Leukemia is a condition of the bone marrow characterized by the abnormal proliferation of immature cancerous cells derived from early stem cells of the blood, referred to as blasts. An excessive expansion of blast cells in the bone marrow impairs the production of normal white blood cells, red blood cells, and platelets. Based on its proliferative presentation, leukemia is classified into acute or chronic forms and categorized as myeloid or lymphoid based on its cell of origin. According to the Surveillance, Epidemiology, and End Results Program database, an estimated 59,610 cases of leukemia were reported in 2023, representing approximately 3% of new cancer diagnoses in the United States.1 The 4 primary subtypes of leukemia are acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia, and chronic myelogenous leukemia. This article will focus on the acute forms of leukemia, ALL and AML.
Patients may present with easy bruising; night sweats; swollen or bleeding gums; shortness of breath; fever; lethargy; loss of appetite; enlarged liver, spleen, or lymph nodes; and weight loss.
Several risk factors are identified in the development of acute leukemia; however, the etiology is largely unknown. Some are attributed to a history of exposure to radiation and/or chemotherapy from prior unrelated cancers, or toxic chemicals such as benzene. Other possible risk factors include history of viral illnesses (human T-lymphotropic virus, Epstein-Barr virus), genetic or congenital disorders (Down’s syndrome, Klinefelter syndrome, Li Fraumeni syndrome). Symptoms of leukemia vary and can be nonspecific, but they are usually manifestations of bone marrow failure and reduced healthy blood cell production. Patients may present with easy bruising; night sweats; swollen or bleeding gums; shortness of breath; fever; lethargy; loss of appetite; enlarged liver, spleen, or lymph nodes; and weight loss.2
In the case of ALL, it is the most common leukemia in childhood, accounting for almost 80% of all leukemia cases, and it makes up about 20% of all adult leukemias. The disease originates from a common lymphoid progenitor cell and is further subtyped into B or T cells, with B-cell ALL accounting for 75% of ALL cases.3 Patients are risk stratified according to their cytogenetic and molecular alterations (Table 1) in addition to clinical predictors related to the patient’s age and white blood cell count at presentation. However, leukemia genetics and the depth of early response to therapy (referred to as minimal residual disease [MRD]) have emerged as the most impactful prognostic factors that can risk stratify patients and guide subsequent postremission therapy. Modern ALL therapy for younger patients is derived from a children’s protocol and can be intricate, consisting of multiple drugs with varying doses and administered in specific time sequences spanning several years. Central nervous system (brain) prophylaxis is an important element during ALL therapy, and it is also delivered periodically throughout treatment as the risk of ALL relapse in the brain can be substantial in the absence of adequate directed prophylaxis. Although there are different protocols available at various institutions, induction treatments all share a common backbone of medicines that includes a combination of anthracyclines, vincristine, and corticosteroids. In children and young adults, the inclusion of asparaginase therapy is a key component of ALL regimens and lead to improved outcomes. However, asparaginase toxicities (including liver, pancreas, and thrombosis) are encountered at higher rates with increased age, and therefore, the drug has been omitted from some regimens for middle-aged and older adults.4
The goal of the initial cycle of therapy, referred to as induction, is to achieve remission, restore growth of normal blood lines, eradicate disease harbored in sanctuary sites such as the central nervous system or the testes, and eliminate any MRD.5 After achieving remission, patients receive additional cycles of multiagent chemotherapy with or without immunotherapy to prevent relapse, which are referred to as consolidation. This is followed by maintenance therapy that uses low-dose chemotherapy, usually administered orally, for a long period. In patients presenting with high-risk disease at diagnosis who attain remission after chemotherapy, hematopoietic stem cell transplantation may be recommended as a potential for curative therapy; stem cell transplantation is a highly effective modality in reducing the risk of leukemia relapse, but it can harbor significant short- and long-term toxicities.6 Blinatumomab, an immunotherapy, has demonstrated significant benefits in improving survival outcomes in patients with B-cell ALL, attaining remission with initial chemotherapy and has recently received approval by the FDA for this indication.
Our understanding of the genetic makeup of ALL has enhanced our ability to individualize ALL therapy. Most notable is the development of ABL tyrosine kinase inhibitors (TKIs), which are oral targeted therapies, in Philadelphia chromosome–positive (Ph+) ALL. Ph+ ALL is known to be a chemotherapy-refractory disease and represents a large proportion of newly diagnosed adults with B-cell ALL. The addition of TKIs to chemotherapy has greatly contributed to improved response rates in addition to the quality and durability of response in Ph+ ALL.7
While initial response rates to chemotherapy remain high in adults, historically, long-term survival was poor due to excessive risks for relapse and poor treatment tolerability, especially in older adults. However, significant advancements have been made in the relapsed setting of ALL, broadening the number of effective salvage therapy options available, and shifting these agents to be used as frontline therapy due to their remarkable effectiveness and favorable tolerability compared with chemotherapy. Innovations in various ALL treatments over the years have contributed to improved outcomes and prolonged survivorship. In addition, antibody therapies have emerged as crucial interventions for relapsed cases in patients expressing targetable cellular markers by giving us a larger arsenal of potentially effective treatments for ALL. Two notable medications currently in use are blinatumomab and inotuzumab, targeting CD19+ and CD22+ cells, respectively. These agents are administered either in conjunction with low-dose chemotherapy or as stand-alone treatments. Inotuzumab and blinatumomab have shown significant superiority in response and survival outcomes over standard chemotherapy when administered to patients with relapsed or refractory B-cell ALL.8,9
The advances made on the immunotherapy front have been exciting, to say the least. Among these, CAR T-cell therapy has significantly expanded our arsenal to treat ALL. The innovative technology behind CAR T-cell therapy harnesses T cells collected from the patient and are then genetically modified in the lab to express parts of antibodies targeting CD19+ leukemic cells. The engineered cells are then infused back into the patient with the goal of targeting the cancerous cells while avoiding toxicity to other tissue as the expression of the CD19+ marker is quite ubiquitous in B cells. This treatment spares healthy cells from being eliminated or damaged.10 While CAR T-cell therapy is highly effective in patients with relapsed B-cell ALL who have limited therapeutic options, it can be associated with significant toxicities, which we have learned how to manage better. Since 2017, 2 CAR T-cell therapies have been approved by the FDA—Kymriah (tisagenlecleucel) and Tecartus (brexucabtagene autoleucel). The groundbreaking therapies in ALL research have altered the treatment landscape, demonstrating an unprecedented response rate in advanced ALL, and offer renewed hope and prospects for improved patient outcomes.
