When Emil J Freireich, MD, retires from the University of Texas MD Anderson Cancer Center on September 1, he will have spent 50 years at the institution and a total of 60 years in the pursuit of curing childhood leukemia as well as other cancers and in the educational development of young physician-scientists. His accomplishments have earned him recognition as one of the legendary figures in the early history of oncology triumphs, alongside such other oncology luminaries as Emil “Tom” Frei III, MD; James Holland, MD; and C. Gordon Zubrod, MD.
Born on March 16, 1927, just 2 years before the Great Depression, Dr. Freireich’s hardscrabble adolescence in the ghettos of Chicago did not portend a celebrated career in medicine. The son of Hungarian immigrants, Dr. Freireich was 2 years old when his father, David, died, forcing his mother, Mary, to take a job working very long hours each day in a hat factory to support her young son and daughter, Annette.
The Accidental Physician
Hoping to prepare her son for a job after he completed high school, Mary encouraged him to study typing and shorthand, but in his senior year, Dr. Freireich’s physics teacher, spotting his intellect for science, steered him in another direction. “I loved physics and won first prize in a project I completed on Bernoulli’s principle of flight,” said Dr. Freireich. “My teacher said, ‘I think you’re smart enough to go to college. What would you like to do for your future?’ and my response was, ‘What is college?’ I had never heard of college.”
At that moment, Dr. Freireich may not have understood the concept of college, but he had already made up his mind to be a doctor. “The ghetto neighborhoods of the 1930s were mostly populated by women, as the men were away all day digging ditches. The only man I ever saw was our family doctor, Dr. Rosenbloom. He worked for nothing and always wore a suit and tie and looked so dignified,” said Dr. Freireich. “So when my physics teacher asked me what I wanted to do, I thought about it a minute and said I wanted to be a doctor like Dr. Rosenbloom.”
After securing the $25 necessary to apply to the University of Illinois in Champaign, Dr. Freireich worked menial jobs and received state aid to cover his tuition and living expenses. With World War II now raging, university classes were accelerated, and after 15 months, Dr. Freireich graduated and moved back home to attend the University of Illinois College of Medicine at Chicago, graduating in 1949 at the age of 22.
Still planning on becoming a family doctor, Dr. Freireich interned at Cook County Hospital, a public urban teaching hospital in Chicago, where he delivered 100 babies in a month and witnessed the inequities of medical care for the poor.
“We would admit 20 to 25 patients a night, and the nurses would cull the dying patients from the living ones and put them in what they called the death room,” said Dr. Freireich. “A patient had come into the hospital with heart failure and I worked hard on him and thought I could save him, but when I looked for him on the ward after I made rounds, a nurse said he was in the death room. I insisted that my patient be put back on the ward, but the nurse refused. The next morning, the hospital administrator called and fired me for being a troublemaker.”
Accepting the Charge to Cure Leukemia
Determined more than ever to protect life and relieve suffering, Dr. Freireich went across the street to Presbyterian Hospital, where he became Chief Resident of Medicine but left soon after to do a fellowship in hematology at Mass Memorial Hospital in Boston. At Mass Memorial Hospital, a revolution in scientific medicine was underway, and Dr. Freireich subsequently made a discovery in anemia that led to the understanding of hemoglobin metabolism.
By 1953, Dr. Freireich was on the fast track to a research faculty position when he was drafted into the army. He was later allowed to serve his time doing public health service at the fledgling National Institutes of Health (NIH), where he would alter the course of childhood leukemia for millions of children.
“When I met Gordon Zubrod [then Clinical Director of the National Cancer Institute], he asked me what I did and I said that I had just completed my hematology fellowship, and he said I should cure leukemia. I said, ‘Yes, Sir.’ And I took it seriously,” said Dr. Freireich.
The challenge forged a collaboration and friendship with his near-namesake Dr. Emil Frei, who was then Chief of the Leukemia Section and Medicine Branch at the National Cancer Institute (NCI), lasting until Dr. Frei’s death in 2013. This collaboration resulted in the development of multiagent combination chemotherapy, which led to cures in over 90% of children with acute lymphoblastic leukemia (ALL) and more effective treatments for various adult cancers, including Hodgkin lymphoma.
