Chemotherapie-freie Behandlung der chronischen lymphatischen Leukämie?

Zusammenfassung

Die Behandlung von CLL-Patienten mit konventionellen Zytostatika ist oft mit signifikanten Nebenwirkungen verbunden, die die breite Anwendung insbesondere bei älteren Patienten verhindert. Zusätzlich muss häufig mit Rezidiven der CLL nach zytostatischer Behandlung gerechnet werden. Kürzlich wurden mehrere Chemotherapie-freie Behandlungsoptionen innerhalb klinischer Studien verfügbar. Hierzu zählen u. a. monoklonale Antikörper, wobei die meisten das CD20-Molekül als Zielstruktur haben: Neben den bereits zugelassenen Substanzen Rituximab und Ofatumumab hat Obinutuzumab, allerdings in Kombination mit Chemotherapie, hohe klinische Aktivität in der Erstlinienbehandlung von älteren Patienten mit CLL gezeigt. Lenalidomid als Monotherapie zeigte klinische Effektivität bei Patienten mit rezidivierter CLL, und erste Daten wurden innerhalb von klinischen Studien auch für die Erstlinientherapie entwickelt. Eine vielversprechende Gruppe neuer Substanzen wurde entwickelt, die die aberrante Signalkaskade ausgehend vom B-Zell-Rezeptors blockiert: Ibrutinib inhibiert die Bruton’s Tyrosinkinase (BTK) während Idelalisib ein spezifischer Inhibitor der Phosphoinositol-3-Kinase (PI3K) Delta-Untereinheit ist. Eine andere Klasse von Substanzen mit Potenz für Chemotherapie-freie Behandlungsstrategien bei der CLL bilden die BH3-Mimetika mit inhibitorischer Wirkung auf die Bcl-2-Familie der pro-apoptotischen Proteine. Andere interessante Kandidaten, die derzeit für CLL Patienten untersucht werden, beinhalten kleine modulare immunpharmazeutische Proteine (SMIP) (z. B. TRU-016), CDK-Inhibitoren (z. B. Dinaciclib), HDAC-Inhibitoren und andere. Angesichts dieser zahlreichen neuen Substanzen und Zielstrukturen sollten Chemotherapie-freie, zumindest jedoch Chemotherapie-reduzierte Behandlungskonzepte bei CLL in naher Zukunft Realität werden.

Abstract

Treatment of CLL patients with conventional cytotoxic agents is often combined with significant toxicity that prevents broad application especially in elderly patients. In addition, relapse frequently occurs after application of conventional chemotherapy in CLL. 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, although in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Lenalidomide as monotherapy has demonstrated clinical efficacy in patients with relapsed disease and first data within clinical trials have been generated in the front-line setting. A promising class of novel agents has 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 are the BH3-mimetic inhibitors of the Bcl-2 family of pro-survival proteins. Other interesting candidate drugs that are currently explored for CLL patients include small modular immunopharmaceutical (SMIP) proteins (e. g. TRU-016), CDK inhibitors (e. g. dinaciclib), HDAC inhibitors and others. 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

chronische lymphatische Leukämie - CLL - Anti-CD20-Antikörper - Rituximab - Lenalidomid - zielgerichtete Therapie

Keywords

chronic lymphocytic leukemia - CLL - CD20 antibodies - rituximab - lenalidomide - targeted drugs

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