FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology

Advanced search

New pharmacotherapeutic approaches for the treatment of peripheral T-cell lymphoma


Today, it is difficult to overestimate the new directions in the pharmacotherapy of peripheral T-cell lymphomas (PTCL): immunotherapy, including adoptive, targeted therapy and chemotherapy. However, there are few biomarkers that predict response to therapy. A big problem is patients with refractory and recurrent PTCL who do not respond to such therapy or demonstrate adverse events, which makes it important to personalize therapy and search for predictive markers, followed by thorough analytical and clinical validation. The literature highlights the importance of using biomarkers obtained from whole exome sequencing and tumor transcriptome sequencing. The review discusses the T cell ontogenesis, as well as the possibilities of personalization of anticancer drugs such as azacitidine, duvelisib, romidepsin, and bortezomib for the treatment of refractory or recurrent PTCL.

About the Authors

M. А. Sorokina
Ivanovo State Medical Academy; Pirogov Russian National Research Medical University
Russian Federation

Maria A. Sorokina – Postgraduate, Chair of Pharmacology, Ivanovo State Medical Academy; Analyst, Neurocampus-2030, Pirogov Russian National Research Medical University.

Scopus Author ID: 57226747037; RSCI SPIN-code: 4142-8679.

8 Sheremetevskiy Ave., Ivanovo 153012
1 Ostrovityanov Str., Moscow 117997

A. V. Rakhteenko
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology
Russian Federation

Arina V. Rakhteenko – Pediatrician, Department of Hematopoietic Stem Cell Transplantation No. 1

1 Samorа Mashel Str., Moscow 117997

T. R. Grishina
Ivanovo State Medical Academy
Russian Federation

Tatiana R. Grishina – Dr. Med. Sc., Professor, Chief of Chair of Pharmacology

RSCI SPIN-code: 1241-0701.

8 Sheremetevskiy Ave., Ivanovo 153012


1. Vose J., Armitage J., Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008; 26 (25): 4124–30.

2. Alaggio R., Amador C., Anagnostopoulos I., et al. The 5th edition of the World Health Organization Classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022; 36 (7): 1720–48.

3. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 1997; 89 (11): 3909–18.

4. Cheson B.D., Fisher R.I., Barrington S.F., 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): 3059–3068.

5. Iqbal J., Weisenburger D.D., Greiner T.C., et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010; 115 (5): 1026–36.

6. Amador C., Greiner T.C., Heavican T.B., et al. Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood. 2019; 134 (24): 2159–70.

7. Torshin I.Yu., Gromova O.A., Tetruashvili N.K. Chemotranscriptome analysis of synergism between D-chiroinositol and myoinositol in the context of postgenomic pharmacology. Obstetrics and Gynecology. 2022; 9: 135–45 (in Russ.).

8. Lila A.M., Torshin I.Yu., Gromov A.N., et al. Pharmacoinformation studies of chondroprotectors. Modern Rheumatology Journal. 2021; 15 (5): 114–20 (in Russ.).

9. Gromova O.A., Torshin I.Yu., Sorokin A.I., et al. Chemotranscriptome analysis of the ethylmethylhydroxypyridine succinate molecule in the context of postgenomic pharmacology. Neurology, Neuropsychiatry, Psychosomatics. 2020; 12 (5): 130–7 (in Russ.).

10. Inghirami G., Chan W.C., Pileri S. Peripheral T-cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications. Immunol Rev. 2015; 263 (1): 124–59.

11. Marchi E., O’Connor O.A. The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin. 2020; 70 (1): 47–70.

12. Pizzi M., Margolskee E., Inghirami G. Pathogenesis of peripheral T cell lymphoma. Annu Rev Pathol. 2018; 13: 293–320.

13. Josefowicz S.Z. Regulators of chromatin state and transcription in CD4 T-cell polarization. Immunology. 2013; 139 (3): 299–308.

14. Iqbal J., Wright G., Wang C., et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014; 123 (19): 2915–23.

15. Wang T., Feldman A.L., Wada D.A., et al. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014; 123 (19): 3007–15.

16. Mourad N., Mounier N., Brière J., et al. Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l'Adulte (GELA) Trials. Blood. 2008; 111 (9): 4463–70.

