Acute myeloid leukemia: Overview of complications

INTRODUCTION — The clinical course of acute myeloid leukemia (AML) is complex, and the care of patients with AML should be entrusted to clinicians with sufficient knowledge and experience. Symptoms associated with anemia, infection, and bleeding occur almost universally as a consequence of the treatment and the disease itself. Other complications, such as leukostasis, metabolic abnormalities, and involvement of the central nervous system (CNS) may also be life-threatening, and must be rapidly diagnosed and treated, lest they interfere with appropriate treatment of the leukemia, either before chemotherapy can be given, or during the recovery period.

This topic will provide an overview of the complications of AML. The clinical features, diagnosis, classification, treatment, and overall prognosis of AML are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●(See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

●(See "Acute myeloid leukemia: Management of medically unfit adults".)

ANEMIA — Patients with AML typically present with a normocytic, normochromic anemia that can vary in severity. This anemia worsens with induction chemotherapy and is managed primarily with blood transfusions. There is no role for the use of erythropoietic stimulating agents during induction therapy of AML. (See "Causes of anemia in patients with cancer".)

The threshold for transfusion of packed red blood cells varies with patient age, symptoms, and the presence of medical comorbidities. In general, most centers recommend transfusion to asymptomatic patients with a hemoglobin ≤8 g/dL (5 mmol/liter). Blood products should be leukocyte depleted to reduce the risk of alloimmunization and transmission of cytomegalovirus (CMV) [1,2]. Although graft versus host disease is very unusual in patients with leukemia receiving conventional chemotherapy, many centers routinely irradiate blood products for such patients. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

Of importance, red cell transfusions may increase the whole blood viscosity of patients with hyperleukocytosis resulting in symptoms of leukostasis. As such, red blood cell transfusions should be administered very slowly, or, if possible, withheld until the blast count is reduced in such patients. (See "Hyperleukocytosis and leukostasis in hematologic malignancies", section on 'Supportive care'.)

INFECTION — The prolonged period of neutropenia associated with chemotherapy in patients with AML is frequently associated with neutropenic fevers and a high risk of infection with bacteria or fungi and viral reactivation. The prophylaxis and treatment of infectious complications in patients with AML is presented separately. (See "Overview of neutropenic fever syndromes" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

BLEEDING — Bleeding in a patient with AML may be due to thrombocytopenia, other platelet disorders, or disorders of coagulation.

Platelet disorders — Approximately 75 percent of patients with AML will have platelet counts below 100 x 10⁹/L (100,000/microL) at diagnosis, and about 25 percent will have counts below 25 x 10⁹/L (25,000/microL). Both morphologic and functional platelet abnormalities may be seen. Based on the results of a number of randomized trials, platelets are usually transfused prophylactically to prevent hemorrhage at counts less than 10,000/microL and at higher counts in patients with active bleeding or with clinical problems such as hyperleukostasis, fever, severe infection, pulmonary compromise, or coagulopathy [3]. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)

Disseminated intravascular coagulation — Disseminated intravascular coagulation (DIC) may be seen with all leukemia subtypes. It can be an especially prominent feature in patients with acute promyelocytic leukemia (see "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Coagulopathy and APL'). DIC is often present in association with hyperleukocytosis in patients with acute myelomonocytic or acute monocytic leukemia. Coagulation profiles, including fibrinogen and measurements of fibrin degradation products should be obtained at the time of leukemia diagnosis.

Treatment with platelet transfusions and appropriate coagulation factors (eg, cryoprecipitate for severe hypofibrinogenemia) can be considered in select situations. It should be noted that the plasma in which platelets are suspended contains coagulation factors that can be of sufficient concentration for patients with milder DIC. This is discussed in more detail separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Initial treatment of acute promyelocytic leukemia in adults", section on 'Control of coagulopathy'.)

Menorrhagia — Premenopausal women are at risk for severe and prolonged menorrhagia during induction therapy. Prevention and treatment of this complication is presented separately. (See "Management of menorrhagia during chemotherapy".)

DIFFERENTIATION SYNDROME — Differentiation syndrome (DS) is a treatment complication that requires urgent management with systemic glucocorticoids to prevent progressive respiratory or renal insufficiency, heart failure, and other life-threatening complications. (See "Differentiation syndrome associated with treatment of acute leukemia".)

DS is most often caused by treatment of AML with inhibitors of isocitrate dehydrogenase (IDH; eg, ivosidenib, enasidenib) or treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). It generally presents several days to several weeks after treatment initiation with fever, peripheral edema, hypotension, weight gain, and/or effusions. Laboratory studies usually reveal leukocytosis (which may include a rapid increase in blast count), acute renal failure, radiographic opacities, and/or pleuro-pericardial effusion. The clinical and laboratory abnormalities of DS must be distinguished from findings of infection/sepsis, thromboembolism, heart failure, alveolar hemorrhage, drug allergy, and acute kidney injury. (See "Differentiation syndrome associated with treatment of acute leukemia", section on 'Clinical presentation' and "Differentiation syndrome associated with treatment of acute leukemia", section on 'Differential diagnosis'.)

