Acute leukemia is a neoplasm of the stem cell that results in rapid accumulation of immature myeloid or lymphoid precursors (functionally inert blasts) in the bone marrow. This accumulation—termed clonal proliferation—takes up space necessary for normal hematopoiesis and causes secondary cytopenias. Leukemia affects different cell lineages in hematopoietic tissues, including erythrocytes, lymphocytes, granulocytes, and megakaryocytes. Individual leukemic cells do not divide more rapidly than do normal cells; however, at any given moment, a larger proportion of leukemic cells are dividing. Chemotherapy exploits this increase in mitotic activity.1 When acute leukemia is left untreated, the accumulation of 1012 cells is fatal.1
The World Health Organization of Tumors of Hematopoietic and Lymphoid Tissues2 defines leukemia as the presence of >20% blasts in the bone marrow or peripheral blood. Leukemia is subdivided by lineage into myeloid and lymphoid disease. Acute myeloid leukemia (AML) is further subdivided into seven subgroups based on cytology, cytogenetics, and molecular analysis. In some instances, a diagnosis of AML is made regardless of the percentage of bone marrow blasts—specifically, in patients with translocations between chromosome 8 and 21 or 15 and 17, inversions in chromosome 16, or myeloid sarcomas. Acute lymphoblastic leukemia (ALL) is divided into three major subgroups based on differences in treatment and prognosis: (1) precursor B- or T-cell ALL, with further subdivision made based on recurring molecular–cytogenetic abnormalities; (2) Burkitt leukemia/lymphoma; and (3) biphenotypic acute leukemia. Approximately 90% of leukemia is of myeloid origin, with 10% of lymphoid origin.2
The annual incidence of AML is 3.5 per 100,000; an estimated 13,780 patients were diagnosed in the United States in 2012.3 AML incidence increases with age, with a median age at diagnosis of 67 according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results data.4 If untreated, AML is fatal and confers an average overall survival of <20 weeks from time of diagnosis.5 Six thousand and fifty total adult and pediatric cases of ALL were reported in the United States in 2012.3 ALL is five times more likely to occur in the pediatric population than in the adult population; it represents 30% of all childhood neoplasms, with the average age at diagnosis of 13 years.6 With improved treatment strategies, the 5-year overall cure rate for ALL in the pediatric population is over 80%; the lower adult cure rate of 30% to 40% is largely due to age-related adverse molecular features and resistance to therapy.7
Most cases of acute leukemia are idiopathic. Known risks include exposure to cytotoxic chemotherapy (particularly topoisomerase II inhibitors and alkylating agents8), pesticides, benzene, or radiation.9 Genetic disorders, including trisomy 21 and inherited bone marrow failure syndromes, have also been associated with AML.2
In AML, specific prognostic features guide patient survival prediction. These include, but are not limited to, advanced age10; previous exposure to chemotherapy11; cytogenetic features that stratify disease prognosis into favorable, intermediate, and poor12; and evolution of a patient’s AML from a previous myelodysplasia or myeloproliferative neoplasms.13 Molecular screening investigations can further delineate prognosis, with poor outcomes conferred by the presence of the FMS-like tyrosine kinase 3 (FLT-3)14 and c-kit mutation,15 and favorable outcomes conferred by nucleophosmin-1 and CEBPA16 mutations. In ALL, as well, several prognostic factors—including age, leukocyte count, and molecular genotypes such as BCR-ABL1 positivity—guide selection of treatment.17
Patient symptoms vary according to clinical stage of acute leukemia. Symptoms on initial presentation are due to increased tumor cell mass, factors released by leukemic cells, pancytopenia, and immunologic reactions. Later symptoms are usually secondary to either the sequelae of pancytopenia or complications of chemotherapy. Table 27.1 reviews pertinent clinical history and physical exam findings of patients on their initial presentation.
TABLE 27.1 Pertinent Findings on Patient History and Physical Exam with First Presentation
From Miller KB, Daoust PR. Clinical manifestations of acute myeloid leukemia. In: Hoffman R, ed. Hematology Basic Principles and Practice. 4th ed. Philadelphia, PA: Elsevier Inc.; 2005:1071–1095; Zuckerman T, Ganzel C, Tallman M, et al. How I treat hematologic emergencies in adults with acute leukemia. Blood. 2012;120(10):1993–2002.18
The following studies are recommended for any patient in whom acute leukemia is suspected:
- CBC with peripheral blood film, ideally read by an experienced hematologist or pathologist. In cases of elevated blast counts, a manual platelet count should be made, as automated cell counters may erroneously count fragments of blast cells as platelets.