17. Reimer P., Rüdiger T., Geissinger E., et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009; 27 (1): 106–13.

18. Simon A., Peoch M., Casassus P., et al. Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematol. 2010; 151 (2): 159–66.

19. d’Amore F., Relander T., Lauritzsen G.F., et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012; 30 (25): 3093–9.

20. Swerdlow S.H., Campo E., Pileri S.A., et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127 (20): 2375–90.

21. de Leval L., Rickman D.S., Thielen C., et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007; 109 (11): 4952–63.

22. Waitkus M.S., Diplas B.H., Yan H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell. 2018; 34 (2): 186–95.

23. Wang C., McKeithan T.W., Gong Q., et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood. 2015; 126 (15): 1741–52.

24. Odejide O., Weigert O., Lane A.A., et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014; 123 (9): 1293–6.

25. Dan H., Zhang S., Zhou Y., Guan Q. DNA methyltransferase inhibitors: catalysts for antitumour immune responses. Onco Targets Ther. 2019; 12: 10903–16.

26. Feinberg A.P., Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004; 4 (2): 143–53.

27. Yoder J.A., Walsh C.P., Bestor T.H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 1997; 13 (8): 335–40.

28. Akhavan-Niaki H., Samadani A.A. DNA methylation and cancer development: molecular mechanism. Cell Biochem Biophys. 2013; 67 (2): 501–13.

29. Lemonnier F., Dupuis J., Sujobert P., et al. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood. 2018; 132 (21): 2305–9.

30. O’Connor O.A., Falchi L., Lue J.K., et al. Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study. Blood. 2019; 134 (17): 1395–405.

31. Falchi L., Ma H., Klein S., et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. Blood. 2021; 137 (16): 2161–70.

32. Clozel T., Yang S., Elstrom R.L., et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 2013; 3 (9): 1002–19.

33. Martin P., Bartlett N.L., Chavez J.C., et al. Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL. Blood. 2022; 139 (8): 1147–59.

34. Palomero T., Couronné L., Khiabanian H., et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014; 46 (2): 166–70.

35. Abbas H.A., Reville P.K., Jiang X., et al. Response to hypomethylating agents in myelodysplastic syndrome is associated with emergence of novel TCR clonotypes. Front Immunol. 2021; 12: 659625.

36. Ruan J., Moskowitz A.J., Mehta-Shah N., et al. Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma. Blood. 2023; blood.2022018254.

37. Grimm J., Simnica D., Jäkel N., et al. Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients. Blood Cancer J. 2022; 12 (1): 19.

38. Bodo J., Zhao X., Sharma A., et al. The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways. Br J Haematol. 2013; 163 (1): 72–80.

39. Bodo J., Zhao X., Sharma A., et al. The PI3K inhibitor GS-1101 (CAL-101) synergistically potentiates HDAC-induced proliferation inhibition and apoptosis through the activation of JNK in lymphoma cells. Blood. 2012; 120 (21): 3714.

40. Ozaki K.I., Kosugi M., Baba N., et al. Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. Biochem Biophys Res Commun. 2010; 391 (4): 1610–5.

41. Zhou C., Qiu L., Sun Y., et al. Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA’s effect on cell death and migration in human ovarian cancer cells. Int J Oncol. 2006; 29 (1): 269–78.

42. Quan P., Moinfar F., Kufferath I., et al. Effects of targeting endometrial stromal sarcoma cells via histone deacetylase and PI3K/AKT/mTOR signaling. Anticancer Res. 2014; 34 (6): 2883–97.

43. Ferreira A.C., Robaina M.C., Rezende L.M., et al. Histone deacetylase inhibitor prevents cell growth in Burkitt’s lymphoma by regulating PI3K/Akt pathways and leads to upregulation of miR-143, miR-145, and miR-101. Ann Hematol. 2014; 93 (6): 983–93.

44. Yamada T., Horinaka M., Shinnoh M., et al. A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol. 2013; 43 (4): 1080–6.

45. Nguyen T., Dai Y., Attkisson E., et al. HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo. Clin Cancer Res. 2011; 17 (10): 3219–32.

46. Wozniak M.B., Villuendas R., Bischoff J.R., et al. Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma. Haematologica. 2010; 95 (4): 613–21.

47. Bhende P.M., Park S.I., Lim M.S., et al. The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. Leukemia. 2010; 24 (10): 1781–4.

