Molekular zielgerichtete Therapien – brauchen wir überhaupt noch Chemotherapie?

Fortschritte im Verständnis der Biologie maligner Lymphome haben die Entwicklung zahlreicher molekular zielgerichteter Therapien ermöglicht. So kann die chronische lymphatische Leukämie heutzutage fast vollständig chemotherapiefrei behandelt werden. Doch wie sieht diese Entwicklung bei anderen Lymphomen aus? Im vorliegenden Artikel wollen wir eine Übersicht über molekular zielgerichtete Therapieansätze bei malignen B- und T-Zell-Lymphomen geben.

Abstract

Advances in the understanding of the biology of malignant lymphoma has facilitated the development of numerous molecularly targeted therapies. The incorporation of these precision therapeutics has produced more effective and often less-toxic treatment regimens leading to a significant improvement of treatment outcomes for individuals with lymphoid malignancies.

In relapsed diseases, molecularly targeted therapeutic approaches have demonstrated superior outcomes compared to conventional chemotherapy, leading to a growing number of patients being treated entirely chemotherapy-free. This review outlines the current landscape of targeted therapies for both B-cell (B-NHL) and T-cell non-Hodgkin lymphomas (T-NHL) and provides an overview of targeted agents currently approved for the treatment of malignant lymphoma.

Kernaussagen

• Die Einführung molekular zielgerichteter Substanzen hat zu einer signifikanten Verbesserung der Therapieergebnisse für Patienten mit malignen Lymphomen geführt.

• In der Erstlinie bleibt die Immunochemotherapie für die Mehrzahl der Patienten der Standard.

• In der Rezidivsituation werden immer mehr Patienten vollständig chemotherapiefrei behandelt.

• Ideale Kombinationspartner und Therapieabfolgen müssen für viele der neuen Substanzen in Studien erst noch definiert werden.

• Bei T- und NK-Zell-Lymphomen besteht ein großer Forschungs- und Entwicklungsbedarf, um die bisher unbefriedigenden Therapieergebnisse für diese Patienten zu verbessern.

Schlüsselwörter

Therapie - zielgerichtet - Lymphome - Non-Hodgkin-Lymphom - Hodgkin-Lymphome

Keywords

therapy - targeted - lymphoma - Non-Hodgkin-lymphoma - Hodgkin-lymphoma

Publication History

Article published online:
15 May 2024

• Literatur

• 1 Minson A, Tam C, Dickinson M. et al. Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas. Cancers (Basel) 2022; 14: 1276 DOI: 10.3390/cancers14051276. (PMID: 35267584)
• 2 Gill S, Vides V, Frey NV. et al. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv 2022; 6: 5774-5785 DOI: 10.1182/bloodadvances.2022007317.
• 3 Tam CS, Opat S, D’Sa S. et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020; 136: 2038-2050 DOI: 10.1182/blood.2020006844. (PMID: 32731259)
• 4 Byrd JC, Hillmen P, Ghia P. et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol 2021; 39: 3441-3452 DOI: 10.1200/JCO.21.01210. (PMID: 34310172)
• 5 Fruman DA, Chiu H, Hopkins BD. et al. The PI3K Pathway in Human Disease. Cell 2017; 170: 605-635 DOI: 10.1016/j.cell.2017.07.029. (PMID: 28802037)
• 6 Xu W, Berning P, Lenz G. Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma. Blood 2021; 138: 1110-1119 DOI: 10.1182/blood.2020006784. (PMID: 34320160)
• 7 Johnston PB, Pinter-Brown LC, Warsi G. et al. Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma. Exp Hematol Oncol 2018; 7: 12 DOI: 10.1186/s40164-018-0103-z. (PMID: 29774169)
• 8 Rule S, Jurczak W, Jerkeman M. et al. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia 2018; 32: 1799-1803 DOI: 10.1038/s41375-018-0023-2.
• 9 Hess G, Herbrecht R, Romaguera J. et al. Phase III Study to Evaluate Temsirolimus Compared With Investigator’s Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma. JCO 2009; 27: 3822-3829 DOI: 10.1200/JCO.2008.20.7977.
• 10 Wang M. Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. ASH. 2023 Accessed March 10, 2024 at: https://ash.confex.com/ash/2023/webprogram/Paper191921.html
• 11 Robak T, Jin J, Pylypenko H. et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. The Lancet Oncology 2018; 19: 1449-1458 DOI: 10.1016/S1470-2045(18)30685-5.
• 12 Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood 2015; 126: 2366-2369 DOI: 10.1182/blood-2015-07-567958. (PMID: 26438514)
• 13 Morschhauser F, Fowler NH, Feugier P. et al. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med 2018; 379: 934-947 DOI: 10.1056/NEJMoa1805104. (PMID: 30184451)
• 14 Morin RD, Mendez-Lago M, Mungall AJ. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011; 476: 298-303 DOI: 10.1038/nature10351. (PMID: 21796119)
• 15 Pastore A, Jurinovic V, Kridel R. et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. The Lancet Oncology 2015; 16: 1111-1122 DOI: 10.1016/S1470-2045(15)00169-2. (PMID: 26256760)
• 16 Béguelin W, Popovic R, Teater M. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013; 23: 677-692 DOI: 10.1016/j.ccr.2013.04.011. (PMID: 23680150)
• 17 Morschhauser F, Tilly H, Chaidos A. et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 2020; 21: 1433-1442 DOI: 10.1016/S1470-2045(20)30441-1. (PMID: 33035457)
• 18 Nachmias B, Schimmer AD. Targeting nuclear import and export in hematological malignancies. Leukemia 2020; 34: 2875-2886 DOI: 10.1038/s41375-020-0958-y. (PMID: 32624581)
• 19 Kalakonda N, Maerevoet M, Cavallo F. et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 2020; 7: e511-e522 DOI: 10.1016/S2352-3026(20)30120-4. (PMID: 32589977)
• 20 Marcus R, Davies A, Ando K. et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. New England Journal of Medicine 2017; 377: 1331-1344 DOI: 10.1056/NEJMoa1614598. (PMID: 28976863)
• 21 Herrera AF, LeBlanc ML, Castellino SM. et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). JCO 2023; 41: LBA4-LBA4 DOI: 10.1200/JCO.2023.41.17_suppl.LBA4.
• 22 Cheson BD, Bartlett NL, LaPlant B. et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2020; 7: e808-e815 DOI: 10.1016/S2352-3026(20)30275-1. (PMID: 33010817)
• 23 Stuver R, Moskowitz AJ. Therapeutic Advances in Relapsed and Refractory Peripheral T-Cell Lymphoma. Cancers (Basel) 2023; 15: 589 DOI: 10.3390/cancers15030589. (PMID: 36765544)
• 24 Mehta-Shah N, Jacobsen E, Luigi Zinzani P. et al. P1124: DUVELISIB IN PATIENTS WITH RELAPSED/REFRACTORY PERIPHERAL T-CELL LYMPHOMA FROM THE PHASE 2 PRIMO TRIAL EXPANSION PHASE: OUTCOMES BY BASELINE HISTOLOGY. Hemasphere 2023; 7: e3891642 DOI: 10.1097/01.HS9.0000971392.38916.42.
• 25 Ruan J, Moskowitz A, Mehta-Shah N. et al. Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL. Blood 2023; 141: 2194-2205 DOI: 10.1182/blood.2022018254. (PMID: 36796016)