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-2B3 M-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.

Schlüsselwörter

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

Key words

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

Literatur

• 1 Harris N L, Jaffe E S, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.  J Clin Oncol. 1999;  17 3835-3849
• 2 Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow S I. The growth fraction of human myeloma cells.  Blood. 1981;  57 333-338
• 3 Hamburger A, Salmon S E. Primary bioassay of human myeloma stem cells.  J Clin Invest. 1997;  60 846-854
• 4 Eppstein J. Myeloma stem cell phenotype: Implications for treatment.  Hematol Oncol Clin North Am. 1997;  11 43-49
• 5 Berenson J R, Vescio R A, Said J. Multiple Myeloma: The cells of origin – a two-way street.  Leukemia. 1998;  12 121-127
• 6 Matsui W, Huff C A, Wang Q et al. Characterization of clonogenic multiple myeloma cells.  Blood. 2004;  103 2332-2336
• 7 Pilarski L M, Hipperson G, Seeberger K, Pruski E, Coupland R W, Belch A R. Myeloma progenitors in the blood of patients with aggressive or minimal disease: Engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice.  Blood. 2000;  95 1056-1065
• 8 Attal M, Harousseau J L, Facon T et al. Single versus double autologous stem-cell transplantation for multiple myeloma.  N Engl J Med. 2003;  349 2495-2502
• 9 Barlogie B, Jagannath S, Desikan K R et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma.  Blood. 1999;  93 55-65
• 10 Clift R A, Buckner C D, Appelbaum F R et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimen.  Blood. 1990;  76 1867-1871
• 11 Santos G W, Tutschka P J, Brookmeyer R et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and and cyclophosphamide regimen.  N Engl J Med. 1983;  309 1347-1353
• 12 Copelan E A. Hematopoietic stem cell transplantation.  New Engl J. 2006;  354 1813-1826
• 13 Hill G R, Crawford J M, Cooke K R et al. Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines.  Blood. 1997;  8 3204-3213
• 14 Holler E, Kolb H J, Mittermüller J et al. Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor α (TNFα) release in the course of pretransplant conditioning: Role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNFα (MAK 195F).  Blood. 1995;  86 890-899
• 15 Levine J E, Uberti J P, Ayash L et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignany.  Biol Blood Marrow Transplant. 2003;  9 189-197
• 16 Boiron J M, Lerner D, Pigneux A et al. Allogeneic transplantation for patients with advanced acute leukemia: A single center retrospective study of 92 patients.  Leuk Lymphoma. 2001;  41 285-296
• 17 Newland A. Progress in the treatment of acute myeloid leukaemia in adults.  Int J Hematol. 2002;  76 (suppl) 253-258
• 18 Witherspoon R P, Deeg H J, Storer B et al. Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.  J Clin Oncol. 2001;  19 2134-2141
• 19 Zhu Z, Ghose T, Iles S, Yang C, Lee S H, Fernandez L A, Lee C L. Pharmacokinetics, biodistribution and tumor localization of two anti-human B-cell chronic lymphocytic leukemia monoclonal antibodies and their F(ab)′2 fragments in a xenograft model.  Cancer Lett. 1994;  76 31-44
• 20 Richman C M, Denardo S J, O'Donnell R T et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111 / yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.  Clin Cancer Res. 2005;  11 5920-5927
• 21 Behr M, Griesinger F, Riggert J et al. High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study.  Cancer. 2002;  94 (4 suppl) 1363-1372
• 22 Nademanee A, Forman S, Molina A, Fung H, Smith D, Kwok C, Yamauchi D. A phase 1 / 2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma.  Blood. 2005;  106 2896-2902
• 23 Matthews D C, Appelbaum F R, Eary J F et al. Development of a marrow transplantation regimen for acute leukemia using targeted hematopoietic irradiation delivered by I-131-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation.  Blood. 1995;  85 1122-1131
• 24 Bunjes D, Buchmann I, Duncker C et al. Re-188-labeled anti-CD 66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukaemia or myelodysplastic syndrome: results of a phase I–II study.  Blood. 2001;  98 565-572
• 25 Buchmann I, Bunjes D, Kotzerke J et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-Antibody for conditioning of high-risk leukemia patients prior to stem cell transplantation.  Cancer Biother & Radiopharm. 2002;  17 151-163
• 26 Bunjes D. Re-188-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia.  Leukemia & Lymphoma. 2002;  43 2125-2131
• 27 Loevinger R, Berman M A. A revised schema for calculating the absorbed dose from biologically distributed radionuclides. Society of Nuclear Medicine, New York 1976; MIRD Pamphlet No. 1
• 28 Wessels B W, Bolch W E, Bouchet L G et al. Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: A multiinstitutional comparison.  J Nucl Med. 2004;  45 1725-1733