48. Kim A., Park S., Lee J.E., et al. The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells. Leuk Res. 2012; 36 (7): 912–20.

49. Alzahrani A.S. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019; 59: 125–32.

50. Li H., Prever L., Hirsch E., Gulluni F. Targeting PI3K/AKT/mTOR signaling pathway in breast cancer. Cancers (Basel). 2021; 13 (14): 3517.

51. Yoshioka K., Yoshida K., Cui H., et al. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med. 2012; 18 (10): 1560–9.

52. Raiborg C., Schink K.O., Stenmark H. Class III phosphatidylinositol 3-kinase and its catalytic product PtdIns3P in regulation of endocytic membrane traffic. FEBS J. 2013; 280 (12): 2730–42.

53. Reif K., Okkenhaug K., Sasaki T., et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J Immunol. 2004; 173 (4): 2236–40.

54. Soond D.R., Bjørgo E., Moltu K., et al. PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood. 2010; 115 (11): 2203–13.

55. Okkenhaug K., Patton D.T., Bilancio A., et al. The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol. 2006; 177 (8): 5122–8.

56. Furman R.R., Sharman J.P., Coutre S.E., et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014; 370 (11): 997–1007.

57. Balakrishnan K., Peluso M., Fu M., et al. Inhibition of PI3K-δ and -γ isoforms by IPI-145 in chronic lymphocytic leukemia overcomes signals from PI3K/AKT/S6 pathway and promotes apoptosis. Blood. 2013; 122 (21): 4167.

58. Huang X., Proctor J., Yang Y., et al. The potent PI3K-δ,γ inhibitor, IPI-145, exhibits preclinical activity in murine and human T-cell acute lymphoblastic leukemia. Blood. 2013; 122 (21): 1438.

59. Horwitz S.M., Porcu P., Flinn I., et al. Duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Blood. 2014; 124 (21): 803.

60. Flinn I., Oki Y., Patel M., et al. A Phase 1 evaluation of duvelisib (IPI-145), a PI3K-δ,γ inhibitor, in patients with relapsed/refractory iNHL. Blood. 2014; 124 (21): 802.

61. Goy A., Younes A., McLaughlin P., et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005; 23 (4): 667–75.

62. Zinzani P.L., Khuageva N.K., Wang H., et al. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012; 5: 67.

63. Ruan J., Martin P., Furman R.R., et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011; 29 (6): 690–7.

64. Anderson K.C., Alsina M., Bensinger W., et al. Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013. J Natl Compr Canc Netw. 2012; 10 (10): 1211–9.

65. Karin M., Cao Y., Greten F.R., Li Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002; 2 (4): 301–10.

66. Moreau P., Pylypenko H., Grosicki S., et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12 (5): 431–40.

67. Zinzani P.L., Musuraca G., Tani M., et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25 (27): 4293–7.

68. Lee J., Suh C., Kang H.J., et al. Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced, aggressive T-cell or NK/T-cell lymphoma. Ann Oncol. 2008; 19 (12): 2079–83.

69. Kim S.J., Yoon D.H., Kang H.J., et al. Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 trial. Eur J Cancer. 2012; 48 (17): 3223–31.

70. Hatzi K., Melnick A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol Med. 2014; 20 (6): 343–52.

71. Rasheed W., Bishton M., Johnstone R.W., Prince H.M. Histone deacetylase inhibitors in lymphoma and solid malignancies. Expert Rev Anticancer Ther. 2008; 8 (3): 413–32.

72. Coiffier B., Pro B., Prince H.M., et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012; 30 (6): 631–6.

73. Lavrol Clin. Cancer trial results. Horwitz S., Nikitina A., Kotlov N., et al. The combination of duvelisib and romidepsin (DR) is highly active against relapsed/refractory peripheral T-cell lymphoma with low rates of transaminitis: final results and biomarker analysis. 2021. Available at: (accessed 10.02.2023).


For citations:

Sorokina M.А., Rakhteenko A.V., Grishina T.R. New pharmacotherapeutic approaches for the treatment of peripheral T-cell lymphoma. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2023;16(2):291-302. (In Russ.)

Views: 224

ISSN 2070-4909 (Print)
ISSN 2070-4933 (Online)