Evaluating Signs and Symptoms

The following section includes common signs and symptoms associated with AML. Not all symptoms of AML are discussed—always recommend for patients to consult their healthcare professional(s) with any concerns about signs or symptoms.

Signs and Symptoms Related to Anemia

  • Anemia in AML occurs when blasts crowd out normal red blood cell production in bone marrow and can lead to symptoms such as fatigue and shortness of breath1
  • Patients with AML typically present with normocytic, normochromic anemia that can vary in severity2
  • A shortage of red blood cells reduces the amount of oxygen carried throughout the body, resulting in signs and symptoms of hypoxia1
  • General fatigue is present in the majority of patients with AML and often precedes diagnosis for a number of months3
  • In a study of 249 patients with AML, 79.2% reported fatigue as a symptom and 20.4% experienced shortness of breath4
  • In a small study of 53 newly diagnosed adults, retinal or optic nerve abnormalities were documented in nearly two-thirds of patients2
    • Hemorrhage and cotton wool spots were the most frequent finding; cotton wool spots may be caused or exacerbated by nerve fiber ischemia resulting from anemia2

Signs and Symptoms Related to Thrombocytopenia

  • Thrombocytopenia occurs when blasts crowd out maturation of functional platelets in bone marrow; this can lead to symptoms including, but not limited to1:
    • Petechial rash
    • Bleeding
      • Epistaxis
      • Gingival bleeding
      • Menorrhagia
    • Ecchymosis
  • Premenopausal women may experience severe/prolonged menorrhagia2
  • Thrombocytopenia is common in AML with about 75% of all patients having platelet counts <100 × 109/L at diagnosis2
    • Approximately 25% of patients will have counts <25 × 109/L
    • Both morphologic and functional platelet abnormalities might be observed
  • 42% of patients report skin changes4
    • Skin changes, such as petechial rash and bruising, can be related to thrombocytopenia1
    • Petechial rash is caused by damage/bleeding of capillaries just under the skin and is typically seen on arms, legs, stomach, buttocks, and inside the mouth3

Signs and Symptoms Related to Neutropenia

  • Neutropenia occurs when infiltration of the bone marrow by leukemia cells leads to decreased production of white blood cells, and can cause symptoms including, but not limited to1:
    • Increased infections
    • Fever
    • Night sweats
  • Neutropenia is defined as absolute neutrophil count (ANC) <1000 neutrophils/μL; the low number of immune cells results in an increased risk of infection6
  • Certain signaling pathways may be activated in response to infection, leading to a release of cytokines that mount an immune response and result in fever7
    • Cytokines that can cause fever include: IL-1, IL-6, TNF, IFN-alpha7
  • The presence of fever in patients with AML is almost always due to infection and should prompt thorough investigation of potential infectious sites3
  • A small minority of patients develop fever solely due to the underlying leukemia and fever resolves with appropriate chemotherapy. This is most commonly seen in patients with acute promyelocytic leukemia (APL), a subtype of AML3
  • Elevated levels of pyrogenic cytokines can lead to drenching night sweats during AML,8 reported in 38% of patients4

Signs and Symptoms Related to Leukostasis9

  • Leukostasis, also known as symptomatic hyperleukocytosis, is a medical emergency that results from an extremely high blast count, typically diagnosed when a patient with AML with a blast cell count >100 × 109/L presents with respiratory or neurologic stress
  • Leukostasis is associated with symptoms of decreased tissue perfusion, including, but not limited to:
    • Pulmonary symptoms (dyspnea, hypoxia)
    • Neurological symptoms (visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, increased risk of intracranial hemorrhage, and sometimes coma)
    • Fever
  • Less common symptoms include myocardial ischemia, right ventricular overload, worsening renal insufficiency, priapism, acute limb ischemia, and bowel infarction
  • The incidence of leukostasis in newly diagnosed AML is between 10% and 20%
  • The pathophysiology of leukostasis is not fully understood but two major theories exist:
    • Increased blood viscosity and impeded blood flow due to plugs formed from the large circulating population of rigid blasts
    • Decreased blood oxygen levels due to increased metabolic activity of dividing blasts
    • It is likely that both mechanisms and possible additional unidentified mechanisms contribute
  • Patients experiencing leukostasis require prompt medical attention; the 1-week mortality rate is ~20% to 40% if left untreated
  • The main clinical symptoms and cause of early death in patients with leukocytosis are related to CNS and lung involvement

