Leukemia is a disease characterized by the uncontrolled proliferation of immature white blood cells in the bone marrow. These abnormal cells disrupt the normal process of maturation and differentiation and overcrowd the bone marrow. This crowding leads to a decrease in the production of normal blood cells, resulting in anemia, increased susceptibility to infections, and bleeding.
Acute leukemias, in contrast to chronic ones, develop rapidly and require prompt therapeutic intervention. They can be divided into two types based on the type of abnormal cell involved: Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). Both types of leukemia can occur at any age, but AML is more common in adults, while ALL is more prevalent in children.
The treatment for AML is based on chemotherapy. The initial treatment aims to induce remission (induction therapy), and if the patient responds well, additional treatments are given to consolidate the achieved remission (consolidation therapy). A patient who achieves remission without relapse may not require consolidation therapy. Some patients may be referred for bone marrow transplantation at some stage of their treatment. Various factors influence the decision to transplant a patient, including different biological measures of the disease, the patient's overall health status (age, functional status, underlying diseases, etc.), and the patient's response to treatment.
Unlike other hematological malignancies, it is quite surprising to discover that the standard treatment protocol for AML has hardly changed in decades. So what has changed over the years of AML treatment? What progress have we made?
1. Disease Classification into Subgroups: Nowadays, leukemia patients are categorized into subgroups, and their risk levels are estimated in advance. In the past, patients were classified based on the morphological appearance of the leukemic cells, while today we rely more on cytogenetic and molecular changes in the leukemic cells. This approach provides a more accurate prognostic prediction for patients and helps in making the challenging decision of whether to proceed with bone marrow transplantation or stick to chemotherapy.
2. Biological Age Over Chronological Age: In the past, intensive treatment was only given to AML patients up to around the age of 55. However, today we assess the overall health status of the patient and treat even those in their 70s and 80s if they are fit enough. This change in approach is significant as AML incidence increases with age, and most AML patients are in the older age group.
3. Therapeutic Drugs: New biological therapies that are not conventional chemotherapy have been developed to combat leukemia. These drugs can be divided into two types: those that act on specific mutant proteins in the leukemic cell and monoclonal antibodies against various proteins on the leukemic cell's surface. There are different techniques within the realm of monoclonal antibodies; some attach to the protein on the cell surface and trigger cell signaling to induce apoptosis, some are conjugated to cytotoxic agents, leading to direct killing of the leukemic cell, some are conjugated to localized radiation-emitting agents, some attach to the leukemic cell on one side and to a healthy T lymphocyte on the other, allowing the lymphocyte to execute its function and destroy the leukemic cell, and more. Research in this field is ongoing, with several drugs already on the market.
4. Infection Management: Due to severe immunosuppression caused by the disease itself and its treatments, acute leukemia patients are susceptible to severe and life-threatening infections. Developments in broad-spectrum antibiotics, antifungals, and antiviral treatments allow patients to undergo intensive therapies and overcome these challenging infections.
5. Monitoring Treatment Response: In the past, response monitoring was done by observing surface cells obtained from the patient's bone marrow under a microscope and counting how many immature cells (blasts) were present. However, now a new term has emerged in the medical arena - Minimal Residual Disease (MRD). MRD refers to the tiny remaining amount of disease that can be detected with highly sensitive and accurate methods. These methods include molecular markers and PCR testing, as well as cell profiling using Flow Cytometry. In recent years, whole-genome/exome sequencing methods have been recruited for MRD monitoring as well. The sensitivity of these tests ranges from detecting one leukemic cell in 10,000 examined cells (10-4) to one in a million (10-6).
In the Hematology Department at Shaare Zedek, we have the privilege of treating a considerable number of leukemia patients each year. Some receive intensive treatment, with or without bone marrow transplantation, in an attempt to cure them, while others receive less aggressive treatment to control their disease. We participate in several clinical trials, allowing us to offer patients new, cutting-edge medications even before they are approved in the country and included in the healthcare basket.
Dr. Hazi Genzel and Prof. Yaakov Ro'u