Patients with one or more clinical features of DS should be treated promptly with systemic glucocorticoids, rather than waiting to complete the diagnostic evaluation. Supportive care generally includes empiric antibiotics, fluid management, and supplemental oxygenation; severe cases may require renal replacement therapy or mechanical ventilation. Treatment may also include hydroxyurea to control leukocytosis and/or temporary discontinuation of the antileukemic therapy, as discussed separately. (See "Differentiation syndrome associated with treatment of acute leukemia", section on 'Treatment'.)

HYPERLEUKOCYTOSIS AND LEUKOSTASIS — Hyperleukocytosis has been variably defined in the setting of AML as a total white blood cell count greater than 50 x 10⁹/L (50,000/microL) or greater than 100 x 10⁹/L (100,000/microL). It is present in 10 to 20 percent of patients with newly diagnosed AML. Symptomatic hyperleukocytosis (ie, leukostasis), typically presenting with respiratory or neurological distress, constitutes a medical emergency. An absolute myeloblast count approaching 100,000/microL is a medical emergency even in the asymptomatic patient. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

METABOLIC ABNORMALITIES — Patients with AML can experience a wide range of metabolic problems as a consequence of vomiting, diarrhea, impaired nutrition, excessive fluid administration, diuretics, or renal dysfunction, usually due to side effects from the use of antibiotics and/or chemotherapy.

Other metabolic disorders are related to the leukemic process itself and are discussed below.

Tumor lysis syndrome — Tumor lysis syndrome, caused by rapid leukemic cell death following the onset of chemotherapy, can be seen in patients with AML, especially those with hyperleukocytosis, impaired baseline renal function, and hyperuricemia at the time of diagnosis [4,5].

Tumor lysis syndrome is characterized by hyperphosphatemia, hypocalcemia, hyperuricemia, hyperkalemia, and renal insufficiency. The inciting cause seems to be release of large amounts of phosphate from lysed blasts, which coprecipitates with calcium in the kidneys, leading to hypocalcemia and sometimes to oliguric renal failure. Hyperuricemia further contributes to this problem. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Hyperuricemia — Hyperuricemia is the most frequent metabolic abnormality seen in patients with AML. It is also one of the diagnostic criteria for tumor lysis syndrome. (See "Uric acid kidney diseases" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Hyperuricemia can result in renal insufficiency due to uric acid nephropathy, as well as acute gout. Patients should receive intravenous hydration and medical therapy to reduce uric acid levels during induction therapy. The prevention and treatment of tumor lysis syndrome is discussed in more detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Hyperphosphatemia — Hyperphosphatemia is seen in patients with AML and tumor lysis syndrome. Acute severe hyperphosphatemia with symptomatic hypocalcemia can be life-threatening. Treatment includes vigorous hydration, if possible, and the administration of a phosphate binder with or without dialysis (table 1). The prevention and treatment of tumor lysis syndrome is discussed in more detail separately. (See "Overview of the causes and treatment of hyperphosphatemia" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Hypocalcemia — Hypocalcemia is a component of tumor lysis syndrome. Patients with acute hypocalcemia and hyperphosphatemia due to tumor lysis syndrome should not be treated with calcium until the hyperphosphatemia is corrected. Hemodialysis is often indicated in such patients who have renal failure (table 1). The prevention and treatment of tumor lysis syndrome is discussed in more detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Treatment of hypocalcemia".)

Hyperkalemia — Hyperkalemia can occur as a consequence of renal dysfunction in patients with severe tumor lysis syndrome. Treatments include insulin plus glucose, sodium bicarbonate, beta-2-adrenergic agonists, loop or thiazide diuretics, cation exchange resin, and/or dialysis (table 1). The prevention and treatment of tumor lysis syndrome is discussed in more detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Treatment and prevention of hyperkalemia in adults".)

Hyperkalemia can also be an artifact of blood drawing in patients with AML, a phenomenon called pseudohyperkalemia. In this setting, the plasma potassium using an anticoagulated specimen is normal, but the measured serum potassium may be elevated due to release of potassium during clotting from the increased number of white cells [6]. (See "Causes and evaluation of hyperkalemia in adults", section on 'Pseudohyperkalemia'.)

