi: 10.1002/cncr.10364.
22. Menon NC, Buchanan JG. Bilateral trephine bone marrow biopsies in Hodgkin’s and non-Hodgkin’s lymphoma. Pathology. 1979;11(1):53–7. doi: 10.3109/00313027909063538.
23. Almeida J, Garcia-Marcos MA, Vallejo C, et al. Results of a series of 104 consecutive bilateral bone marrow biopsy specimens in lymphoproliferative disorders. Sangre (Barc). 1995;40(5):365–8.
24. Luoni M, Fava S, Declich PJ. Bone marrow biopsy for staging Hodgkin’s lymphoma: the value of bilateral or unilateral trephine biopsy. J Clin Oncol. 1996;14(2):682–3. doi: 10.1200/JCO.1996.14.2.682.
25. Kluin-Nelemans HC, Noordijk EM. Staging of patients with Hodgkin’s disease: what should be done? Leukemia. 1990;4(2):132–5.
26. Bartl R, Frisch B, Burkhardt R, et al. Assessment of bone marrow histology in the malignant lymphomas (non-Hodgkin’s): correlation with clinical factors for diagnosis, prognosis, classification and staging. Br J Haematol. 1982;51(4):511–30. doi: 10.1111/j.1365-2141.1982.tb02815.x.
27. Straus DJ, Gaynor JJ, Myers J, et al. Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin’s disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol. 1990;8(7):1173–86. doi: 10.1200/JCO.1990.8.7.1173.
28. Даниленко А.А. Поражение костного мозга у больных лимфогранулематозом (диагностика, клинические формы, патогенез): Автореф. дис. … канд. мед. наук. М., 2004.
    [Danilenko AA. Porazhenie kostnogo mozga u bolnykh limfogranulematozom (diagnostika, klinicheskie formy, patogenez). (Bone marrow lesions in Hodgkin lymphoma patients (diagnosis, clinical presentations, pathogenesis). [dissertation] Moscow; 2004. (In Russ)]
29. Kaplan HS. Contiguity and progression in Hodgkin’s disease. Cancer Res. 1971;31(11):1811–3.
30. Macintyre EA, Vaughan Hudson B, Linch DC, et al. The value of staging bone marrow trephine biopsy in Hodgkin’s disease. Eur J Haematol. 1987;39(1):66–70. doi: 10.1111/j.1600-0609.1987.tb00166.x.
31. Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31(11):1860–1.
32. Hines-Thomas MR, Howard SC, Hudson MM, et al. Utility of bone marrow biopsy at diagnosis in pediatric Hodgkin’s lymphoma. Haematologica. 2010;95(10):1691–6. doi: 10.3324/haematol.2010.025072.
33. Ellis ME, Diehl LF, Granger E, Elson E. Trephine needle bone marrow biopsy in the initial staging of Hodgkin disease: sensitivity and specificity of the Ann Arbor staging procedure criteria. Am J Hematol. 1989;30(3):115–20. doi: 10.1002/ajh.2830300302.25.
34. Doll DC, Ringenberg QS, Anderson SP, et al. Bone marrow biopsy in the initial staging of Hodgkin’s disease. Med Pediatr Oncol. 1989;17(1):1–5. doi: 10.1002/mpo. 2950170102.
35. Munker R, Hasenclever D, Brosteanu O, et al. Bone marrow involvement in Hodgkin’s disease: an analysis of 135 consecutive cases. German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 1995;13(2):403–9. doi: 10.1200/JCO.1995.13.2.403.
36. Howard MR, Taylor PR, Lucraft HH, et al. Bone marrow examination in newly diagnosed Hodgkin’s disease: current practice in the United Kingdom. Br J Cancer. 1995;71(1):210–2. doi: 10.1038/bjc.1995.43.
37. MacCormick R, Covert A, Gross M. Primary bony involvement in Hodgkin’s disease. CMAJ. 1989;140(9):1059–60.
38. Borg MF, Chowdhury AD, Bhoopal S, Benjamin CS. Bone involvement in Hodgkin’s disease. Australas Radiol. 1993;37(1):63–6. doi: 10.1111/j.1440-1673.1993.tb 00011.x.
