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Cladribine: Polish Wonder Drug for Leukemia
Research on a chemotherapy drug called cladribine has won international acclaim for Polish hematologists. The story begins in the early 1980s, when Polish chemist Zygmunt Kazimierczuk developed an innovative method for the chemical synthesis of cladribine.

Since then, cladribine has been the drug of first choice in treating a form of leukemia known as hairy cell leukemia. It is also used to help patients with lymphoid leukemia and chronic lymphocytic leukemia.

Leukemia, or malignant tumors of the human hemopoietic system—the bodily system of organs and tissues involved in the production of blood, primarily the bone marrow, spleen, tonsils and lymph nodes—attacks the bone marrow and the lymphatic system. There are acute and chronic leukemias and their symptoms and course of development vary. Treatment is primarily based on chemotherapy. Bone marrow transplants are also used.

Cladribine is one of three comparable chemical compounds known as purine analogs. The two others are fludarabine and pentostatin. All are similar to compounds present in the human body and used for building nucleic acids—including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)—which participate in fundamental biological processes such as protein production. Purine analogs inhibit DNA synthesis in leukemic cells, causing them to die. Thanks to their properties, they are widely used as anti-cancer drugs. Purines are natural substances found in all of the body’s cells, and in many foods. They provide part of the chemical structure of human genes and the genes of plants and animals.

Researchers in Western Europe and the United States have focused mainly on the fludarabine purine analog. Cladribine was first administered in an American center to a patient with hairy cell leukemia, a rare form of lymphoid leukemia. The result was a remission, or temporary disappearance, of the disease. However, the cladribine synthesis method was expensive and complicated, even by American standards.

In the early 1980s, Kazimierczuk developed a simpler method for the chemical synthesis of cladribine while on a fellowship in the United States. He described his method in an article, and the university submitted the invention to the patent office. After coming back to Poland, the scientist modified and patented an updated method for the synthesis of cladribine and subsequently, together with Prof. Pawe³ Grieb, launched production of the drug at the Diagnosis and Therapy Development Foundation in Warsaw, in quantities sufficient for preclinical and clinical trials. Assistant professor Tadeusz Robak, then the youngest member of the pathophysiology committee of the Polish Academy of Sciences, proposed that a group of professors and clinic heads team up to conduct a nationwide study of the drug. Today, research conducted by many centers working together is the norm, but in those days, such joint research was rare in Poland.

The Hematology Clinic in the central city of £ód¼, where Robak worked, focused on researching and treating lymphoid leukemia and chronic lymphocytic leukemia. The £ód¼ hematologists began to notch up spectacular successes in 1992, using cladribine obtained from Grieb. Their first hairy cell leukemia patient treated with cladribine 20 years ago is still alive. At one point they diagnosed a relapse of the disease in him, but they administered the drug again and the disease subsided. They subsequently compared cladribine with chlorambucil, a drug routinely used to treat chronic lymphocytic leukemia. At the same time, American scientists were conducting a similar study, but were using fludarabine. The Polish research clearly showed that cladribine was more effective than fludarabine. It was tested in different configurations and combinations and for different types of leukemia. In 2000, the Polish scientists published the results of their research in the American journal Blood. This was the first publication that showed that the drug produced in Poland was more effective than the standard, commercially available drug.

“We pressed ahead with our research on the drug for the next 20 years,” says Robak, who since 1997 has been heading the Hematology Department and Clinic at the Medical University of £ód¼, which played a leading role in this research and where most of the patients were treated. “We published our findings in internationally recognized medical journals, The New England Journal of Medicine and The Journal of Clinical Oncology. Today, leading international magazines are asking us for articles. This is a great success for us.”

Cladribine is still in use around the world. Half of the publications cited on this subject are from Poland. Typically, a week-long round of treatment with the drug results in many years of health for the patient, Robak says. And if a relapse occurs the drug can be used again and produces an improvement that lasts for the next few years.

Even though it has been 25 years since it was used for the first time, cladribine is still used to treat lymphoid leukemia and chronic lymphocytic leukemia, and it is the drug of first choice in treating hairy cell leukemia.

It is estimated that hairy cell leukemia affects four to five people per 1 million every year. This represents about 2-3 percent of all leukemia cases in adults. The average age of a patient diagnosed with the disease is 52 years. In Poland, there are around 100 cases of hairy cell leukemia a year. Hairy cell leukemia is an incurable disease that affects men four times more often than women.

In 2012, The Journal of Clinical Oncology published the findings of a Polish study focusing on the use of cladribine in acute myeloid leukemia. The study was by Prof. Jerzy Ho³owiecki from the Medical University of Silesia in the southern Polish city of Katowice; he now works at the Institute of Oncology in nearby Gliwice. Acute myeloid leukemia accounts for 80 percent of all cases of acute leukemia in adults, and for 18 percent of all leukemia cases in children. The incidence of the disease increases with age. In Poland, the risk for those over 18 is 2.1 per 100,000. Men suffer from the disease significantly more often than women.
Danuta K. Gruszczyńska