CD34-Subpopulations and Clonogenic Progenitors in Mobilized Peripheral Blood Cells from Patients with Acute Myeloid Leukemia

Zusammenfassung

Hintergrund: Der Einsatz von autologen peripheren Blutvorläufer/Stammzellen als Bestandteil der dosisintensivierten Therapieprotokolle für Patienten mit akuter myeloischer Leukämie (AML) ist klinischer Forschungsgegenstand. Methoden: Wir untersuchten den Anteil von CD 34⁺38^– und CD 34⁺DR^– Subpopulationen, klonogenen Vorläuferzellen und koloniebildenden Zellen in der Langzeitkultur (LTC-DC) von peripheren Blutproben von Patienten mit AML nach Chemotherapie und G-CSF, das zur Mobilisierung gegeben wurde. Die Ergebnisse wurden mit denen einer Kontrollpopulation von Patienten mit nicht-hämatologischen malignen Erkrankungen verglichen. Ergebnisse: Wir beobachteten eine geringere Anzahl an CD 34⁺ Zellen (31.2 ± 14.8 vs. 114 ± 36/?l) und eine Reduktion auf weniger als 15 % klonogene Vorläuferzellen (CFU) und LTC-DC unter den mononukleären Zellen des peripheren Bluts von Patienten mit AML nach Konsolidierungstherapie. Im Gegensatz dazu war die Qualität der CD34⁺ Zellen im Vergleich zur Kontrollpopulation mit einem moderat reduzierten Anteil an CFU/CD34⁺ Zellen (5.0 ± 5 % vs. 10.0 ± 2.8 %), einer fast identischen Häufigkeit von LTC-DC/CD34⁺ Zellen (0.5+0.1% vs. 0.6+0.2%), und einem höheren Anteil von CD34⁺38^– Zellen/CD34⁺ Zellen (8.4+1.8 % vs. 3,8+1.1 %) nicht signifikant vermindert. Zusammenfassung: Diese Daten bestätigen, dass es möglich ist mittels Chemotherapie und G-CSF, CD34⁺ Zellen in das periphere Blut von AML Patienten zu mobilisieren. Allerdings sollte die geringe absolute Anzahl an CFU und LTC-DC nach Behandlung mit hochdosiertem Ara-C bei der Planung zukünftiger Behandlungsprotokolle Berücksichtigung finden.

Abstract

Background: The use of autologous peripheral blood progenitor/stem cells as part of dose-intensified treatment protocols for patients with acute myeloid leukemia (AML) is under current clinical investigation. Methods: We analyzed the frequency of CD 34⁺ 38^– and CD 34⁺DR^– subpopulations, clonogenic cells and long-term culture-derived clonogenic cells (LTC-DC) in peripheral blood (PB) samples from patients with AML after chemotherapy and G-CSF given for mobilization in comparison to a control population of patients with non-hematological malignancies. Results: We observed a lower number of CD 34⁺ cells (31.2 ± 14.8 vs. 114 ± 36 /µl) and a reduction to less than 15 % for clonogenic progenitors (CFU) and LTC-DC in peripheral blood mononuclear cells from AML patients after consolidation therapy. In contrast, the quality of these CD 34⁺ cells was not significantly impaired after consolidation therapy determined by a moderately reduced frequency of CFU/CD34⁺ cells (5.0 ± 1.5 % vs. 10.0 ± 2.8 %), a nearly identical frequency of LTC-DC/CD34⁺ cells (0.5 ± 0.1 % vs. 0.6 ± 0.2 %), and a higher percentage of CD 34⁺38^– cells/CD34⁺ cells (8.4 ± 1.8 % vs. 3.8 ± 1.1 %) in comparison to the control population. Conclusion: Our data confirm that it is possible to mobilize CD 34⁺ cells into the peripheral blood of AML patients using chemotherapy and G-CSF. Nevertheless, the low absolute number of CFU and LTC-DC after high-dose ara-C treatment for AML has to be taken into consideration for the design of treatment protocols using autologous progenitor/stem cell transplantation.

Schlüsselwörter

myeloische Leukämie - Akute myeloische Leukämie - Stammzellen - Konsolidationstherapie - G-CSF