39. Ostrowski ML, Inwards CY, Strickler JG. Osseous Hodgkin disease. Cancer. 1999;85(5):1166–78. doi: 10.1002/(sici)1097-0142(19990301)85:5<1166::aid-cncr22>3.0.co;2-v.
40. Langley CR, Garrett SJ, Urand J, et al. Primary multifocal osseous Hodgkin’s lymphoma. World J Surg Oncol. 2008;6:34. doi: 10.1186/1477-7819-6-34.
41. Anderson KC, Kaplan WD, Leonard RC, et al. Role of 99mTc methylene diphosphonate bone imaging in the management of lymphoma. Cancer Treat Rep. 1985;69(12):1347–51.
42. Ferrant A, Rodhain J, Michaux JL, et al. Detection of skeletal involvement in Hodgkin’s disease: A comparison of radiography, bone scanning, and bone marrow biopsy in 38 patients. Cancer. 1975;35(5):1346–53. doi: 10.1002/1097-0142(197505)35:5<1346::aid-cncr2820350516>3.0.co;2-i.
43. Daffner RH, Lupetin AR, Dash N, et al. MRI in the detection of malignant infiltration of bone marrow. Am J Roentgenol. 1986;146(2):353–8. doi: 10.2214/ajr.146.2.353.
44. Vogler JB, Murphy WA. Bone marrow imaging. Radiology. 1988;168(3):679–93. doi: 10.1148/radiology.168.3.3043546.
45. Guckel F, Semmler W, Dohner H, et al. NMR tomographic imaging of bone marrow infiltrates in malignant lymphoma. Rofo. 1989;150(1):26–31. doi: 10.1055/s-2008-1046968.
46. Chiarilli MG, Delli Pizzi A, Mastrodicasa D, et al. Bone marrow magnetic resonance imaging: physiologic and pathologic findings that radiologist should know. Radiol Med. 2021;126(2):264–76. doi: 10.1007/s11547-020-01239-2.
47. Hoane BR, Shields AF, Porter BA, Shulman HM. Detection of lymphomatous bone marrow involvement with magnetic resonance imaging. Blood. 1991;78(3):728–38.
48. Dohner H, Guckel F, Knauf W, et al. Magnetic resonance imaging of bone marrow in lymphoproliferative disorders: correlation with bone marrow biopsy. Br J Haematol. 1989;73(1):12–7. doi: 10.1111/j.1365-2141.1989.tb00211.x.
49. Linden A, Zankovich R, Theissen P, et al. Malignant lymphoma: bone marrow imaging versus biopsy. Radiology. 1989;173(2):335–9. doi: 10.1148/radiology.173.2.2678249.
50. Shields AF, Porter BA, Churchley S, et al. The detection of bone marrow involvement by lymphoma using magnetic resonance imaging. J Clin Oncol. 1987;5(2):225–30. doi: 10.1200/JCO.1987.5.2.225.
51. Tardivon AA, Munck JN, Shapeero LG. Can clinical data help to screen patients with lymphoma for MR imaging of bone marrow? Ann Oncol. 1995;6(8):795–800. doi: 10.1093/oxfordjournals.annonc.a059318.
52. Skillings JR, Bramwell V, Nicholson RL, et al. A prospective study of magnetic resonance imaging in lymphoma staging. Cancer. 1991;67(7):1838–43. doi: 10.1002/1097-0142(19910401)67:7<1838::aid-cncr2820670704>3.0.co;2-o.
53. Vinnicombe SJ, Reznek RH. Computerised tomography in the staging of Hodgkin’s disease and non-Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging. 2003;30(Suppl 1):S42–S55. doi: 10.1007/s00259-003-1159-4.
54. Kniseley RM, Andrews GA, Edwards CL, Hayes RL. Bone-marrow and skeletal scanning. Radiol Clin North Am. 1969;7(2):265–80.
55. Lilien DL, Berger HG, Anderson DP, Bennett LR. 111 In-chloride: a new agent for bone marrow imaging. J Nucl Med. 1973;14(3):184–6.
56. Krause T, Eisenmann N, Reinhardt M, et al. Bone marrow scintigraphy using technetium-99m antigranulocyte antibody in malignant lymphomas. Ann Oncol. 1999;10(1):79–85. doi: 10.1023/a:1008356910239.
57. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol. 1989;7(11):1630–6. doi: 10.1200/JCO.1989.7.11.1630.
