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

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. 90 Y, 188 Re and 131 I are the most frequently used β - -particles. Of these, 90 Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate 90 Y 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 90 Y-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 90 Y-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.