Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33+ AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3,3’-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
Summary:We describe collection and purification of peripheral blood CD34 ؉ cells from volunteer, normal donors and allogeneic stem cell donors. A total of 98 aphereses were performed on 68 volunteer donors using peripheral venous access. The mean number of nucleated cells collected was 4.6 × 10 10 which included 1.9 × 10 8 CD34 ؉ cells corresponding to 2.7 × ilized PBPCs are now being used in related and unrelated allogeneic transplantation. Apheresis collection is well tolerated and is potentially less invasive than bone marrow harvest. Recently, attention has focused on the number of CD34 + cells in the PBPCs as the component responsible for the time to recovery after intensive chemotherapy and the cells likely responsible for long-term engraftment and reconstitution of hematopoiesis. 9-15 Therefore, an enriched population of CD34 + cells may be a superior donor product. In addition, isolation of CD34 + cells may decrease contaminating tumor cells, 16,17 deplete mature T cells for modulation of graft-versus-host disease [18][19][20] and provide the target of choice for both ex vivo expansion 21,22 and gene transfer. [23][24][25][26] Antibodies directed against the CD34 antigen have provided a means for rapidly purifying and concentrating CD34 + cells using immunomagnetic techniques. 27,28 Although apheresis devices have been shown to be effective for collecting large numbers of nucleated white blood cells, the number of CD34 + cells collected is highly variable depending on factors such as the individual's response to cytokine and the number of blood volumes processed. 29,30 Reliable predictors of CD34 + cell purity, recovery, and clonogenic potential are currently needed and would be advantageous in planning efficient use of growth factor during mobilization and minimizing procedural discomfort to the donor.Although there is a large experience with apheresis from patients on cytotoxic therapeutic regimens, limited data are available from normal volunteers on the safety, efficacy and ability to collect purified CD34 + cells. We present the results of a large series of aphereses (n = 98) and CD34 + cell isolations using the Isolex 300i magnetic separator (n = 30) on G-CSF-mobilized PBPCs from normal volunteers. Adverse events, absolute numbers of cells collected, and CD34 + cell purification are presented. In addition, we present results from 38 CD34 + cell isolations using the Isolex 300i performed on normal allogeneic stem cell donors. These data provide further evidence for the safety and feasibility of collecting adequate numbers of CD34 + cells from the peripheral blood of normal donors for stem cell support, transplantation and gene therapy.
Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 antigens, but their less mature precursors, detected by their ability to give rise to CFC in LTC, express only CD34. In three of the four patients with AML, the CD33- CD34+ cells produced CFC in LTC that appeared to be predominantly or completely normal (ie, nonclonal) in origin. In the fourth patient, a significant enrichment of nonclonal progenitors was obtained in the CD33-CD34+ population, but these cells may also have included significant numbers of clonal cells. In contrast, in four of five patients with CML, cultures of both the CD33-CD34+ and CD33+CD34+ populations produced CFC in LTC that were almost entirely clonal in origin, whereas in the fifth patient a substantial number originated from nonclonal stem cells. These data indicate that granulocyte/monocyte progenitors are predominantly clonally derived in CML and AML. In CML, their precursors are also predominantly clonal, but in some cases of AML they are not. These findings may have implications for understanding the success or failure of current therapies of AML and CML.
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