In 1955, Drs. Freireich, Frei, and Zubrod devised a methodology for a controlled clinical trial in ALL to evaluate whether giving a combination of two effective antimetabolites—mercaptopurine and methotrexate—was more effective than giving the drugs sequentially. They were joined in this study, called Protocol I, by Dr. James Holland, who had begun the first combination chemotherapy program in acute leukemia at the NCI in 1953 and had left the Institute the following year to become Chief of Medicine and Director of the Cancer Clinical Research Center at Roswell Park Cancer Institute. The cooperative effort between the two institutions, called the Leukemia Group, became the basis of the development of the Cancer and Leukemia Group B (CALGB).
The results of Protocol I confirmed that the combination therapy was more effective in staving off cancer than giving the drugs sequentially.1 “Protocol I turned out to be quite important because it proved first of all how many children got responses to methotrexate, how many got responses to mercaptopurine, how long the responses lasted, and whether giving both drugs at the same time was better or worse,” said Dr. Freireich. “Everyone said it would be worse, because if you fail with the combination there is nothing else to give, whereas if you fail with one drug, you’ve got another one to use. But it turned out that the combination was better than the sequence, and we were off.”
Birth of the Randomized Trial
The results from Protocol I were later tested in a larger three-arm trial called Protocol 2.2 That study, too, found that giving two agents simultaneously produced higher rates of remission than giving the drugs sequentially.
“When Protocol 2 was being developed, 13 academic institutions had joined the study because by then everyone could see the road ahead was clear: Objective randomized clinical trials were the way to go,” said Dr. Freireich. The trials also helped to define quantitatively the natural history of childhood leukemia and provide early clues on the variables involved in treatment duration response and disease relapse.
A third trial, Protocol 3,3 was launched in 1959 to test the efficacy of mercaptopurine vs placebo in maintaining clinical remissions in patients with ALL, a new concept at the time. The study results showed that not only was remission prolonged for patients treated with mercaptopurine, but also that a significant number of patients experienced a substantially prolonged remission—approximately 10% of patients were still in remission after over a year and a half of continued therapy.
Although buoyed by the findings of these clinical trials, Dr. Freireich was devastated by the fact that many children brought to the NCI for treatment still died of their leukemia. “In the terminal stages of their disease, the children developed a hemorrhagic diathesis. They were bleeding to death before our eyes, and when we gave them these drugs, it made the bleeding worse,” said Dr. Freireich. “One day, Dr. Zubrod came on rounds to see how we were doing, and said, ‘Freireich, your ward has blood all over it, there is blood on the sheets, on the nurses’ uniforms, on the ceilings. Why don’t you do something about the bleeding?’ So that’s what I did.”
Dr. Freireich examined the medical records of all the children and recorded their platelet counts. He found that there was a direct relationship between the degree of thrombocytopenia and the occurrence of hemorrhage. To prove his theory, Dr. Freireich collected platelets from his own blood and added them to the children’s blood.
“Their clotting parameters immediately went to normal, and the bleeding stopped,” said Dr. Freireich. He then conducted a prospective randomized study4 of supportive platelet therapy in bleeding patients with acute leukemia, which showed that fresh blood was more effective in preventing hemorrhage than banked blood.
“From that day forward, bleeding as a cause of death was essentially eliminated, and I consider that finding my greatest contribution to medicine, because we wouldn’t be able to treat patients with cancer today unless we had allogeneic platelet transfusions to prevent hemorrhage,” said Dr. Freireich. He later went on to develop the first continuous-flow blood cell separator, which collects peripheral blood stem cells for transplantation and is still used today in most pheresis centers.
Grooming the Next Generation of Physician-Scientists
By 1965, Dr. Freireich had reached the limit of what he could accomplish in the leukemia program at the NIH and followed his friend and colleague Emil Frei to MD Anderson Cancer Center—now the University of Texas MD Anderson Cancer Center—in Houston. There they established a chemotherapy program and launched the Department of Developmental Therapeutics, which has been instrumental in training the best minds in oncology.
“We created the first grant to train fellows in medical oncology before there were boards in medical oncology,” said Dr. Freireich. “The people we have recruited and trained are all leaders in the field of oncology.” Some of the people Dr. Freireich has helped train include Kenneth B. McCredie, MD, who pioneered the use of combination agents, including interferon, in the 1980s; Michael J. Keating, MD, Professor of Medicine in the Department of Leukemia at MD Anderson and founder of the Chronic Lymphocytic Leukemia Global Research Foundation; and Hagop M. Kantarjian, MD, Department Chair of Leukemia at MD Anderson and an early developer of targeted therapy in the treatment of chronic myeloid leukemia.