58. Dahlbom M, Hoffman EJ, Hoh CK, et al. Whole-body positron emission tomography: Part I. Methods and performance characteristics. J Nucl Med. 1992;33(6):1191–9.
59. Hoh CK, Hawkins RA, Glaspy JA, et al. Cancer detection with whole-body PET using 2-[18F]fluoro-2-deoxy-D-glucose. J Comput Assist Tomogr. 1993;17(4):582–9. doi: 10.1097/00004728-199307000-00012.
60. Basu S, Hess S, Nielsen Braad PE, et al. The Basic Principles of FDG-PET/CT Imaging. PET Clin. 2014;9(4):355–70. doi: 10.1016/j.cpet.2014.07.006.
61. Paul R. Comparison of fluorine-18-2-fluorodeoxyglucose and gallium-67 citrate imaging for detection of lymphoma. J Nucl Med. 1987;28(3):288–92.
62. Newman JS, Francis IR, Kaminski MR, Wahl RL. Imaging of lymphoma with PET with 2-[F-18]-fluoro-2-deoxy-D-glucose: correlation with CT. Radiology. 1994;190(1):111–6. doi: 10.1148/radiology.190.1.8259386.
63. Hoh CK, Glaspy J, Rosen P, et al. Whole-body FDG-PET imaging for staging of Hodgkin’s disease and lymphoma. J Nucl Med. 1997;38(3):343–8.
64. Buchmann I, Reinhardt M, Elsner K, et al. 2-(fluorine-18)fluoro-2-deoxy-D-glucose positron emission tomography in the detection and staging of malignant lymphoma. A bicenter trial. Cancer. 2001;91(5):889–99.
65. Schaefer NG, Hany TF, Taverna C et al. Non-Hodgkin lymphoma and Hodgkin disease: coregistered FDG PET and CT at staging and restaging – do we need contrast-enhanced CT? Radiology. 2004;232(3):823–9. doi: 10.1148/radiol.2323030985.
66. Hoh CK, Hawkins RA, Dahlbom M, et al. Whole body skeletal imaging with [18F]fluoride ion and PET. J Comput Assist Tomogr. 1993;17(1):34–41. doi: 10.1097/00004728-199301000-00005.
67. Bangerter M, Moog F, Buchmann I, et al. Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin’s disease. Ann Oncol. 1998;9(10):1117–22. doi: 10.1023/a:1008486928190.
68. Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257–60. doi: 10.1080/10428190903040048.
69. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048–58. doi: 10.1200/JCO.2013.53.5229.
70. Moulin-Romsee G, Hindie E, Cuenca X, et al. (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin’s lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. Eur J Nucl Med Mol Imaging. 2010;37(6):1095–105. doi: 10.1007/s00259-009-1377-5.
71. Adams HJ, Kwee TC, de Keizer B, et al. Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol. 2014;25(5):921–7. doi: 10.1093/annonc/mdt533.
72. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–68. doi: 10.1200/JCO.2013.54.8800.
73. Puccini B, Nassi L, Minoia C, et al. Role of bone marrow biopsy in staging of patients with classical Hodgkin’s lymphoma undergoing positron emission tomography/computed tomography. Ann Hematol. 2017;96(7):1147–53. doi: 10.1007/s00277-017-2996-8.
74. Voltin CA, Goergen H, Baues C, et al. Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18. Ann Oncol. 2018;29(9):1926–31. doi: 10.1093/annonc/mdy250.
75. Gallamini A. Hodgkin lymphoma staging 50 years later: no more knives or needles! Ann Oncol. 2018;29(9):1892–3. doi: 10.1093/annonc/mdy262.
76. Gaudio F, Pedote P, Niccoli Asabella A, et al. Bone Involvement in Hodgkin’s Lymphoma: Clinical Features and Outcome. Acta Haematol. 2018;140(3):178–82. doi: 10.1159/000490489.
77. Kwee TC, de Klerk JMH, Nix M, et al. Benign Bone Conditions That May Be FDG-avid and Mimic Malignancy. Semin Nucl Med. 2017;47(4):322–51. doi: 10.1053/j.semnuclmed. 2017.02.004.

