Introduction
NCI-supported (National Cancer Institute) scientists are actively pushing the boundaries of leukemia treatment knowledge. Advances in targeted therapies and immunotherapies promise more efficient and safer approaches. In recent years, notable advancements have been made in the treatment of acute myeloid leukemia (AML), leading to the approval of several new therapeutic options.
Many of these treatments are tailored to specific mutations, such as Gilteritinib for AML patients with FLT3 mutations, or are targeted at defined AML subgroups like AML-MRC or therapy-related AML, as seen with CPX-351. It delves into various aspects of combined epigenetic therapy involving the BCL-2 inhibitor Venetoclax, exploring resistance mechanisms to Venetoclax-based regimens and potential strategies to overcome primary or secondary resistance.
Additionally, it provides a detailed examination of the current status of AML immunotherapy, highlighting promising approaches. This article focuses on clinically relevant aspects of present and future AML treatment concepts while elucidating the molecular basis of specific targeted therapies to better understand the progression and challenges of ongoing clinical trials in AML patients. This article explains leukemia research, showcasing clinical breakthroughs poised to enhance patient care, NCI-backed initiatives driving innovation, and key discoveries from recent investigations.
What Is Leukemia?
The classification of leukemia, whether primary or secondary, is determined by the production of abnormal leukocytes. Leukemia can be categorized as acute or chronic depending on the pace of proliferation and as myeloid or lymphoid based on the cell origin.
Major subtypes include:
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Acute myeloid leukemia (AML).
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Chronic myeloid leukemia (CML).
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Acute lymphoblastic leukemia (ALL).
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Chronic lymphocytic leukemia (CLL).
Less common variants, like mature B-cell and T-cell leukemias and NK (natural killer) cell-related leukemias, originate from mature white blood cells. The 2016 update of the World Health Organization (WHO) classification, facilitated by next-generation sequencing (NGS) and biomarker identification, significantly changed traditional classification for acute leukemias and myeloid neoplasms. Various genetic risk factors contribute to leukemia, including syndromes like Klinefelter and Down syndromes and germline mutations in genes like RUNX1 and CEBPA. Environmental factors such as viral infections, ionizing radiation exposure, and exposure to chemicals like benzene and certain chemotherapy agents also play a role in leukemia development.
Symptoms are often nonspecific and may include fever, fatigue, weight loss, bone pain, and bruising. Definitive diagnosis typically involves a bone marrow biopsy, guiding hematologists and stem cell transplant physicians in selecting treatment options ranging from chemotherapy to allogeneic stem cell transplantation.
The prognosis varies depending on the leukemia subtype. Acute vs. chronic myeloid leukemia is differentiated by the percentage of blasts in the bone marrow or peripheral blood smear. Acute leukemias feature greater than 20 percent blasts, leading to rapid symptom onset, while chronic leukemia presents with less than 20 percent blasts and a relatively slower symptom progression. The accelerated or blast phase signifies a transformation of chronic myeloid leukemia into an acute phase with a higher blast count.
The four major subtypes of leukemia are:
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Acute Lymphoblastic Leukemia (ALL): This disease predominantly affects pediatric patients and involves the blastic transformation of B and T cells.
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Acute Myelogenous Leukemia (AML): The most common acute leukemia in adults, characterized by over 20 percent myeloid blasts with variable prognosis.
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Chronic Lymphocytic Leukemia (CLL): It occurs in older individuals and results from the proliferation of monoclonal lymphoid cells, often considered an indolent disease.
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Chronic Myelogenous Leukemia (CML): Arises from the fusion of BCR and ABL1 genes, leading to dysregulated tyrosine kinase and monoclonal granulocyte proliferation.
How Is Leukemia Treated?
Leukemia treatment aims to induce remission and ultimately achieve a cure. Various treatment options are available, tailored to specific factors, such as:
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The type and subtype of leukemia.
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Disease phase, category, and stage.
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Results of cytogenetic analysis.