In addition to his landmark research and clinical work in leukemia, Dr. Freireich is renowned for the contributions he has made in medical education. He is the recipient of numerous awards for both his research and medical education efforts, including ASCO’s David A. Karnofsky Memorial Award and Lecture (1976), the First NIH Distinguished Alumni Award (1990), the Medical Oncology Fellows Outstanding Teacher Award, MD Anderson Cancer Center (1996), the Pollin Prize for Pediatric Research, Columbia University (2003), and the Paul Ehrlich Magic-Bullet Lifetime Achievement Award (2008), among others.
Dr. Freireich became Director of MD Anderson’s Adult Leukemia Research Program in 1985 and is currently the cancer center’s Ruth Harriet Ainsworth Chair; Distinguished Teaching Professor; Director, Adult Leukemia Research Program; and Director, Special Medical Education Programs. Although he is no longer doing research or seeing patients, Dr. Freireich plans to continue to be involved in the center’s medical education program and in Institutional Grand Rounds, which consists of weekly lectures of advances in oncology presented to faculty members and trainees, after he officially retires in September.
“Dr. Freireich was a true pioneer that challenged the conventional wisdom at the time with a very high level of both courage and sense of urgency that changed the standard of care for children with cancer in a way that allowed those children to grow up to be grandparents,” said Ronald DePinho, MD, President of The University of Texas MD Anderson Cancer Center. “I’m very proud that he is a member of our faculty and very proud of the accomplishments that he and others made at that critical point in the history of the field, and it is my hope and aspiration that we can apply similar courage and urgency to the challenges that patients face today with leukemias and solid tumors.”
The Love of Family and Friends
When asked to assess his life’s accomplishments, Dr. Freireich praised the work of Drs. Frei and Zubrod and the good fortune he had to be their friend. “I was friends with Emil Frei until the day he died,” said Dr. Freireich. “I loved Emil Frei and Gordon Zubrod. They were two enormously competent, compassionate, and intelligent people, and I was very lucky to be at the NIH during their tenure.”
He also credits his wife of 62 years, Haroldine Lee Cunningham Freireich, with making it possible for him to attain his professional goals and providing him with a grounded family life. “My wife is the secret to my academic success,” he said. “She is just the most wonderful partner in life.” Dr. Freireich and his wife have four children, six grandchildren, and two great-grandchildren.
“I have been the most fortunate of men. I have a wonderful wife and a beautiful family. I have had the privilege of working with outstanding people and have been blessed every day,” said Dr. Freireich. “I have also been fortunate to have opportunities that very few people have, and, of course, the secret of success is to grab opportunities when you see them. I’m good at that.”
Medicine Is Man’s Highest Calling
Looking at what lies ahead, Dr. Freireich is optimistic about his future and the future of patients with cancer. “We will always have cancer, but we are curing cancers every day, and patients are doing great things after their disease,” said Dr. Freireich. “It’s the wonder of medicine. Medicine is man’s highest calling. Every day, including today, when I go to work, I help people, save lives, prolong lives, and relieve suffering. It doesn’t get any better than that.” ■
Disclosure: Dr. Freireich reported no potential conflicts of interest.
References
1. Frei E III, Holland JF, Schneiderman MA, et al: A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13:1126-1148, 1958.
2. Frei E III, Freireich EJ, Gehan EA, et al: Studies of sequential and combination antimetabolite therapy in acute leukemia: 6-Mercaptopurine and methotrexate. Blood 18:431-454, 1961.
3. Freireich EJ, Gehan EA, Frei E III, et al: The effect of 6-mercaptopurine on the duration of steroid-induced remissions in acute leukemia: A model for evaluation of other potentially useful therapy. Blood 21:699-716, 1963.
4. Freireich EJ, Schmidt PJ, Schneiderman MA, Frei E III: A comparative study of the effect of transfusion of fresh and preserved whole blood on bleeding in patients with acute leukemia. N Engl J Med 260:6-11, 1959.