AS Zhuk¹, II Kostroma², EI Stepchenkova^3,4, DV Kachkin³, OB Belopolskaya⁵, IV Zotova^3,4, AD Garifullin², SV Voloshin^2,6, SV Gritsaev², AYu Aksenova³

¹ ITMO National Research University, 49 lit. A Kronverkskii pr-t, Saint Petersburg, Russian Federation, 197101

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

³ Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

⁴ NI Vavilov Institute of General Genetics, Saint Petersburg branch, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

⁵ Bio-Bank Resource Center, Saint Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

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

For correspondence: Elena Igorevna Stepchenkova, PhD in Biology, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034; Tel.: +7(905)282-57-72; e-mail: stepchenkova@gmail.com

For citation: Zhuk AS, Kostroma II, Stepchenkova EI, et al. Molecular Profiling of Normal and Tumor Plasma Cells in a Patient with Newly Diagnosed Multiple Myeloma: A Case Report. Clinical oncohematology. 2023;16(3):337–49. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-337-349

ABSTRACT¹ 

¹The editorial board of the “Clinical Oncohematology. Fundamental Studies and Clinical Practice” reserves the right to independently interpret the results of next-generation sequencing (NGS) in line with international recommendations (ACMG/AMP, doi: 10.1038/gym.2015.30) and national guidelines (https://mgs.med-gen.ru/) for clinical use. Despite considerable points of divergence with personal views of the authors, the editorial board of the journal finds it possible to publish the present paper.

This paper is a case report of a patient with newly diagnosed multiple myeloma (MM) who underwent exome sequencing of peripheral blood lymphocytes and CD138+ tumor plasma cells prior to therapy. This patient showed some inherited genetic variants which are associated with underlying risk for MM. This patient’s genotype was reported to have some variants in the DNA repair genes, including inherited mutations in the RFDW3 and TP53 genes. They are involved in the maintenance of genome stability and accumulation rate of somatic mutations, including structural rearrangements and chromosome aberrations. A large number of structural variations

and mutational signature ID6 in the tumor genetic material point to the disruption of DNA damage repair. The tumor cell exome analysis yielded a profile of somatic mutations, also the mutations in the genes previously associated with MM, as well as a functional significance of the detected abnormalities. Somatic mutations also included damaging mutations and highly significant mutations in the other tumor-associated genes, such as ASCC3, TET3, and CHD1, as well as in the antimicrobial peptide-coding genes CAMP and HTN3. With the exception of an extra copy of 1q arm in the tumor plasma cell genome, the patient showed no genetic risk factors associated with poor prognosis of the disease. Based on literature, inherited (ABCB1 mutations) and somatic (trisomy 3) variations detected in the patient’s genetic material can be characterized as positive prognostic factors in MM.

Keywords: multiple myeloma, next-generation sequencing, exome, inherited mutations, somatic mutations.

