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University of Rochester Medical Center, Rochester, New York, USA
Correspondence:
Marshall A. Lichtman, M.D., Professor of Medicine, Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Avenue, Box 610, Rochester, New York 14642, USA. Telephone: 716-275-2205; Fax: 716-271-1876; e-mail: mal{at}urmc.rochester.edu
The initiation of effective chemotherapy of acute myelogenous leukemia began about a decade after World War II. It followed the first use of nitrogen mustard, adrenocorticotropic hormone, glucocorticoids, and the folic acid antagonist, aminopterin (a new class of DNA synthesis inhibitors), principally for lymphoid malignancies, such as Hodgkin's and non-Hodgkin's lymphoma and for childhood acute lymphocytic leukemia. The use of amethopterin (methotrexate), a congener of aminopterin, and, thereafter, 6-mercaptopurine, the latter representative of the second class of drugs designed to interrupt DNA synthesis, resulted in remission of acute myelogenous leukemia, albeit infrequently and usually of short duration. The introduction of cytarabine and, soon after, the anthracycline antibiotics, resulted in an increased frequency and duration of remission. This dyad of drugs has formed the centerpiece of treatment for acute myelogenous leukemia during the last 30 years.
When chemotherapy for leukemia was introduced, success resulting from killing of leukemic blast cells required the subsequent restitution of normal hematopoiesis. At the time chemotherapy was first tried, there had been no formal identification of residual normal stem cells in the marrow of patients with myelogenous leukemia. Indeed, the induction of remission in the early days of treatment with chemotherapy was accepted as a happy, albeit infrequent and transient, outcome. Once remissions were observed, it was presumed that normal primitive hematopoietic cells coexisted with leukemic cells and could be recruited after leukemic cells were killed. As more potent drugs became available, initial treatment was applied with the goal of clearing the marrow of leukemic cells. Empirically, it was realized that such a goal greatly increased the probability of the reappearance of apparently normal hematopoiesis. With the advent of ancillary treatments, such as platelet transfusion and more effective antimicrobial agents, more patients survived the period of hematopoietic aplasia induced by chemotherapy that was usually required to permit normal hematopoiesis to return.
Chronic myelogenous leukemia and other chronic or subacute clonal myeloid diseases are resistant to intensive multidrug chemotherapy. Thus, the pattern of relapse and remission seen in the acute disease did not occur. It required the use of other techniques, including cell culture, to uncover that normal stem cells were present in the marrow in these diseases as well but, like the acute disease, these stem or progenitor cells were suppressed and usually unable to express themselves. In very occasional cases, the presence of cytogenetically normal and abnormal cells at the time of diagnosis indicated that mosaic hematopoiesis can exist for a time. With new approaches to therapy with interferon-alpha or STI 571, mosaic hematopoiesis is observed frequently after treatment of chronic myelogenous leukemia. The factors that result in normal hematopoietic suppression in chronic myelogenous leukemia, polycythemia vera, and other clonal myeloid diseases are probably different but no less interesting or important than those that operate in acute myelogenous leukemia.
Acute and chronic lymphocytic leukemia appear to have a less suppressive effect on normal hematopoiesis. In the latter case, mosaic hematopoiesis is the rule, some effective level of normal hematopoiesis is present despite a marrow replete with leukemic lymphocytes. Hairy cell leukemia is an exception, presumably related to suppressive cytokine elaboration, especially of granulocyte and monocyte maturation, but mosaic hematopoiesis is still the rule. Acute lymphocytic leukemia is associated with severe suppression of normal hematopoiesis. However, in vitro studies show less suppression of granulocyte progenitor cell cultures by leukemic lymphoblasts than leukemic myeloblasts and, the return of normal hematopoiesis after therapy of acute lymphoblastic leukemia seems more rapid and robust than after acute myelogenous leukemia, although this may be explained in part by the different drug regimens used in treatment.
