History of the disease

Acute lymphoblastic Leukæmia (ALL) is a disease in which cancer cells are found in the blood and the bone marrow. The bone marrow is the spongy tissue inside the large bones of the body. Normally, the bone marrow makes cells called “blasts” that mature into several different types of blood cells that have specific functions in the body. These include red cells, white cells and platelets. Red blood cells carry oxygen and other materials to all tissues of the body. White blood cells fight infection. Platelets make the blood clot. When Leukæmia develops, the bone marrow produces large numbers of abnormal blood cells.

There are several types of leukemias. Acute lymphoblastic Leukæmia is a cancer of certain white blood cells called lymphocytes.

The idea of using antimetabolites as anticancer compounds was not evident in the middle of the 20ieth century. At that time, the scientific community did not know what genes were made of. Only in 1944 did Oswald Avery publish a paper suggesting that deoxyribonucleic acid, DNA, formed the genes. Nine years later, James Watson and Francis Crick discovered the DNA structure: the double-helix. By that time, Sidney Farber had worked on ways to prolong life of children ongoing acute leukæmia. He had delayed the death of a very sick child with the first anticancer drug in 1947 (Aminopterin). This promising work encouraged the search for anti-cancer drugs.

Despite the arrival of new anti-cancer drugs, treated patients that had no more symptoms of the cancer would most of the time develop the same cancer several years after being treated. By performing trials on leukemic patients, Emil Frei III and Emil J. Freireich, who joined the US NCI in 1955, defined the state of relapse patients entered after being temporarily cured. During these trials, they also invented the concept of performing a double blind study, where neither doctors, nor patients are aware of which drug (active or placebo) they are treated with, so as to reduce evaluation bias and to improve trial quality.

As scientists understood that a single leukemic cell was enough to start a new leukæmia, the idea of prolonging treatments to avoid relapses emerged. Schabel and Skipper developed a statistical model of leukemic cells’ growth in 1966 helping doctors estimate how long, with which frequency, and with what intensity they would prolong the treatment. Scientists also studied the non-overlapping effects of various drugs so as to administer them concomitantly. The maintenance treatment was born. Since then, treatment protocols have evolved considerably and the survival rate has augmented very significantly. 6-Mercaptopurine and Methotrexate use in the maintenance phase of ALL has never been contradicted.