Received: August 12, 2022

Accepted: May 20, 2023

Read in PDF

REFERENCES

1. Aksenova AY, Zhuk AS, Lada AG, et al. Genome instability in multiple myeloma: Facts and factors. Cancers. 2021;13(23):5949. doi: 10.3390/cancers13235949.
2. Аксенова А.Ю., Жук А.С., Степченкова Е.И., Грицаев С.В. Стратификация больных множественной миеломой: современное состояние вопроса и дальнейшие перспективы. Клиническая онкогематология. 2022;15(3):259–70. doi: 10.21320/2500-2139-2022-15-3-259-270.
   [Aksenova AYu, Zhuk AS, Stepchenkova EI, Gritsaev SV. Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects. Clinical oncohematology. 2022;15(3):259–70. doi: 10.21320/2500-2139-2022-15-3-259-270. (In Russ)]
3. Walker BA, Mavrommatis K, Wardell CP, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132(6):587–97. doi: 10.1182/blood-2018-03-840132.
4. Fu X, Yucer N, Liu S, et al. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Nat Acad Sci USA. 2010;107(10):4579–84. doi: 10.1073/PNAS.0912094107.
5. Feeney L, Munoz IM, Lachaud C, et al. RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health. Mol Cell. 2017;66(5):610–621.e4. doi: 10.1016/j.molcel.2017.04.021.
6. Mitchell JS, Li N, Weinhold N, et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun. 2016;7:12050. doi: 10.1038/ncomms12050.
7. Went M, Sud A, Forsti A, et al. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun. 2018;9(1):3707. doi: 10.1038/s41467-018-04989-w.
8. Hou P, Su X, Cao W, et al. Whole-exome sequencing reveals the etiology of the rare primary hepatic mucoepidermoid carcinoma. Diagn Pathol. 2021;16(1):29. doi: 10.1186/s13000-021-01086-3.
9. Huang X, Wu F, Zhang Z, Shao Z. Association between TP53 rs1042522 gene polymorphism and the risk of malignant bone tumors: a meta-analysis. Biosci Rep. 2019;39(3):20181832. doi: 10.1042/BSR20181832.
10. Akter R, Islam MS, Islam MS, et al. A case-control study investigating the association of TP53 rs1042522 and CDH1 rs16260 polymorphisms with prostate cancer risk. Meta Gene. 2021;30:100962. doi: 10.1016/J.MGENE.2021.100962.
11. Henner WD, Evans AJ, Hough KM, et al. Association of codon 72 polymorphism of p53 with lower prostate cancer risk. Prostate. 2001;49(4):263–6. doi: 10.1002/PROS.10021.
12. Dunna NR, Vure S, Sailaja K, et al. TP53 codon 72 polymorphism and risk of acute leukemia. Asian Pacif J Cancer Prevent. 2012;13(1):347–50. doi: 10.7314/APJCP.2012.13.1.349.
13. Kochethu G, Delgado J, Pepper C, et al. Two germ line polymorphisms of the tumour suppressor gene p53 may influence the biology of chronic lymphocytic leukaemia. Leuk Res. 2006;30(9):1113–8. doi: 10.1016/J.LEUKRES.2005.12.014.
14. Bergamaschi D, Samuels Y, Sullivan A, et al. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet. 2006;38(10):1133–41. doi: 10.1038/ng1879.
15. Dumont P, Leu JIJ, Della Pietra AC, et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003;33(3):357–65. doi: 10.1038/ng1093.
16. Weng Y, Lu L, Yuan G, et al. p53 codon 72 polymorphism and Hematological Cancer Risk: An Update Meta-Analysis. PLoS ONE. 2012;7(9):e45820. doi: 10.1371/journal.pone.0045820.
17. Ortega MM, Honma HN, Zambon L, et al. GSTM1 and codon 72 P53 polymorphism in multiple myeloma. Ann Hematol. 2007;86(11):815–9. doi: 10.1007/S00277-007-0347-X/TABLES/3.
18. Hattori Y, Ikeda Y, Suzuki Y, et al. Codon 72 polymorphism of TP53 gene is a novel prognostic marker for therapy in multiple myeloma. Br J Haematol. 2014;165(5):728–31. doi: 10.1111/BJH.12784.