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Overall health status at diagnosis.
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Disease symptoms and white cell count.
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Localization and spread of cancer cells.
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Rate of disease progression and past medical history.
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Potential impact of treatment on quality of life and pregnancy status
The personalized leukemia treatment plan may include one or more of the following therapies:
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Watchful waiting: Vigilant monitoring without specific therapy is suitable for cases like CLL, where symptoms are absent initially.
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Chemotherapy: Primary treatment for many leukemia types involves administering multiple drugs to destroy cancer cells by various mechanisms.
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Radiation therapy: Utilizes high-energy waves to disrupt cancer cell DNA, alleviating discomfort from organ enlargement or bone marrow damage.
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Targeted therapy: Directs drugs or substances to attack specific cancer cell types, minimizing harm to healthy cells while impeding cancer growth and survival.
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Bone Marrow or Stem Cell Transplants: Involves replacing damaged stem cells with healthy ones, often after destroying abnormal cells.
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Immunotherapy: This treatment boosts the immune system's ability to combat cancer using synthetic or donor antibodies, enhancing the immune response against cancer cells.
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Clinical Trials: Offer experimental treatments for cases unresponsive to standard therapies, contributing to advancing leukemia treatment options.
What Are the Advancements In Leukemia Treatment?
Traditional adult leukemia treatments have primarily included chemotherapy, radiation therapy, and stem cell transplantation. However, over the past twenty years, targeted therapies have become increasingly integral to treatment protocols for certain leukemia types. These therapies target specific proteins that regulate cancer cell growth, division, and spread. The combination of treatments varies depending on the type of leukemia.
Despite significant advancements in treating certain leukemia types, others still exhibit relatively low survival rates. Additionally, with an aging population, there is a growing demand for less toxic treatment options. Rapid intervention is crucial for adult acute lymphoblastic leukemia (ALL), which involves excessive production of lymphocytes in the bone marrow. Recent research explores several avenues:
1. Combining Less-Toxic Therapies: Intensive chemotherapy regimens often pose severe side effects, particularly for older patients. Clinical trials, including those conducted by NCI, investigate whether combinations of targeted therapies could replace chemotherapy in older patients with B-cell ALL.
2. Immunotherapy: This approach enhances the body's immune system to combat cancer more effectively. Strategies include CAR T-cell therapy, where a patient's immune cells are genetically modified to target cancer cells. CAR T-cell therapy has shown promise in children and young adults with ALL and is now being explored in older adults with B-cell ALL. Another avenue is Bispecific T-cell engagers (BiTEs), which facilitate immune cells in locating and destroying cancer cells. Blinatumomab (Blincyto), a BiTE, has demonstrated improved survival rates for ALL patients in remission after chemotherapy.
3. Improving Treatment for Adolescents and Young Adults (AYAs): Treatment protocols initially developed for children with ALL have shown benefits for newly diagnosed AYA patients as well. Studies are underway to explore the addition of targeted therapies to these regimens. These advancements significantly enhance leukemia treatment efficacy while minimizing toxicity, particularly for older and more vulnerable patient populations.
Conclusion
The treatment landscape for AML is becoming increasingly popular. However, the complexity and severity of the treatment lie in the treatment itself. It is difficult to admit the mutation and develop new technologies. The newer technologies are administered orally, thus enabling more outpatient treatment. With an array of new therapeutic options available, personalized treatment for each patient will hinge on various factors such as disease stage, genetic and molecular profiles, overall health status, previous treatments, and tolerance to potential side effects.
Anticipations are high that forthcoming clinical trial data within the next year will introduce even more groundbreaking therapeutic choices. Ideally, future studies will compare different treatments directly or explore innovative trial designs to evaluate combined or sequential approaches. By integrating molecular assessments and advanced technologies for minimal residual disease (MRD) detection to achieve complete eradication, strategies with the greatest potential for curing patients grappling with this devastating ailment will emerge.