Hypokalemia — Severe, occasionally symptomatic, hypokalemia is not infrequent, particularly in patients with monocytic leukemias. The mechanism appears to be renal potassium loss secondary to tubular damage induced by high levels of lysozyme [7]. Aggressive replacement with parenteral potassium is required; hypokalemia usually abates after cytoreduction by chemotherapy. Hypokalemia can also be a side effect of therapy with certain drugs, such as amphotericin B. (See "Causes of hypokalemia in adults", section on 'Salt-wasting nephropathies' and "Causes of hypokalemia in adults", section on 'Amphotericin B' and "Clinical manifestations and treatment of hypokalemia in adults", section on 'Severe or symptomatic hypokalemia'.)

Hypercalcemia — Despite markedly hypercellular marrows, hypercalcemia is extremely unusual in AML [4]. It has been described in other leukemic conditions, such as plasma cell leukemia, blast crisis in chronic myeloid leukemia, and adult T cell leukemia-lymphoma. (See "Hypercalcemia of malignancy: Mechanisms" and "Treatment of hypercalcemia" and "Plasma cell leukemia" and "Treatment and prognosis of adult T cell leukemia-lymphoma".)

Lactic acidosis — Rare patients have been described in whom lactic acidosis has been a metabolic accompaniment of the leukemia, both at the time of presentation and relapse [4,8,9]. The mechanism is unclear, although anaerobic metabolism by the leukemic cells at sites of leukostasis has been postulated. The prognosis of this complication is grave; chemotherapy, if effective, corrects the acute acidosis in some, but not all, patients.

CNS LEUKEMIA — Involvement of the central nervous system (CNS) at the time of AML diagnosis is uncommon, and routine evaluation is not recommended for asymptomatic patients.

Patients with focal neurologic findings who present with newly diagnosed AML should have a diagnostic lumbar puncture (LP). The cerebrospinal fluid sample should be assessed with cell counts, cytology, and flow cytometry.

Patients with evidence of other extramedullary disease (eg, myeloid sarcoma, leukemia cutis, gingival hyperplasia), hyperleukocytosis (white blood cell >50,000/microL), or acute myelomonocytic/monocytic subtype are at higher risk of CNS involvement at presentation. For such individuals who are asymptomatic, a diagnostic LP can be performed at the time of the count nadir (eg, day 14 to 21) to rule out asymptomatic CNS involvement, as discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

OCULAR INVOLVEMENT — Any ocular structure may be involved in acute leukemia and ocular involvement more frequently dominated the clinical picture in the prechemotherapy era [10]. Involvement of the choroid and retina is most common. However, leukemic cells can infiltrate the conjunctiva and lacrimal glands, producing obvious masses.

Ophthalmic examination — Patients suspected of having ocular involvement should undergo a full evaluation by an ophthalmologist including a slit lamp examination [11,12].

A comprehensive, prospective study of 53 newly diagnosed adults with AML documented retinal or optic nerve abnormalities in 64 percent [13]. Hemorrhage and cotton wool spots (a consequence of nerve fiber ischemia) were the most frequent findings. Their occurrence was unrelated to patient age, AML subtype, white blood cell count, or hematocrit. Initial platelet counts were lower in patients with retinopathy. Ten patients had decreased visual acuity, including five with macular hemorrhages. Cotton wool spots may be a consequence of or exacerbated by ischemia due to anemia. Definite leukemic infiltration of the retina could not be confirmed in this study.

Treatment — Patients with ocular involvement, but no other evidence of CNS involvement, are treated in a similar fashion to patients without CNS involvement (ie, induction chemotherapy followed by post-remission therapy). Early empiric use of antifungal therapy has decreased the likelihood of hematogenous spread of fungal infection to the eye.

All patients in the study described above received induction chemotherapy [13]; no patient received intrathecal chemotherapy or cranial or ocular irradiation. All ocular findings resolved in patients achieving complete remission and there was no residual visual deficit in any patient. Infectious ocular problems were not noted and seem to be uncommon, perhaps because of the rapid, empiric use of antibiotics.

NEUTROPENIC ENTEROCOLITIS — Neutropenic enterocolitis (typhlitis) tends to occur after chemotherapy administration at the time of the neutrophil count nadir and has been associated with high mortality rates [14].

Neutropenic enterocolitis must be considered in the differential diagnosis of any profoundly neutropenic patient (absolute neutrophil count <500/microL) who presents with abdominal pain, usually in the right lower quadrant, with or without fever. Additional symptoms may include abdominal distension, nausea, vomiting, and watery or bloody diarrhea. Signs of peritoneal irritation and shock suggest the possibility of bowel wall perforation. It is usually diagnosed by characteristic findings on computed tomography scan in high-risk patients. Early imaging should be encouraged whenever the suspicion of this potentially lethal entity arises. Tests to exclude infection with Clostridioides difficile should be done, particularly in patients with significant diarrhea. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Management is mostly supportive, although surgical intervention may be required if bowel wall perforation, necrosis, or uncontrollable bleeding is present. Use of myeloid colony stimulating factors and granulocyte transfusions may be considered in select patients with an expected prolonged duration of neutropenia. (See "Neutropenic enterocolitis (typhlitis)" and "Granulocyte transfusions" and "Management of acute chemotherapy-related diarrhea", section on 'Neutropenic enterocolitis'.)