19. Greenberg AJ, Lee AM, Serie DJ, et al. Single-nucleotide polymorphism rs1052501 associated with monoclonal gammopathy of undetermined significance and multiple myeloma. Leukemia. 2013;27(2):515–6. doi: 10.1038/leu.2012.232.
20. Broderick P, Chubb D, Johnson DC, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet. 2012;44(1):58–61. doi: 10.1038/ng.993.
21. Ford AQ, Heller NM, Stephenson L, et al. An Atopy-Associated Polymorphism in the Ectodomain of the IL-4Rα Chain (V50) Regulates the Persistence of STAT6 Phosphorylation. J Immunol. 2009;183(3):1607–16. doi: 10.4049/JIMMUNOL.0803266.
22. Luo Y, Ye Z, Li K, et al. Associations between polymorphisms in the IL-4 and IL-4 receptor genes and urinary carcinomas: a meta-analysis. Int J Clin Exp Med. 2015;8(1):1227–33.
23. Ivansson EL, Gustavsson IM, Magnusson JJ, et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. Int J Cancer. 2007;121(11):2451–7. doi: 10.1002/IJC.22989.
24. Alvarez JV, Frank DA. Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther. 2004;3(11):1045–50. doi: 10.4161/cbt.3.11.1172.
25. Vikova V, Jourdan M, Robert N, et al. Comprehensive characterization of the mutational landscape in multiple myeloma cell lines reveals potential drivers and pathways associated with tumor progression and drug resistance. Theranostics. 2019;9(2):540–53. doi: 10.7150/thno.28374.
26. Waller RG, Darlington TM, Wei X, et al. Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk Epstein MP, editor. PLOS Genet. 2018;14(2):e1007111. doi: 10.1371/journal.pgen.1007111.
27. Bolli N, Barcella M, Salvi E, et al. Next-generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles. Cancer. 2017;123(19):3701–8. doi: 10.1002/cncr.30777.
28. Greipp P, Cascino G, Kimlinger T, et al. Plasma Cell Folate Receptor Overexpression Differentiates Multiple Myeloma from Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma. Blood. 2004;104(11):3649. doi: 10.1182/BLOOD.V104.11.3649.3649.
29. Song J, Freeman ADJ, Knebel A, et al. Human ANKLE1 Is a Nuclease Specific for Branched DNA. J Mol Biol. 2020;432(21):5825–34. doi: 10.1016/J.JMB.2020.08.022.
30. Antoniou AC, Wang X, Fredericksen ZS, et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet. 2010;42(10):885–92. doi: 10.1038/NG.669.
31. Tian J, Ying P, Ke J, et al. ANKLE1 N6-Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. Int J Cancer. 2020;146(12):3281–93. doi: 10.1002/IJC.32677.
32. Rhie SK, Coetzee SG, Noushmehr H, et al. Comprehensive functional annotation of seventy-one breast cancer risk Loci. PloS One. 2013;8(5):e63925. doi: 10.1371/journal.pone.0063925.
33. Hodges LM, Markova SM, Chinn LW, et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011;21(3):152–61. doi: 10.1097/FPC.0B013E3283385A1C.
34. Hassen W, Kassambara A, Reme T, et al. Drug metabolism and clearance system in tumor cells of patients with multiple myeloma. Oncotarget. 2014;6(8):6431–47. doi: 10.18632/ONCOTARGET.3237.
35. Salama NN, Yang Z, Bui T, Ho RJY. MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells. J Pharm Sci. 2006;95(10):2293–308. doi: 10.1002/JPS.20717.
36. Drain S, Catherwood M, Orr N, et al. ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk lymphoma. 2009;50(4):566–70. doi: 10.1080/10428190902853144.
37. Buda G, Ricci D, Huang CC, et al. Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann Hematol. 2010;89(11):1133. doi: 10.1007/S00277-010-0992-3.
38. Maggini V, Buda G, Martino A, et al. MDR1 diplotypes as prognostic markers in multiple myeloma. Pharmacogenet Genomics. 2008;18(5):383–9. doi: 10.1097/FPC.0B013E3282F82297.
