Chronische lymphatische Leukämie

Was ist neu?

• Diagnostik: Die Diagnose wird aus einer durchflusszytometrischen Analyse des peripheren Blutes gestellt, eine diagnostische Knochenmarkpunktion ist nicht notwendig. Vor Therapiebeginn muss eine 17p-Deletion oder eine TP53-Mutation mittels Interphase-FISH bzw. Mutationsanalyse ausgeschlossen werden.

• Erstlinien-Therapie: Für fitte Patienten sind die Chemoimmuntherapien FCR (Fludarabin, Cyclophosphamid, Rituximab) und BR (Rituximab, Bendamustin) als Erstlinienstandard etabliert. Bei weniger fitten Patienten sollte eine Kombination eines monoklonalen anti-CD20-Antikörpers mit Chlorambucil erwogen werden. Bei 17p-Deletion oder TP53-Mutation können Chemoimmuntherapien oder Alemtuzumab-haltige Therapien als kurzfristige Tumorreduktion in Vorbereitung einer allogenen Transplantation eingesetzt werden. Zusätzlich gibt es für diese Patienten neue, gezielt wirkende Kinaseinhibitoren wie Ibrutinib und Idelalisib in der Erstlinientherapie.

• Zweitlinientherapie: Auch in der Rezidivtherapie zeigen Ibrutinib und Idelalisib Erfolge. Neue zielgerichtete Apoptoseinduktoren wie ABT-199 erreichen auch bei Hochrisikopatienten hohe Ansprechraten.

Abstract

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient‘s physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton‘s tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT-199. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.

Schlüsselwörter

Immunochemotherapie - zielgerichtete Therapie - TP53-Mutation

Keywords

immunochemotherapy - targeted treatment - TP53 mutation

• Literatur

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