Myeloablative Radioimmuntherapien zur Konditionierung bei Patienten mit AML, MDS und multiplem Myelom vor Stammzelltransplantation

Zusammenfassung

Die Einführung aggressiver Konsolidierungstherapien und hämopoetischer Stammzelltransplantationen hat die Prognose von Patienten mit akuter myeloischer Leukämie (AML), myelodysplastischem Syndrom (MDS) und mutiplem Myelom verbessert. Nur ein kleiner Teil der Patienten erreicht nach der Stammzelltransplantation jedoch ein dauerhaft krankheitsfreies Überleben. Ursache sind neben Rezidiven auch die therapieassoziierten Toxizitäten und Komplikationen nach der Transplantation. Die myeloablative Radioimmuntherapie setzt radioaktiv markierte, monoklonale Antikörper (mAb) mit Affinität für das hämopoetische Knochenmark ein. Sie erzeugt hohe Strahlendosen im Knochenmark und senkt damit die medulläre Tumorlast. Die normalen Organe werden geschont. Die myeloablative Radioimmuntherapie wird zusätzlich zur konventionellen Konditionierung durchgeführt. Wird eine optimale Nuklid-Antikörper-Kombination gewählt, steigt die akute Toxizität und therapie-abhängige Mortalität nicht signifikant an. Die β-Strahler ⁹⁰Y, ¹⁸⁸Re und ¹³¹I werden am häufigsten eingesetzt, möglich ist jedoch auch ¹⁷⁷Lu. ⁹⁰Y hat einen hohen Kreuzfeuereffekt und sollte daher die Energie homogen ins Zentrum des Knochenmarks transferieren. ¹⁷⁷Lu hat einen geringen Kreuzfeuereffekt und sollte daher nach Bindung an randständige Knochenmarkzellen auch in der Peripherie eine ausreichend hohe Dosis erzeugen können. Beide Nuklide werden idealerweise über rückgratstabilisiertes DTPA an die mAb gekoppelt. Als Antikörper werden Anti-CD66-, -45- und -33-mAb eingesetzt. Der anti-CD66-mAb BW250 / 183 bindet an normale hämopoetische Zellen, aber nicht an leukämische Blasten und Myelomzellen. Er ist optimal für Patienten mit einem Infiltrationsgrad des Knochenmarks durch leukämische Blasten < 25 %. Die spezifischen Dosen (Gy / GBq) sind 10,2 ± 1,8 für das Knochenmark, 2,7 ± 2 (Leber) und < 1 (Nieren). Anti-CD33- und -CD45-Antikörper hingegen binden sowohl an weiße Blutzellen als auch an leukämische Blasten. Dadurch können auch therapierefraktäre und rezidivierte Patienten mit einer hohen medullären Tumorlast oder mit extramedullärer leukämischer Blasteninfiltration behandelt werden. Die spezifischen Dosen (Gy / GBq) für den ⁹⁰Y-anti-CD45-mAb YAML568 sind 6,4 ± 1,2 (Knochenmark), 3,9 ± 1,4 (Leber) und 1,1 ± 0,4 (Nieren). CD45 wird ebenfalls auf der extramedullären klonogenen Myelom-Vorläuferzelle exprimiert, und der anti-CD45-mAb könnte das Therapiespektrum beim multiplen Myelom erweitern. Der Übersichtsartikel gibt einen systematischen und kritischen Überblick über myeloablative Radioimmuntherapien, die aktuell in Konditionierungsschemata eingesetzt werden, und stellt dar, wie optimale Radionuklid- und Antikörperkombinationen individuell gewählt werden können.

Abstract

Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic / antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. ⁹⁰Y, ¹⁸⁸Re and ¹³¹I are the most frequently used β^--particles. Of these, ⁹⁰Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate ⁹⁰Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250 / 183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The ⁹⁰Y-2B3M-DTPA-BW250 / 183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow < 25 %. The specific doses (Gy / GBq) are 10.2 ± 1.8 (bone marrow), 2.7 ± 2 (liver) and < 1 (kidneys). In contrast, radiolabeled anti-CD33- and anti-CD45-antibodies bind to both, most of white blood cells and leukemic blasts. They enable the treatment of leukemia patients with a high medullar tumor load or extramedullar leukemic blast infiltration. Specific doses (Gy / GBq) for the ⁹⁰Y-anti-CD45-mAb YAML568 are 6.4 ± 1.2 (bone marrow), 3.9 ± 1.4 (liver) and 1.1 ± 0.4 (kidneys). CD45 is expressed also on the extramedullar clonogenic myeloma progenitor cell that circulates in the peripheral blood. Thus, the conditioning of patients with multiple myeloma may markedly be improved using a combination of α- and β-anti-CD45-mAbs. This review provides a systematic and critical overview of the currently used radionuclides and antibodies for the treatment of AML, MDS and multiple myeloma and summarizes the present literature on clinical trials of myeloablative radioimmunotherapies for conditioning before both, autologous and allogeneic stem cell transplantation.

myeloablative Radioimmuntherapie - Konditionierung vor Stammzelltransplantation - Anti-CD66-Antikörper - Anti-CD45-Antikörper - Leukämie

myeloablative radioimmunotherapy - conditioning prior to stem cell transplantation - anti-CD66-antibodies - anti-CD45-antibodies - leukaemia

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