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Originally published as JCO Early Release 10.1200/JCO.2008.19.2260 on December 8 2008 © 2009 American Society of Clinical Oncology.
Chronic Myeloid Leukemia Stem Cells: Now on the Run
Department of Haematology, Imperial College London, London, United Kingdom To the Editor: Kavalerchik et al1 have written an interesting and informative review of chronic myeloid leukemia (CML) stem cells, but it leaves many questions unanswered. A hematopoietic stem cell can theoretically be characterized by molecular, immunophenotypic, or in vitro culture techniques or by in vivo transplantation experiments. The authors accept immunophenotypic criteria for a human hematopoietic stem cell (CD34+CD38–CD90+lin–) and make the questionable assumption that these features also define a CML stem cell. It is much more likely that CML stem cells form only a tiny population of the CD34+CD38–CD90+lin–, and far from certain that a quiescent stem cell expresses the same surface markers as a cycling stem cell. The authors refer to various molecular mechanisms that may perturb stem-cell self-renewal or cause progression from chronic to advanced phase, but for the present, the only genetic marker clearly specific to CML is the BCR-ABL fusion gene, and this is of little use in defining a leukemia stem cell (LSC). It is even possible that a truly quiescent LSC is transcriptionally silent and thus invisible to an assay on the basis of cDNA.2 Thus for the present, the recognition of a CML stem cell remains elusive. Since the introduction of tyrosine kinase inhibitors (TKIs) to treat CML, much attention has focused on the fact that LSCs apparently survive and could cause relapse even in patients who respond extremely well. But is this necessarily true? In most responding patients, BCR-ABL transcript numbers continue to decrease for some years after starting treatment with imatinib3-5 and increasing numbers of patients achieve transcript-undetectable status.4 A few even remain transcript negative after imatinib is stopped.6 Even among those patients who do have persisting low levels of BCR-ABL transcripts, the risk of disease progression after 4 years in complete cytogenetic response seems to be negligible or nonexistent.7 These separate lines of evidence suggest that eradicating the bulk of Philadelphia-positive progenitors and their more differentiated progeny may be more important than targeting residual quiescent stem cells, which may be relatively innocuous. A rationale for the possibility that small numbers of residual stem cells may be clinically irrelevant is provided by the authors’ own work.8 If one assumed that CML progresses in most or even in all patients as a result of additional molecular events occurring not in a stem cell but in a more differentiated progenitor, and if TKIs were effective in eradicating these progenitors and preventing additional stem-cell differentiation, progression would be unlikely or impossible, though most patients might need to continue taking a TKI indefinitely—perhaps not all. The real target would then be to improve clinical results in the poor responders, rather than chasing the elusive LSC that may really have been arrested. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: John M. Goldman, Novartis (C), Bristol-Myers Squibb Co (U) Stock Ownership: None Honoraria: John M. Goldman, Novartis, Bristol-Myers Squibb Co Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. Kavalerchik E, Goff D, Jamieson CHM: Chronic myeloid leukemia stem cells. J Clin Oncol 26:2911-2915, 2008 2. Goldman JM, Gordon M: Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: Does it really matter? Leukemia Lymphoma 47:1-7, 2006[CrossRef][Medline] 3. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423-1432, 2003 4. Branford S, Seymour JF, Grigg A, et al: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 13:7080-7085, 2007 5. de Lavallade H, Apperley JF, Khorashad J, et al: Imatinib for newly diagnosed patients with chronic myeloid leukemia: Incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26:3358-3363, 2008 6. Rousselot P, Huguet F, Rea D, et al: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109:58-60, 2007 7. Druker BJ, Guilhot F, O'Brien S, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006 8. Jamieson CH, Ailles LE, Dylla SJH, et al: Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657-667, 2004
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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