Nada Hussein
Giza, Egypt

“The longer you can look back, the farther you can look forward,” said Winston Churchill in a meeting at The Royal College of Physicians in 1944. At that time, leukemia was a fatal disease.¹ Representing 8% of all cancers incidence today,² it had long been regarded as an inflammatory disorder because of the link between splenic enlargement and anemia, malaria, and some infectious diseases.³ An important breakthrough came with the development of the microscope by Robert Hooke and advances in lens grinding by Anton van Leeuwenhoek, who was the first to describe red blood cells in 1674.^4,5 White blood cells were first reported in 1749 by Joseph Lieutaud as globuli albicantes, followed by William Hewson’s description of the lymphatic system and lymphocytes in 1774.^6,7

About the time of these discoveries, there were a few case reports of pus with colorless and nucleated cells—the globules blancs du pus.^1,8,9 The generally accepted concept was that pus and inflammation were associated with the blood.¹ Post-mortem examination of cases reports by Alfred Donné (1801–1878) revealed that more than half of the cells were mucus globules but he was not able to decide whether these were white blood cells or pus.¹⁰ The clinical presentation of leukemia remained a mystery, but this was partially resolved by David Craigie when in 1841 he described a patient admitted to the Royal Infirmary with clinical features of chronic leukemia. Post-mortem examination showed the purulent matter and lymph had been mixed with the blood and had been circulated.¹¹ Three years later, another patient was admitted to the Royal Infirmary with similar symptoms as well as a splenic tumor. Treatment consisted of bleeding with leeches, purgatives, and potassium iodide. The patient was discharged only to return three months later. Retrospectively, Craigie recognized that the “internal pathological state” was congruent in both patients and therefore the same outcome was to be expected. Indeed, the patient died three days later. Donné’s student, Hughes Bennet, performed a post-mortem examination and became the first to correctly characterize leukemia as a systemic disorder independent of inflammation.¹² Following this lead, Henry William Fuller achieved the first microscopic diagnosis of leukemia in a living patient in 1846.¹³

Early treatment of leukemia was symptomatic: quinine relieved fever, opium was used to treat diarrhea and pain, iron was given for anemia, and iodine used as an antibacterial agent.⁸ Arsenic was introduced as a treatment by Lissauer in 1865.¹⁴ Nitrogen mustard was first studied by Gilman and Philips in 1942, but because of the World War, reports were first published four years later.¹⁵ Because of the role of folic acid in hematopoiesis, Sidney Farber and Yellapragada Subbarow tested the impact of folic acid antagonists on leukemic children in 1947: only temporary improvement was observed.¹⁶ These discoveries pushed others to investigate chemotherapeutic agents such as 6-mercaptopurine, l-asparaginase, and vincristine.¹⁷ Despite some success, detrimental side effects persisted and remission periods were short. This encouraged the use of combination approaches in the late 1950s using prednisone, vincristine, methotrexate, and 6-mercaptopurine.^18,19 Some of these approaches achieved the first long-term remissions and cures in children and adults with Acute Lymphoblastic Leukemia.^18,19

At the beginning of a new decade in the third millennia, we need to look back at our accomplishments in fighting leukemia. Today, technology has revolutionized many aspects of leukemia care. Diagnosis is made using cell surface markers, fluorescence-activated cell sorting (FACS), and microchip analysis.⁸ A major advance is targeted therapy and immunotherapy that treats cancer cells while leaving normal cells intact. This has significantly improved outcomes and decreased cytotoxic side effects. One example is Gemtuzumab for CD33 positive AML and Gleevec for CLL.⁸ However, great caution is still needed when testing new therapeutic modalities and should include modern pharmaco-economic principles and tools such as Health Technology Assessment and Health Related Quality of Life.^20,21