- Coagulation studies: PT, PTT, fibrinogen, d-dimer. Consider fibrinogen assays for the bleeding patient.
- Complete biochemical profile to assess for tumor lysis syndrome (TLS) (electrolytes, creatinine, calcium, magnesium, phosphate, uric acid, LDH).
- Liver enzymes and liver function tests.
- Viral serologies: HSV, VZV, CMV, hepatitis B and C.
- Screening for syphilis.
- In the case of fever: blood cultures, urine cultures, imaging guided by physical exam, and a complete evaluation of oral hygiene, as the mouth is a common site of bacterial seeding.
- In the case of significant CNS signs or symptoms: CT head or MRI imaging to rule out intracerebral hemorrhage, leptomeningeal disease, or extramedullary disease.
Hematology should be consulted and will typically coordinate the following studies:
- CT chest to rule out occult fungal infection
- Bone marrow aspirate and biopsy
- Cardiac function test: if anthracyclines are to be administered, MUGA nuclear imaging is preferred over echocardiography because of cardiotoxicity risk
- Lumbar puncture: provided the patient is not coagulopathic and neuroimaging is normal
- HLA typing of the patient and siblings if considering a transplant
Acute leukemia is diagnosed when the peripheral blood or bone marrow contains >20% blasts. Typically, a bone marrow aspirate and biopsy are performed to distinguish AML from ALL and high-grade myelodysplasia. Alternative diagnoses to consider in the setting of severe pancytopenia include aplastic anemia, severe B12 deficiency, or drug-induced aplasia. In patients with blasts on peripheral blood film, myeloproliferative neoplasms, including myelofibrosis and chronic myelogenous leukemia, should also be considered.
EMERGENCIES IN ACUTE LEUKEMIA
Hyperleukocytosis is a medical emergency that typically occurs when the blast count exceeds >100,000/μL. It is seen in 5% to 18% of acute leukemia, predominantly in disease of monocytic origin.19 Increased blood viscosity in hyperleukocytosis is due to the rigidity of the myeloblast membrane and an up-regulation of blast adhesion molecules; this results in blasts occluding circulatory flow, with subsequent tissue hypoxia, tissue infiltration, and secondary hemorrhage. Hyperviscosity does not occur with similar elevations of neutrophils (as seen in severe infections) or lymphocytes (as seen in chronic lymphocytic leukemia). Presenting symptoms of hyperleukocytosis are variable and include respiratory distress and hypoxia, as well as seizure, confusion, abdominal pain, angina, priapism, and visual complaints. Funduscopy should be performed to rule out papilledema, dilated vessels, or hemorrhage. In circumstances of respiratory decline, it is important to consider alternative explanations, including pneumonia, volume overload, or transfusion complications, including transfusion-related acute lung injury (TRALI).18 Pulse oximetry provides a more reliable measure of oxygen saturation for the hypoxic patient than does PaO2, which can be misleadingly low because of blast consumption of oxygen in the collection medium.20 If untreated, hyperleukocytosis confers a mortality of 20%; its most serious complications are pulmonary failure and intracerebral hemorrhage.21
Treatment of symptomatic hyperleukocytosis (aka leukostasis) varies by institution; a standard approach includes the prompt initiation of hydroxyurea for cytoreduction, with 2 to 5 g/day administered in divided doses.22 The role of leukapheresis is controversial; most studies that support its impact on survival are retrospective in design.23–25 Finally, caution should be used in transfusing patients with hyperleukocytosis because of the risk of worsening blood viscosity and aggravating symptoms.
Anemia and Transfusions
No clinical trials have evaluated a specific transfusion trigger in patients with acute leukemia. In critically ill patients without cardiac disease, the TRICC trial demonstrated that a restrictive transfusion strategy in the ICU (maintaining hemoglobin values between 7 and 9 g/dL) resulted in a reduced mortality rate at 30 days.26 For the leukemic patient, this approach has unclear benefit; thus, the threshold for transfusion is often practice dependent, with most providers transfusing for hemoglobin levels below 8 g/dL or as warranted given clinical symptoms.27 Caution must be exercised when transfusing patients with high blast counts in order to avoid inciting hyperviscosity. There is no role for erythropoietin-stimulating agents.
