The history of leukemia is a long one: In 2015, scientists detected signs of leukemia in a 7,000-year-old human skeleton. Though the condition has evidently existed for thousands of years, it was not understood as a disease until far more recently. What’s more, humankind’s limited ability early on to observe with the naked eye and understand the characteristics of “normal blood” and “normal cells” further hindered our understanding of leukemia.
Through research and innovations in medicine and technology, we now have a much better grasp of the underlying causes of leukemia, as well as ways to treat it.
The first microscopes powerful enough to distinguish blood cells were invented in the 1600s. By the early 1800s, scientists were able to distinguish white blood cells from red blood cells. However, they didn’t yet understand white blood cells’ role in the immune system, helping to fight infection and other diseases. (For that matter, they didn’t understand there was such a thing as the immune system.) Instead, they thought that these strange cells might be mucous or pus.
In the 1840s and 1850s, several doctors wrote case studies of people who had swollen abdomens, fevers, weight loss, and weakness — symptoms that we now associate with leukemia. While performing blood tests during autopsies, the doctors noticed that these people had abnormal amounts of white blood cells — so much so that they described the disease as “white blood” or “leukemia.” The name “leukemia” was derived from the Greek words “leukos,” which means "white," and “haima,” which means "blood."
Doctors debated the cause of this abnormal level of white blood cells. In 1856, Rudolf Virchow, a German physician and pioneer in cellular pathology, proposed that the cause of leukemia would be found in the organs that produced the white blood cells — especially the spleen. Other doctors found that people with leukemia had bone marrow that was yellowish-green, instead of the normal, healthy red. Leukemia wasn’t just a disease of the organs: The bones were involved as well. This destruction of the bone marrow accounted for the anemia (lack of red blood cells) that went along with leukemia.
In 1877, a German medical student named Paul Ehrlich developed a stain that let scientists see the details of blood cells. Using this stain, Ehrlich was able to find “primitive cells” that would go on to develop into different types of blood cells. This was the earliest definition of what we now know as “stem cells.”
Ehrlich’s work also led to classifications of types of leukemia by which cells were affected. Lymphocytic leukemia affected cells that were supposed to develop into a type of white blood cells called lymphocytes, while myeloid leukemia affected cells that were supposed to become red blood cells, platelets, or other types of white blood cells.
Doctors also were able to distinguish acute from chronic leukemia. People with acute leukemia have lots of very immature cancer cells, called myeloblasts or lymphoblasts, in their blood. Ehrlich went on to win a Nobel Prize in medicine in 1908.
These discoveries paved the way for the definitions of the four major subtypes of leukemia:
Virchow’s and Ehrlich’s discoveries did not immediately lead to effective treatments for leukemia. In the late 19th and early 20th centuries, the newly discovered X-ray was used to treat leukemia. Doctors found that radiation therapy worked best against chronic leukemias, but it was useless against acute types. X-rays could provide months or even years of remission for people with chronic leukemia, but the disease would always return.
The first medications for leukemia grew out of the horrors of World War I, when it was discovered that the chemical weapon mustard gas suppressed the production of blood cells. Research on these chemicals continued through World War II, and in the 1940s, “nitrogen mustards” were used as primitive oncology treatments for leukemia — to little effect. However, this research led to the development of such chemotherapy drugs as chlorambucil and busulfan, which remained prime treatments for CLL and CML until the end of the 20th century, despite their harsh side effects.
Another new drug, the folic acid blocker aminopterin, was used for the first time in the 1940s to treat cases of childhood leukemia. Aminopterin would eventually be developed into the medication methotrexate, which is still commonly used to treat cancer today.
Scientists hypothesized that they could treat leukemia by replacing diseased bone marrow with healthy marrow capable of creating the stem cells that develop into healthy blood cells. By the middle of the 20th century, researchers found that such transplants were effective in treating disease in rats and other animals. However, these researchers quickly found that humans were different from the often-inbred animals used in animal testing. Without a close match in bone marrow type (usually from a close relative), a person undergoing a transplant would suffer a severe reaction called graft-versus-host disease. This would often lead to infection or death.
As scientists figured out how to better match bone marrow type, transplants became much safer. The creation of a bone marrow registry made it easier to find appropriate matches. Over time, pre-transplant chemotherapy regimens became more precise. Today, haploidentical — or “half-matched” — transplants can now be performed.
At one point, bone marrow transplants were used as a standard treatment for CML. However, these transplants are no longer first-line treatments for CML and other forms of leukemia. The procedure is still risky, and advances in targeted drugs have made them a preferable initial treatment option. Nevertheless, bone marrow transplants are still used today for people whose leukemia hasn’t responded to chemotherapy and for some cases of childhood leukemia.
By the 1970s, the field of medical oncology was beginning to take shape. Cancer was no longer just treated through surgery and radiation therapy. Medication was a viable alternative. As the science of chemotherapy advanced, researchers began to combine medications for maximum effect. Treatment of leukemia and other blood cancers, such as Hodgkin lymphoma, led the way in these advances.
However, chemotherapy came with side effects. Chemotherapy regimens didn’t just target leukemia cells — they destroyed healthy cells as well. In addition, some forms of leukemia — especially CML — still remained resistant to treatment. An adult diagnosed with CML could expect to live for just a year or less, unless they were still young enough to risk a bone marrow transplant. Even then, death rates were high.
The solution to CML treatment turned out to be tucked away in DNA. Scientists had found that people with CML almost always have an abnormal chromosome. This abnormality, which is called the Philadelphia chromosome — after the city where it was discovered — is present in CML leukemia cells. In the 1990s, researchers developed the tyrosine kinase inhibitor drug Gleevec (imatinib), which targets the gene product of the Philadelphia chromosome, killing abnormal cells and sparing others. The results were amazing: In one of the first clinical trials of Gleevec, participants had a 100 percent response rate. Gleevec quickly became the gold standard for treating CML. The discovery of Gleevec also led to other targeted therapies that are tailored to treat various types of leukemia, such as Imbruvica (ibrutinib) and Venclexta (venetoclax).
Targeted antibody treatment has also advanced leukemia treatment. In the 1980s, scientists found that cancerous B cells (a type of white blood cell) contained a particular type of protein called an antigen. This specific type of antigen was named CD20. By 1990, Rituxan (rituximab) had been developed. Rituxan is an antibody that attaches to this CD20 antigen. This targeted approach meant that Rituxan killed more malignancies and fewer healthy cells. Rituximab is especially useful in treating certain types of ALL in adults.
Over 55 years, the five-year survival rate for leukemia has risen from 14 percent to 66 percent in the United States. A disease that was once considered a death sentence can now be treated and, in some cases, cured. However, leukemia research hasn’t stopped. Current research focuses on making treatment less toxic and modifying the immune cells of people with leukemia to create new, personalized treatments.
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