JOINT INVOLVEMENT — Invasion of the synovial membrane of the joints with leukemic blasts is an uncommon manifestation of AML. It may antedate the clinical diagnosis of AML, may mimic other acute arthritic syndromes such as rheumatoid arthritis, and responds only to treatment directed at the leukemic process [15-17]. (See "Malignancy and rheumatic disorders", section on 'Leukemia'.)

VENOUS THROMBOEMBOLISM — Patients with AML may have an increased risk of developing venous thromboembolism (VTE), especially during the first three months of treatment [18]. Retrospective analyses have reported incidence rates of VTE among patients with AML that range from 2 to 13 percent [19-23]. The incidence appears to be higher in patients with acute promyelocytic leukemia with rates of 6 to 43 percent [19-23]. The majority of thromboses appear to occur within the first month of treatment [23]. Most of the thromboses are related to the presence of indwelling central venous catheters.

No controlled studies or society guidelines are available to guide decisions regarding prophylaxis or treatment of VTE in patients with AML. Prophylaxis for VTE is not commonly given to patients with AML because of the prolonged thrombocytopenia and associated bleeding risk during induction treatment. However, severe thrombocytopenia does not completely eliminate the risk of VTE in this population. VTE may be related to prolonged immobility and venous stasis from bed rest during induction therapy. Therefore, it is reasonable to encourage patients to be out of bed as much as possible during the induction phase of therapy. In addition, increased early mobility may also help ameliorate leg edema that frequently complicates induction therapy.

The treatment of VTE in patients with malignancy is presented separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

ACUTE PULMONARY FAILURE — Acute pulmonary failure (APF) during induction therapy for AML is an uncommon but serious complication. Potential causes include lung hemorrhage, capillary leak from tumor lysis or fluid overload, infections, sepsis, and the differentiation syndrome in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) [24]. (See "Differentiation syndrome associated with treatment of acute leukemia".)

In one series of 1541 patients referred for remission induction chemotherapy for AML or high-risk myelodysplasia, 120 (8 percent) developed APF and required ventilatory support within two weeks of the initiation of chemotherapy [24]. The mortality rate during induction therapy for these patients was 73 percent.

Multivariable analysis indicated five prognostic features predicting for APF: male sex, APL, poor performance status, lung infiltrates at diagnosis, and increased serum creatinine. Patients with zero to 1, 2, 3, or 4 to 5 adverse factors had estimated incidences of APF of 3, 13, 23, and 34 percent, respectively.

PERICARDIAL EFFUSION — There is a paucity of data describing the incidence and complications of pericardial effusions in patients with AML. In a retrospective study of 2592 patients with acute leukemia or myelodysplastic syndrome, echocardiogram data was available for 1600 patients (62 percent) [25]. A pericardial effusion was present in 21 percent of patients with AML, 70 percent of which were minimal or trace in size. Moderate or large effusions accounted for only 5 and 0.5 percent, respectively, and only 3 percent of effusions required pericardiocentesis due to tamponade at the time of detection. Patients with pericardial effusions had similar survival rates to those without effusions. (See "Pericardial disease associated with cancer: Clinical presentation and diagnosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY

●Description – Patients with acute myeloid leukemia (AML) frequently encounter complications, either due to their underlying disease or related to the administration of chemotherapy.

●Complications – The following complications are associated with AML and require prompt diagnosis and intervention:

•Anemia (see 'Anemia' above)

•Infections (see 'Infection' above)

•Bleeding (see 'Bleeding' above)

•Differentiation syndrome (see 'Differentiation syndrome' above)

•Hyperleukocytosis/leukostasis (see 'Hyperleukocytosis and leukostasis' above)

•Metabolic abnormalities (see 'Metabolic abnormalities' above)

•Central nervous system (CNS) involvement (see 'CNS leukemia' above)

•Ocular involvement (see 'Ocular involvement' above)

•Neutropenic enterocolitis (typhlitis) (see 'Neutropenic enterocolitis' above)

•Joint involvement (see 'Joint involvement' above)

•Venous thromboembolism (see 'Venous thromboembolism' above)

•Respiratory failure (see 'Acute pulmonary failure' above)

•Pericardial effusion (see 'Pericardial effusion' above)