Key words

Acute myeloid leukemia - stem cells - consolidation therapy - G-CSF

References

• 1 Büchner T. Treatment of adult acute leukemia.  Curr Opin Oncol. 1997;  9 18-25
• 2 Mayer R J, Davis R B, Schiffer C A et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B.  N Engl J Med. 1994;  331 896-903
• 3 Burnett A K, Goldstone A H, Stevens R M et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children’s Leukaemia Working Parties.  Lancet. 1998;  351 700-708
• 4 Cahn J Y, Labopin M, Mandelli F et al. Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group.  Blood. 1995;  85 575-579
• 5 Cassileth P A, Harrington D P, Appelbaum F R et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission.  N Engl J Med. 1998;  339 1649-1656
• 6 Zittoun R A, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups.  N Engl J Med. 1995;  332 217-223
• 7 Harousseau J L, Cahn J Y, Pignon B et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM).  Blood. 1997;  90 2978-2986
• 8 Tsimberidou A M, Stavroyianni N, Viniou N et al. Comparison of allogeneis stem cell transplantation, high-dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de novo acute myelogenous leukemia.  Cancer. 2003;  97 1721-1731
• 9 Buchner T, Berdel W E, Schoch C et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia.  J Clin Oncol. 2006;  24 2480-2489
• 10 Suciiu S, Mandelli F, Witte de T et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeliod leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEAAML-10 trial.  Blood. 2003;  102 1232-1240
• 11 To L B, Haylock D N, Simmons P J et al. The biology and clinical uses of blood stem cells. The biology and clinical use of blood stem cells.  Blood. 1997;  89 2233-2258
• 12 Schlenk R F, Dohner H, Pforsich M et al. Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone.  Br J Haematol. 1997;  99 386-393
• 13 To L B, Haylock D N, Dyson P G et al. An unusual pattern of hemopoietic reconstitution in patients with acute myeloid leukemia transplanted with autologous recovery phase peripheral blood.  Bone Marrow Transplant. 1990;  6 109-114
• 14 Roberts M M, Dyson P G, Willson K et al. Peripheral blood stem cells mobilized from patients with acute myeloid leukaemia have different platelet repopulating abilities compared with those mobilized from patients with other diseases.  Bone Marrow Transplant. 1996;  18 41-45
• 15 Bennett J M, Catovsky D, Daniel M T et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group.  Ann Intern Med. 1985;  103 620-625
• 16 Buchner T, Hiddemann W, Wörmann B et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine. A randomized trial by the German AML Cooperative Group.  Blood. 1999;  93 4116-4124
• 17 Rothe G, Schmitz G. Consensus protocol for the flow cytometric immunophenotyping of hematopoietic malignancies. Working Group on Flow Cytometry and Image Analysis.  Leukemia. 1996;  10 877-895
• 18 Moore M AS, Shapiro F. Regulation and function of hematopoietic stem cells.  Curr Opinion Hematol. 1994;  1 180-186
• 19 Blair A, Hogge D E, Sutherland H J. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD 34(+ )/CD71(-)/HLA-DR-.  Blood. 1998;  92 4325-4335
• 20 Lapidot T, Sirard C, Vormoor J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.  Nature. 1994;  367 645-648
• 21 Schiller G, Lee M, Paquette R et al. Transplantation of autologous peripheral blood progenitor cells procured after high-dose cytarabine-based consolidation chemotherapy for adults with secondary acute myelogenous leukemia in first remission.  Leuk Lymphoma. 1999;  33 475-484
• 22 Vellenga E, Putten W L, Boogaerts M A et al. Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia?.  Bone Marrow Transplant. 1999;  23 1279-1282
• 23 Brenner M K, Rill D R, Moen R C et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation.  Lancet. 1993;  341 85-86
• 24 Chang van J, Geary C G, Testa N G. Long-term bone marrow damage after chemotherapy for acute myeloid leukaemia does not improve with time.  Br J Haematol. 1990;  75 68-72
• 25 Kasper C, Ryder W D, Durig J et al. Content of long-term culture-initiating cells, clonogenic progenitors and CD 34 cells in apheresis harvests of normal donors for allogeneic transplantation, and in patients with acute myeloid leukaemia or multiple myeloma.  Br J Haematol. 1999;  104 374-381
• 26 Bhatia M, Bonnet D, Murdoch B et al. A newly discovered class of human hematopoietic cells with SCID- repopulating activity.  Nat Med. 1998;  4 1038-1045
• 27 Gallacher L, Murdoch B, Wu D M et al. Isolation and characterization of human CD 34-Lin- and C 34 + Lin- hematopoietic stem cells using cell surface markers AC 133 and CD 7.  Blood. 2000;  95 2813-2820
• 28 To L B, Haylock D N, Dowse T et al. A comparative study of the phenotype and proliferative capacity of peripheral blood (PB) CD 34 + cells mobilized by four different protocols and those of steady-phase PB and bone marrow CD 34 + cells.  Blood. 1994;  84 2930-2939
• 29 Terstappen L W, Huang S, Safford M et al. Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD 34 + CD38- progenitor cells.  Blood. 1991;  77 1218-1227
• 30 Sutherland H J, Eaves C J, Lansdorp P M et al. Kinetics of committed and primitive blood progenitor mobilization after chemotherapy and growth factor treatment and their use in autotransplants.  Blood. 1994;  83 3808-3814