39. Ziccheddu B, Biancon G, Bagnoli F, et al. Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma. Blood Adv. 2020;4(5):830–44. doi: 10.1182/bloodadvances.2019000779.
40. Zheleznyak A, Mixdorf M, Marsala L, et al. Orthogonal targeting of osteoclasts and myeloma cells for radionuclide stimulated dynamic therapy induces multidimensional cell death pathways. Theranostics. 2021;11(16):7735–54. doi: 10.7150/THNO.60757.
41. Bolli N, Biancon G, Moarii M, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. 2018;32(12):2604–16. doi: 10.1038/s41375-018-0037-9.
42. Dementyeva E, Kryukov F, Kubiczkova L, et al. Clinical implication of centrosome amplification and expression of centrosomal functional genes in multiple myeloma. J Transl Med. 2013;11(1):1–9. doi: 10.1186/1479-5876-11-77/FIGURES/5.
43. Dango S, Mosammaparast N, Sowa ME, et al. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol Cell. 2011;44(3):373–84. doi: 10.1016/J.MOLCEL.2011.08.039.
44. Fedeles BI, Singh V, Delaney JC, et al. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond. J Biol Chem. 2015;290(34):20734–42. doi: 10.1074/JBC.R115.656462.
45. Jia J, Absmeier E, Holton N, et al. The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. Nat Commun. 2020;11(1):1–13. doi: 10.1038/s41467-020-19221-x.
46. Ko M, An J, Pastor WA, et al. TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunol Rev. 2015;263(1):6–21. doi: 10.1111/IMR.12239.
47. Bray JK, Dawlaty MM, Verma A, Maitra A. Roles and Regulations of TET Enzymes in Solid Tumors. Trends Cancer. 2021;7(7):635–46. doi: 10.1016/j.trecan.2020.12.011.
48. Linowiecka K, Foksinski M, Brozyna AA. Vitamin c transporters and their implications in carcinogenesis. Nutrients. 2020;12(12):1–19. doi: 10.3390/nu12123869.
49. Kari V, Mansour WY, Raul SK, et al. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016;17(11):1609–23. doi: 10.15252/EMBR.201642352.
50. Zhou J, Li J, Serafim RB, et al. Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus. Nucleic Acids Res. 2018;46(8):3891–905. doi: 10.1093/nar/gky128.
51. Cardoso AR, Lopes-Marques M, Oliveira M, et al. Genetic variability of the functional domains of chromodomains helicase DNA-binding (CHD) proteins. Genes. 2021;12(11):1–15. doi: 10.3390/genes12111827.
52. Burkhardt L, Fuchs S, Krohn A, et al. CHD1 Is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 2013;73(9):2795–805. doi: 10.1158/0008-5472.CAN-12-1342.
53. Li Y, Roberts ND, Wala JA, et al. Patterns of somatic structural variation in human cancer genomes. Nature. 2020;578(7793):112–21. doi: 10.1038/s41586-019-1913-9.
54. Chretien ML, Corre J, Lauwers-Cances V, et al. Understanding the role of hyperdiploidy in myeloma prognosis: Which trisomies really matter? Blood. 2015;126(25):2713–9. doi: 10.1182/blood-2015-06-650242.
55. Perrot A, Lauwers-Cances V, Tournay E, et al. Development and validation of a cytogenetic prognostic index predicting survival in multiple myeloma. J Clin Oncol. 2019;37(19):1657–65. doi: 10.1200/JCO.18.00776.
56. Talevich E, Shain AH, Botton T, Bastian BC. CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLOS Comput Biol. 2016;12(4):e1004873. doi: 10.1371/JOURNAL.PCBI.1004873.
57. Lee J, Lee AJ, Lee JK, et al. Mutalisk: A web-based somatic MUTation AnaLyIS toolKit for genomic, transcriptional and epigenomic signatures. Nucleic Acids Res. 2018;46(W1):W102–W108. doi: 10.1093/nar/gky406.
58. Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 2011;25(23):2436. doi: 10.1101/GAD.179184.111.
59. Schmidt TM, Barwick BG, Joseph N, et al. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J. 2019;9(12):94. doi: 10.1038/s41408-019-0254-0.