The Impact of Hematology Research

Success Story: Chronic Myeloid Leukemia Mortality Falls Significantly in a Generation

Just five decades ago, chronic myeloid leukemia (CML) was usually fatal. Because of a better understanding of the precise molecular basis for this disease, the mortality rate has decreased remarkably, such that fatalities from CML are now uncommon. This remarkable success story started in 1960, when a team of scientists in Philadelphia, using a simple desk-top microscope, found that bone marrow cells from patients with CML had a unique chromosome. They called this abnormality the Philadelphia chromosome. It was later found to be the result of a translocation between chromosomes 9 and 22. Other hematologists uncovered the fusion gene formed by the translocated chromosome, known as BCR-ABL, which caused the myeloid cell proliferation that marks CML.

Despite that critical understanding of the disease biology, treatment advances for this disease took more than two decades of meticulous work. Bone marrow transplants were often used, but this treatment was both economically and physically costly. Treatment of CML with the drug interferon could also produce remissions in some patients, but it was expensive, it had severe side effects, and the remissions were usually not long-lasting.

Many years later, the hematology community made a discovery that would forever change treatment and prognosis of this disease. A team of hematologists studying compounds that might prevent tumor cells from proliferating found one compound in particular that seemed to rapidly kill CML cells. Later studies confirmed that the compound, today known as imatinib, was remarkably effective in the treatment of CML and had very low toxicity.

This hematology drug has since been used to treat a number of other types of cancer and has spawned a new generation of drugs known as the kinase inhibitors. There are now many distinct kinase inhibitors approved to treat a wide variety of cancers throughout the body. The success of imatinib did more than transform CML from a fatal cancer into a treatable disease; it also demonstrated that inhibition of kinase activity could be a successful cancer treatment strategy in general.

Success Story: Multiple Myeloma Survival Doubles in 10 Years

For many decades, multiple myeloma was an incurable bone cancer with an average survival of just three years. This poor prognosis remained unchanged until the past decade, when survival has been extended three to four fold thanks to a significantly improved understanding of the disease. This success has been the result of dedicated research on how myeloma cells are able to grow within the bone marrow environment. There have been multiple significant advances to achieve this remarkable success: the introduction of autologous stem cell transplantation, bone stabilizing drugs called bisphosphonates, and the discovery of several classes of novel anti-myeloma drugs that are particularly effective when used in combination.

In the 1990s, the use of autologous stem cell transplantation increased survival in myeloma patients versus conventional drug therapy, but the full effect of this procedure was not seen until the early 2000s, when it was vastly improved and a wider range of patients was made eligible for the procedure. The bisphosphonates in the 1990s remarkably reduced bone disease, the major cause of morbidity and limitation of patients’ quality of life.

In the past 12 years there have been 16 FDA approved new treatments for myeloma, including 7 new approvals in 2015 alone. The discovery of immunomodulatory drugs thalidomide, lenalidomide and pomalidomide, as well as proteasome inhibitors bortezomib, carfilzomib, and ixazomib, has transformed patient therapy and markedly improved patient outcome. This year for the first time immune therapies including monoclonal antibodies elotuzumab and daratumab have effectively treated patients resistant even to these novel therapies, further improving patient outcome. Therefore, myeloma is now a chronic disease in many patients, and the prospect of long term disease free survival and cure is now a realistic potential goal.

Success Story: The Unlikely Cure of Acute Promyelocytic Leukemia

The success of the treatment of acute promyelocytic leukemia (APL) has undergone some of the most dramatic improvements, not only in the history of hematology, but in all of medicine. This rare disease was historically one of the most deadly forms of leukemia, with rapid proliferation and multiple complications (such as bleeding) that often killed patients within weeks of diagnosis.

In the 1970s, a regimen of cytotoxic chemotherapy helped cure up to one-third of APL patients, yet many patients still died from bleeding complications before the chemotherapy could take effect. Then in the mid-1980s, a natural product called retinoic acid, originally used to treat skin disorders, was found to differentiate APL cells into nearly normal mature neutrophils that rapidly died on their own. Retinoic acid also improved coagulation in this disease, thereby protecting patients from the hemorrhagic complications that often resulted in early mortality. Further research found that when used alone, the effect of retinoic acid was only temporary, but when combined with chemotherapy, it improved cure rates by up to 70 percent. Later, investigators found that arsenic trioxide, once used to treat syphilis, could also cure up to 70 percent of APL patients.

Evaluation of the mechanism of action of these two compounds found that they both directly degrade the oncogenic fusion protein PML-RARα, which results from the diagnostic chromosomal translocation of APL, and is responsible for this disease. Because each of the drugs has different targets within that protein, clinical trials have demonstrated that greater than 90 percent of APL patients treated with a combination of these two agents are cured. In fact, many patients with APL who receive this regimen never need conventional cytotoxic chemotherapy.

The success in APL epitomizes many aspects of modern cancer molecular biology, such as the role of cloning of the translocated genes, identification of drugs that combat the resulting fusion protein, use of genetically engineered mice in pre-clinical modeling of the disease, and clinical trials with active international cooperation, all converging to generate a cure.

In addition, children Philadelphia positive acute lymphoblastic leukemia now are treated with chemotherapy and a kinase inhibitor instead of stem cell transplantation, sparing these children the possible toxicity of transplantation. Relapsed acute lymphoblastic leukemia is exceedingly difficult to cure with chemotherapy, and is a leading cause of childhood cancer death. Recent studies using chimeric antigen receptor (CAR) T cell therapy have shown the remarkable efficacy of this therapy in inducing a high rate of durable remission in relapsed/refractory disease. Further research is needed to identify suitable targets for immunotherapy in non-B cell malignancies, to test combinatorial efficacy with checkpoint blockade therapy and to explore the feasibility of implementing this therapy in frontline treatment regimens.