Signs and Symptoms Related to Organ Infiltration

  • Organ infiltration results when leukemic cells begin to move into a patient’s organs, and can lead to symptoms including, but not limited to3:
    • Gingival hypertrophy
    • Bone pain
    • Joint involvement
    • Infiltrative skin lesions
    • Organomegaly
  • Gingival infiltration is present in ~5% of patients as an initial complication of AML10
    • In a study of 1076 patients, gingival hyperplasia was most commonly seen in the following AML subtypes:
      • Acute monocytic leukemia (66.7%)
      • Acute myelomonocytic leukemia (18.5%)
      • Acute myelocytic leukemia (3.7%)
  • Bone pain may be caused by expansion of the medullary cavity due to crowding of the bone marrow by leukemic blasts and may be reported as discomfort, aching, or tenderness in the sternum and long bones, and lower extremities3
  • ~4% of patients with AML present with symmetric or migratory polyarthritis/arthralgia3
  • Infiltrative lesions of the skin may develop due to leukemic involvement and occur in up to 13% of patients; they are more common in AML with prominent monocytic or myelomonocytic component3
  • Infiltration of organs can lead to organomegaly, with hepatomegaly and splenomegaly each occurring in ~10% of patients3

Signs and Symptoms Related to Central Nervous System (CNS) Involvement

  • CNS involvement is common in pediatric patients but uncommon in adult patients
  • CNS involvement may be diagnosed due to the presence of blasts in the cerebrospinal fluid and/or with intracerebral myeloid sarcoma or meningeal AML11
  • Patients with the following symptoms should be evaluated for CNS involvement12:
    • Symptoms of increased intracranial pressure (persistant headache, lethargy, other neurologic changes)
    • Cranial nerve palsies
    • Symptoms of CNS hemorrhage (seizure, altered mental state, headache, neurological deficits)
    • Symptoms of spinal cord compression (back pain, weakness, paresthesia, bladder dysfunction)
    • Visual changes
  • In one study, 21 (0.6%) patients with AML had CNS symptoms at diagnosis, with symptoms more common (34 patients, 2.9%) at relapse11
  • Patients with CNS involvement at initial diagnosis have worse overall survival compared to those without CNS involvement at initial diagnosis11
  • CNS involvement is more common in patients with a high peripheral blast count than those with a low peripheral blast count13

References: 1. Signs and Symptoms of Acute Myeloid Leukemia (AML). American Cancer Society website. http://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/signs-symptoms.html. Updated August 21, 2018. Accessed April 22, 2021. 2. Schiffer CA. Overview of the complications of acute myeloid leukemia. UpToDate website. https://www.uptodate.com/contents/overview-of-the-complications-of-acute-myeloid-leukemia. Updated August 15, 2019. Accessed April 22, 2021. 3. Schiffer CA, Gurbuxani S. Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia. UpToDate website. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-acute-myeloid-leukemia. Updated June 4, 2021. Accessed April 22, 2021. 4. Zimmermann C, Yuen D, Mischitelle A, et al. Symptom burden and supportive care in patients with acute leukemia. Leuk Res. 2013;37(7):731-736. 5. Rauch PJ, Ellegast JM, Widmer CC, et al. MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia. Blood. 2016;128(18):2253-2257. 6. Understanding Your Lab Test Results. American Cancer Society website. https://www.cancer.org/content/dam/CRC/PDF/Public/7174.pdf. Updated April 22, 2016. Accessed April 22, 2021. 7. Dinarello CA, Porat R. Pathophysiology and treatment of fever in adults. UpToDate website. https://www.uptodate.com/contents/pathophysiology-and-treatment-of-fever-in-adults. Updated September 17, 2018. Accessed April 22, 2021. 8. Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer. 2001;92(6 Suppl):1684-1688. 9. Schiffer CA. Hyperleukocytosis and leukostasis in hematologic malignancies. UpToDate website. https://www.uptodate.com/contents/hyperleukocytosis-and-leukostasis-in-hematologic-malignancies. Updated November 13, 2019. Accessed April 22, 2021. 10. Demirer S, Özdemir H, Şencan M, Marakoğlu Í. Gingival hyperplasia as an early diagnostic oral manifestation in acute monocytic leukemia: a case report. Eur J Dent. 2007;1(2):111-114. 11. Alakel N, Stölzel F, Mohr B, et al. Symptomatic central nervous system involvement in adult patients with acute myeloid leukemia. Cancer Manag Res. 2017;9:97-102. 12. Schiffer CA. Involvement of the central nervous system with acute myeloid leukemia. UpToDate website. https://www.uptodate.com/contents/involvement-of-the-central-nervous-system-with-acute-myeloid-leukemia. Updated June 22, 2020. Accessed April 22, 2021. 13. Cheng CL, Li CC, Hou HA, et al. Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults. BMC Cancer. 2015;15:344.