• 29 Mulford D A, Scheinberg D A, Jurcic J G. The promise of targeted [alpha]-particle therapy.  J Nucl Med. 2005;  46 (Suppl 1) 199-204
• 30 Jurcic J G. Antibody therapy for residual disease in acute myelogenous leukemia.  Crit Rev Oncol Hematol. 2001;  38 37-45
• 31 Buchegger F, Perillo-Adamer F, Dupertuis Y M, Delaloye A B. Auger radiation targeted into DNA: A therapy perspective.  Eur J Nucl Med Mol Imaging. 2006;  33 1352-1363
• 32 Quadri S M, Mohammadpour H. Synthesis of 2-p-aminobenzyl-3-methy and 2 aminobenzyl-3-benzyl derivatives of diethylenetriaminepentaacetic acid (DTPA): Carbon backbone modified bifunctional chelating agents.  Bio-organic and Medicinal Chemistry Letters. 1992;  2 1661-1664
• 33 Jowsey J, Rowland R E, Marshall J H. The deposition of the rare earths in bone.  Radiation Res. 1958;  8 490-501
• 34 Shih L B, Thorpe S R, Griffiths G L et al. The processing and fate of antibodies and their radiolabels bound to the surface of tumor cells in vitro: A comparison of nine radiolabels.  J Nucl Med. 1994;  35 899-908
• 35 Buchholz H G, Herzog H, Forster G J et al. PET imaging with yttrium-86: Comparisons of phantom measurements acquired with different PET scanners before and after applying background subtraction.  Eur J Nucl Med Mol Imaging. 2003;  30 716-720
• 36 Lovqvist A, Humm J L, Sheikh A et al. PET imaging of (⁸⁶)Y-labeled anti-Lewis Y monoclonal antibodies in a nude mouse model: Comparison between (⁸⁶)yttrium and (¹¹¹)In radiolabels.  J Nucl Med. 2001;  42 1281-1287
• 37 Kotzerke J, Fenchel S, Guhlmann A et al. Pharmacokinetics of ⁹⁹Tcm-pertechnetate and ¹⁸⁸Re-perrhenate after oral administration of perchlorate: option for subsequent care after the use of liquid ¹⁸⁸Re in a balloon catheter.  Nucl Med Comm. 1998;  19 795-801
• 38 Zenz T, Schlenk R F, Blumstein N et al. Bone marrow transplantation nephropathy after an intensified conditioning regimen with radioimmunotherapy and allogeneic stem cell transplantation.  J Nucl Med. 2006;  47 278-286
• 39 Caron P C, Co M S, Bull M K et al. Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies.  Cancer Res. 1992;  52 6761-6767
• 40 Caron P C, Jurcic J G, Scott A M et al. A phase 1 B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: Specific targeting without immunogenicity.  Blood. 1994;  83 1760-1768
• 41 Scheinberg D A, Tanimoto M, McKenzie S et al. Monoclonal antibodyM195: A diagnostic marker for acute myelogenous leukemia.  Leukemia. 1989;  3 440-445
• 42 Schwartz M A, Lovett D R, Redner A et al. Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias.  J Clin Oncol. 1993;  11 294-303
• 43 Sgouros G, Ballangrud A M, Jurcic J G et al. Pharmacokinetics and dosimetry of an alpha-particle emitter labeled antibody: Bi-213-HuM195 (anti-CD33) in patients with leukemia.  J Nucl Med. 1999;  40 1935-1946
• 44 Matthews D C. Immunotherapy in acute myelogenous leukemia and myelodysplastic syndrome.  Leukemia. 1998;  12 (suppl) 33-36
• 45 Buchmann I, Kull T, Glatting G et al. A comparison of biodistribution and biokinetics of ⁹⁹mTc-anti-CD66-mAb BW250 / 183 and ⁹⁹mTc-anti-CD45-mAb YTH24.5 with regard to suitability for myeloablative radioimmunotherapy.  Eur J Nucl Med Mol Imaging. 2003;  30 667-673
• 46 Glatting G, Müller M, Koop B et al. Anti-CD45 monoclonal antibody YAML568: A promising radioimmunoconjugate for targeted radioimmunotherapy for acute leukemia.  J Nucl Med. 2006;  47 1335-1341
• 47 Jurcic J G, Caron P C, Nikula T K et al. Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias.  Cancer Res. 1995;  55 (suppl) 5908-5910
• 48 Jurcic J G, Larson S M, Sgouros G et al. Targeted α-particle immunotherapy for myeloid leukemia.  Blood. 2002;  100 1233-1239
• 49 Matthews D C, Appelbaum F R, Eary J F et al. Phase I study of I-131-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.  Blood. 1999;  94 1237-1247
• 50 Buchmann I, Mutschler J, Steinbach G et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-mAb before stem cell transplantation does not increase cytokine levels [abstract].  J Nucl Med. 2002;  43 (suppl) 314P
• 51 Buchmann I, Schulz A, Sparber M et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-mAb in paediatric leukaemia patients: A phase I-trial [abstract].  J Nucl Med. 2002;  43 (suppl) 37P
• 52 Ringhoffer M, Blumstein N, Neumaier B et al. ¹⁸⁸Re- or ⁹⁰Y-labeled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukemia or myelodysplastic syndrome over the age of 55: results of a phase I–II study.  Brit J Haematol. 2005;  130 604-613
• 53 Orchard K H, Cooper M, Lewington V et al. Targeted radiotherapy in haematopoietic stem cell transplantation: Results of a phase I trial using a yttrium-90 labelled anti-CD66 murine monoclonal antibody demonstrating consistent BM targeting [abstract].  Bone Marrow Transplantation. 2006;  37 p45 , O338