References

1. Piller, G.J. (2001), Leukaemia – a brief historical review from ancient times to 1950. British Journal of Haematology, 112: 282-292. doi:1046/j.1365-2141.2001.02411.x
2. Jahedi M, Shamsasenjan K, Sanaat Z, Aliparasti M, Almasi S, Mohamadian M, et al. Aberrant Phenotype in Iranian Patients with Acute Myeloid Leukemia. Adv Pharm Bull. 2014;4(1):43.
3. Isaacs, R.(1937) Haematology in the Bible and Talmud. Medical Leaves, 78–80. New York.
4. Hooke, Robert. Micrographia: or some physiological descriptions of minute bodies made by magnifying glasses, with observations and inquiries thereupon. Courier Corporation, 2003.
5. Van Leeuwenhoek, A.(1674) Philosophical Transactions of the Royal Society, vol. 9, pp. 121–128. London.
6. Lieutaud, J.(1749) Elementa Physiologiae, pp. 82–84. Amsterdam (later translated and quoted in Dreyfus, C., 1957, Milestones in the History of Haematology, pp. 11–12, New York).
7. Hewson, William. Experimental Inquiries: Part the Second. Containing a Description of the Lymphatic System In the Human Subject, And in Other Animals. Illustrated with Plates. Together with Observations on the Lymph, and the Changes which it Undergoes in Some Diseases. By William Hewson, FRS and Teacher of Anatomy. J. Johnson, No. 72, St. Paul’s Church Yard, 1774.
8. Mehranfar, Sahar, Sirous Zeinali, Rana Hosseini, Mozhdeh Mohammadian, Abolfazl Akbarzadeh, and Abbasali Hossein Pour Feizi. “History of Leukemia: Diagnosis and Treatment from Beginning to Now.” Galen Medical Journal6, no. 1 (2017): 12-22.
9. Sénac, Jean-Baptiste. Traité de la structure du coeur, de son action, et de ses maladies. Vol. 2. Briasson, 1749.
10. Donné, Alfred.Cours de microscopie complémentaire des études médicales: anatomie microscopique et physiologie des fluides de l’économie. J.-B. Baillière, 1844.
11. Craigie, D.(1845) Case of disease and enlargement of the spleen in which death took place from the presence of purulent matter in the blood. Edinburgh Medical and Surgical Journal, 64, 400–413.
12. Bennett, John Hughes. “Case of hypertrophy of the spleen and liver, in which death took place from suppuration of the blood.”Edinburgh Med Sug J 64 (1845): 413-423.
13. Kampen, K. R. (2012). The discovery and early understanding of leukemia.Leukemia research, 36(1), 6-13.‏
14. Bairey O, Vanichkin A, Shpilberg O. Arsenic‐trioxide‐induced apoptosis of chronic lymphocytic leukemia cells. Int J Lab Hematol. 2010;32(1p1):e77-e85.
15. Gilman A, Philips FS. The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides. Science. 1946;103(2675):409-36.
16. Farber S, Diamond LK, Mercer RD, Sylvester Jr RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948;238(23):787-93.
17. Burchenal JH, Murphy M, Ellison R, Sykes M, Tan T, Leone L, et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood. 1953;8(11):965-99.
18. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24(2):265-84.
19. Thomas DA, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, et al. Chemoimmunotherapy With a Modified Hyper-CVADand Rituximab Regimen Improves Outcome in De Novo Philadelphia Chromosome–Negative Precursor B-Lineage Acute Lymphoblastic Leukemia. J Clin Oncol. 2010:JCO. 2009.26. 9456.
20. Friedberg, M., Saffran, B., Stinson, T. J., Nelson, W., & Bennett, C. L. (1999). Evaluation of conflict of interest in economic analyses of new drugs used in oncology. Jama, 282(15), 1453-1457.
21. Hwang, T. J., Vokinger, K. N., & Sachs, R. E. (2019). Evaluating New Rules on Transparency in Cancer Research and Drug Development. JAMA oncology, 5(4), 461-462.