Like patients with ALL, patients with AML who present with a high-risk status at diagnosis may often be considered for stem cell transplantation as an option for consolidative and curative therapy later on.
AML is derived from the myeloid lineage of the hematopoietic stem cell structure. This disease accounts for 80% of acute leukemias in the adult population. AML is a disease of older adults, with an average age at diagnosis of approximately 65 years. AML risk is stratified into favorable, intermediate, or adverse based on patient characteristics and genetic analysis (Table 2). The standard-of-care initial therapy, referred to as induction, is a combination regimen consisting of 2 chemotherapies—cytarabine along with an anthracycline (daunorubicin or idarubicin)—otherwise known as the 7+3 regimen. This therapy is typically offered to younger patients and those who have a good performance status.11 For elderly patients or those ineligible for intensive chemotherapy, a more gentle regimen consisting of a hypomethylating agent such as decitabine or azacitidine given with a BCL-2 inhibitor, venetoclax, is also a commonly used option for frontline therapy with comparable response rates. Venetoclax is an oral medication, and its approved usage in AML has been one of the most significant advancements. It offers an effective therapy for older patients with AML, who represent close to half of all newly diagnosed cases and were otherwise ineligible for curative intense therapy such as the 7+3 regimen. Like patients with ALL, patients with AML who present with a high-risk status at diagnosis may often be considered for stem cell transplantation as an option for consolidative and curative therapy later on.
Advancements in AML therapy are constantly expanding, and targeted therapies are also available to patients who express distinct molecular subtypes of AML. Our deeper understanding of leukemia genetics and the evolution in molecular diagnostic tools, such as polymerase chain reaction and next-generation sequencing, have allowed us to individualize AML therapy to target specific subtypes. Several molecular variations of AML described here include FLT3, IDH, and KMT2A mutations. In the case of FLT3-mutated AML, oral agents such as gilteritinib, quizartinib, or midostaurin may be used in combination with high- or low-intensity chemotherapy as frontline therapy and in relapsed disease. In addition, enasidenib, or ivosidenib are FDA-approved drugs that target IDH mutations and have shown single-agent activity. AML with KMT2A rearrangement is identified in approximately 5% of cases and is associated with a higher risk of relapse. Menin inhibitors are a new class of targeted oral drugs that inhibit the menin-KMT2A interaction that is essential for driving the survival of NPM1-mutated and KMT2A-rearranged leukemias. The AUGMENT-101 trial demonstrated encouraging results using the menin inhibitor revumenib in patients harboring the KMT2A rearrangement or NPM1 mutations.12 Beyond targeted therapies, numerous immunotherapy options have been studied in clinical trials. So far, the only antibody therapy approved for AML therapy is gemtuzumab ozogamicin, which targets CD33. There are also a few CAR T-cell trials for treatment of AML since it has shown promise in lymphoid diseases. AML is a heterogeneous disease, but the availability of small-molecule inhibitors and immunotherapy allows for a more tailored therapeutic approach in patients with AML who express certain genetic variations.
At the first visit with the hematologist, it is crucial to complete comprehensive testing, including a bone marrow biopsy to determine the type of leukemia and identify any associated genetic abnormalities.
Undoubtedly a diagnosis of acute leukemia is daunting and life changing, but it is important to understand that there is hope and support every step of the way. At the first visit with the hematologist, it is crucial to complete comprehensive testing, including a bone marrow biopsy to determine the type of leukemia and identify any associated genetic abnormalities. This vital information will allow the physician to create the optimal treatment plan that will produce the highest likelihood of success. This information will also allow the patient to better engage with the physician and ask questions about the disease to develop a deeper understanding of the condition and what is to be expected when initiating treatment. Following are some key questions that patients may consider asking at their clinic visits upon diagnosis:
While the potential for resistance to treatment or relapse exists, it is reassuring to know that specialized cancer hospitals offer numerous treatments for standard of care, salvage chemotherapy, and a multitude of clinical trials for refractory and progressive disease. It is important to ask the physician about the options available as each of these represents a potential pathway to remission and recovery. Although the treatments for ALL and AML are prolonged and physically taxing, it is important that the patient maintain hope and surround themselves with a strong support system of family and friends. Together, with the dedicated treatment team, the patient can navigate this journey with resilience and optimism.
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