Chronic myelogenous leukemia historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] Mohamad Alkateb, MBBCh [3] Sima NoorAli, M.D.

Overview

In the 1840s, the first cases of chronic myelogenous leukemia (splenomegaly with high leukocyte count) was reported in France, Germany, and Scotland. In 1960, the association of Philadelphia chromosome with the pathogenesis of chronic myelogenous leukemia was first discovered. In 1973, (9;22) translocation was first discovered.Definition of the breakpoint cluster region (BCR) on chromosome 22 was first reported in 1984 and the demonstration of the BCR-ABL transcript in CML was first discovered in 1985. From 1980 on wards allogeneic stem cell transplantation (SCT) became the treatment of choice for eligible patients. In 1998, the era of tyrosine kinase inhibitors (TKI) began.

Historical Perspective

Important dates in chronic myelogenous leukemia:

  • The early history of leukemia reaches back 200 years.[1]
  • In 1811, Peter Cullen defined a case of splenitis acutus with un explainable milky blood.
  • Alfred Velpeau, mentioned the leukemia associated symptoms, and observed pus in the blood vessels (1825).
  • Alfred Donné, demonstrated a maturation arrest of the white blood cells (1844).
  • John Bennett named the disease leucocythemia, based on the microscopic collection of purulent leucocytes (1845)
  • In 1845, Edinburgh pathologist, John Hughes Bennett, presented a “Case of Hypertrophy of the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal. [2]
  • Few weeks later, Rudolf Virchow, in Berlin published a similar case.
  • In 1872, Ernst Neumann stated that leukemia cells originated in the bone marrow.
  • The next decades described the pathophysiologic differentiation into myeloid versus lymphoid and acute versus chronic leukemias.
  • In 1973, (9;22) translocation was discovery by Philadelphia cytogeneticists Peter Nowel and David Hungerford of an abnormally small G-group chromosome that we know as the Philadelphia chromosome (Ph).[3]
  • In 1986 Janet Rowley established that Ph was the product of a reciprocal translocation between chromosomes 9 and 22 which were termed as BCR and ABL
  • This then lead to discovery of unregulated tyrosine kinase activity is critical to BCR-ABL’s ability to transform cells.

Historical perspective of treatment of chronic myelogenous leukemia:

Treatment of chronic myeloid leukemia evolved over an era as described below. [4]

  • In 1865, Heinrich Lissauer, described the use of arsenic in two patients with leukemia.
  • In the 1920s, splenic irradiation was performed which resulted in symptomatic relief.
  • In 1959, effective control of blood counts became possible with busulfan.
  • Ten years later, hydroxyurea was discovered.
  • In mid 1970's, a breakthrough was achieved when the Seattle group described the disappearance of the Ph chromosome in CML patients who underwent allotransplant.
  • Interferon-α was discovered to stimulate cytogenetic responses and resultant long-term survival, however, only in a few patients.
  • In 1992, Alexander Levitzki, proposed the use of ABL inhibitor.
  • At about the same time, scientists at Ciba-Geigy synthesized, a strong inhibitor of ABL that was named GCP57148B and is now known as imatinib.
  • For that 20% to 30% who fail imatinib, second-line inhibitors are an effective salvage therapy.
  • However, once the disease has progressed beyond the chronic phase, allotransplant is still the recommended.
  • Unfortunately, leukemia often persists in the best responders and the therapies directed at the BCR-ABL tyrosine kinase are unable to cure since they can not destroy CML stem cells.

References

  1. Kampen KR (January 2012). "The discovery and early understanding of leukemia". Leuk. Res. 36 (1): 6–13. PMID 22033191. doi:10.1016/j.leukres.2011.09.028. 
  2. Nowell PC (August 2007). "Discovery of the Philadelphia chromosome: a personal perspective". J. Clin. Invest. 117 (8): 2033–5. PMC 1934591Freely accessible. PMID 17671636. doi:10.1172/JCI31771. 
  3. NOWELL PC, HUNGERFORD DA (November 1961). "Chromosome studies in human leukemia. II. Chronic granulocytic leukemia". J. Natl. Cancer Inst. 27: 1013–35. PMID 14480645. 
  4. Deininger, M. W. (2008). "Chronic Myeloid Leukemia: An Historical Perspective". Hematology. 2008 (1): 418–418. ISSN 1520-4391. doi:10.1182/asheducation-2008.1.418. 

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