Advances in the targeted therapy of lymphoma

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The therapeutic landscape for lymphoma diseases has changed considerably in recent years due to our progress in understanding their pathogenesis. A major advantage has been to reduce the need for chemotherapy and to be able to use new types of targeted therapies alone or in combination. In this article we report in particular on BCL2 inhibition and its resistance mechanisms, as well as the role of the MYD88 mutation as well as the CXCR4 mutation in Waldenström’s disease.

With the BTK inhibitor ibrutinib, the BCL2 inhibitor venetoclax and the PI3Kdelta inhibitor idelalisib, three targeted drugs are now available for patients with lymphoma diseases. Chronic lymphocytic leukemia (CLL) in particular is a pioneer disease for the use of these therapies. With this condition, new points of attack for lymphoma therapies were discovered before they were applied to other pathological entities. Several studies have shown the significant advantage of targeted therapies in combination with a CD20 antibody, as a triple combination with chemotherapy or as a monotherapy (RESONATE-1, HELIOS, Murano study), compared to conventional salvage therapy, particularly in the case of progression, refractoriness or early relapse. Patients with evidence of a del(17)(p13) as well as a TP53 mutation benefit almost to the same extent as patients without this risk factor. The same applies to patients with an unmutated IGHV status or evidence of a complex karyotype. Such subgroup analyses in particular have revealed the relevance of genetic examinations already at the initial diagnosis. On the basis of these results, conventional immunochemotherapy is now only considered in first-line CLL therapy for patients without these risk factors (Onkopedia guideline CLL 2020). For first-line therapy, the second generation inhibitor of Bruton’s tyrosine kinase (BTK) acalabrutinib was approved by the European Medicines Agency (EMA) in the summer of 2020 as another potent oral therapy (ELEVATE-TN study). As is already known from tyrosine kinases, specific resistance mutations (in BTK, PLCG2 or BCL2) can appear after therapy with BTK or BCL2 inhibitors, the presence of which makes the continuation of the corresponding therapy seem almost pointless. For these issues, the MLL offers genetic examinations as well as mutation and resistance tests to better assess any continuation of therapy.

The MYD88L265P mutation plays an important role in lymphoplasmocytic lymphoma. It is found in 90% of patients with this pathological entity. The simultaneous presence of a CXCR4 mutation results in a poorer response to BTK inhibitors, which is why both mutations should be determined before starting any therapy (Treon S.P., Tripsas C.K., Meid K. et al.: Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. (2015) 372(15): 1430–1440). Furthermore, the combination of both mutations encourages interleukin-1 receptor-associated kinases (IRAK) and BTKs to activate oncogenic factors during the development of malignant lymphomas.

In summary, targeted drugs have become indispensable in the therapeutic landscape for lymphoma diseases. The BTK inhibitor ibrutinib is already approved for refractory and relapsed mantle cell lymphoma (MCL) and the Pl3Kdelta inhibitor idelalisib is approved for refractory follicular lymphoma. It is to be expected that, in the future, targeted therapeutic approaches will accompany or completely replace conventional chemotherapies even with other lymphomas.