In acute myelogenous leukemia with cytogenetic abnormalities, the normal karyotype of dividing marrow cells during remission strongly suggested that normal hematopoiesis was restored, although the possibility that a karyotypically normal, "leukemia minor" clone was responsible for the remission could not be completely excluded. This concept was that chemotherapy, having decreased the more disturbed subclones derived from the leukemic stem cell, may have permitted the expression of a leukemic subclone without cytogenetic changes and with greater degrees of differentiation and maturation. With the introduction of techniques to determine the monoclonal or polyclonal derivation of tissues, the polyclonal nature of blood cell production of women, and presumably men, in remission was established. The disappearance of clonal cytogenetic abnormalities and the reappearance of polyclonal hematopoiesis supported the concept that restitution of normal hematopoiesis occurs during the remission of patients with acute myelogenous leukemia. Fortunately, in the aftermath of the chemotherapeutic onslaught, normal hematopoietic function often is transiently more efficient than leukemic hematopoiesis, permitting return of nearly normal blood counts at least for a time before relapse ensues. The competition between normal and leukemic hematopoiesis is depicted in Figure 1
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An alternative means of remission induction is observed in acute promyelocytic leukemia. If the patient is treated with all-trans retinoic acid or arsenic trioxide, the leukemic cells, blasts, and promyelocytes mature and undergo apoptosis, decreasing the primitive leukemic cell population sufficiently to release the inhibition of normal hematopoiesis. Normal blood cell production is restored, although relapse is virtually inevitable if chemotherapy is not administered concurrently.
If the acute myelogenous leukemic cells lose their growth or survival advantage after intensive chemotherapy, as is often the case, remission ensues. The inhibitory effect after chemotherapy on leukemia cells could be intrinsic to the cell (e.g., DNA damage) or to suppressive effects extrinsic to the leukemic cells. There has been evidence in both lymphomas and childhood leukemia that cured patients retain residual quiescent neoplastic cells. This mosaic state may exist in apparently cured patients with acute myelogenous leukemia as well.
The duration of remission or clinical cure (indefinite remission) is probably a function of A) the degree of reduction in the leukemic cell population; B) release of inhibition of normal hematopoietic cell function; C) a new steady-state in the rate of growth and death of the residual leukemic cell population, or D) elimination of leukemic cells (improbable).
Thus, at least two critical biologic processes remain underexplored and unexplained. First, what specific factors related to leukemic cell expansion result in inhibition of normal hematopoiesis? Such an effect can be related to the concentration of chemicals (e.g., cytokines, chemokines) released from the expanding leukemic population. The effect on hematopoiesis seems to begin at about one hundred million to one billion leukemia cell burden. Alternatively, the leukemic cell proliferation in the microenvironment of the marrow may affect the supporting stroma so as to interfere with critical signals required for normal stem or progenitor cell functional expression. In addition, leukemic cells may act as a sink for critical cytokines acting over short distances in the marrow. Second, in contradistinction to the first question, what alteration in the residual leukemic (stem) cells permits quiescence at a lowered leukemia cell burden in those patients with prolonged remission or cure? Presumably this burden of less than one hundred million cells is insufficient to inhibit normal hematopoiesis. This quiescence occasionally can be lost years after apparent cure with relapse of the original leukemia.
The discovery of the chemical factors that induce inhibition of normal hematopoietic function could provide a novel approach to treatment, either primary or adjunctive. One could synthesize antagonists to these factors or use immunological methods to neutralize them. It may also be possible to stimulate selectively normal multipotential or oligopotential progenitors with pharmacological concentrations of early-acting growth factors. These treatments could alter the balance between leukemic and normal hematopoiesis in favor of the latter. More explicit knowledge of the factors induced by leukemia cells that suppress normal hematopoiesis could introduce additional approaches to therapy.
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Received on August 12, 2000;
accepted for publication on August 14, 2000.
This article has been cited by other articles:
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  M. A. Lichtman Battling the Hematological Malignancies: The 200 Years' War Oncologist, February 1, 2008; 13(2): 126 - 138. [Abstract] [Full Text] [PDF]
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