All transfused blood products should be irradiated and leukocyte depleted to minimize risk of transfusion-associated graft versus host disease (TA-GvHD). If a patient’s cytomegalovirus (CMV) status is unknown, exclusively CMV-negative blood products should be used. TA-GvHD is seen in immunocompromised hosts, particularly those undergoing AML therapy, post–allogeneic stem cell transplantation, or post–purine analogue therapy. One to four weeks post-transfusion patients with TA-GvHD can present with severe cytopenias and with associated fever, hepatitis, rash, and/or diarrhea. A bone marrow biopsy will reveal complete bone marrow aplasia. No treatment is effective, and the mortality rate of TA-GvHD exceeds 95%; it is therefore imperative to provide these patients with blood products that are leukoreduced and irradiated.18
Coagulopathy and Thrombocytopenia
All patients with leukemia should be transfused to maintain a platelet count of >10,000/μL in cases of nonactive bleeding or >50,000/μL in cases of active bleeding.28–31 All coagulopathic derangements should be promptly reversed with frozen plasma or cryoprecipitate. Note that patients with APL, acute monocytic, or myelomonocytic leukemias are at highest risk of disseminated intravascular coagulation (DIC); in these populations, coagulation screening should be performed at least twice daily to ensure proper replacement of platelets, coagulation factors, and fibrinogen.32 As with red blood cell support, all products should be irradiated and CMV negative if a patient’s CMV status is unknown.
Acute Promyelocytic Leukemia
APL is a subset of AML defined by the translocation of the retinoic acid receptor t(15;17); “PML;RAR-alpha” in 95% of patients. APL constitutes 10% of AML cases in the United States with most patients being diagnosed between ages 30 and 40. APL has an overall cure rate of 80% to 90%.33 Unlike other leukemias, APL poses an increased risk of fatal hemorrhage from DIC or primary hyperfibrinolysis and has a pretreatment mortality rate reported to be as high as 10% to 17%.34 Because of this, any patient suspected of having leukemia (i.e., blasts reported on their CBC differential) and a concurrent unexplained coagulopathy should be evaluated promptly for APL. A pathologist or hematologist should assess blast morphology; if APL is confirmed, treatment with all-trans retinoic acid (ATRA), which allows for differentiation of APL promyelocytes and restoration of coagulation, should begin immediately.35 Doses in children may be modified because of the potential risk of pseudotumor cerebri.36 Concurrent anthracycline chemotherapy is typically reserved for the patient with high-risk disease (i.e., WBC > 10,000/μL) to minimize the risk of leukocytosis, differentiation syndrome (previously ATRA syndrome), and provocation of coagulopathy—all potential risks when ATRA is administered alone.37 Because of the risk of fatal coagulopathy and hyperfibrinolysis, the platelet count, PT, PTT, and fibrinogen should be closely monitored. There are scant data on the optimal trigger for platelet and plasma product infusion, but consensus opinion targets a platelet count of 30,000 to 50,000/μL and a fibrinogen level of >150 mg/dL.32 Coagulopathy of APL can last for up to 20 days despite ATRA therapy.38 Placement of a central venous catheter, or invasive procedures such as lumbar punctures, should be avoided until the coagulopathy has been corrected. The hypogranular variant, a subset of APL, is conversely associated with thrombosis in up to 5% of patients39 and is typically managed with intravenous heparin and replacement of factor product as needed.
Tumor Lysis Syndrome
TLS occurs secondary to rapid cell death, as cellular products are excreted into the circulation. This can be observed at the time of leukemia diagnosis or after initiation of chemotherapy. TLS manifests biochemically either as increased uric acid that may result in concomitant renal failure or as marked hyperphosphatemia that leads to hypocalcemia and its attendant complications. Patients at highest risk of TLS include those with a high tumor burden, preexisting renal failure, chemotherapy-sensitive tumors with rapid lysis, and inadequate TLS prophylaxis (i.e., allopurinol).40 Uncontrolled TLS places patients at risk of renal failure, cardiac dysrhythmias, seizure, and death.41
TLS-Associated Uric Acid Nephropathy
Treatment of TLS focuses on intravenous hydration to attain a urine output of 80 to 100 mL/m.2,18 Patients often require more than 4 L of daily intravenous fluid support to achieve this goal.40 Alkalinization of the urine is no longer a routine treatment, as it has the potential to cause calcium phosphate or xanthine precipitation in renal tubules.42 Reduction in uric acid is typically achieved with renal-dosed allopurinol, a xanthine oxidase inhibitor, which generally lowers uric acid within 1 to 3 days. Rasburicase, a recombinant version of urate oxidase, has proven effective in cases of renal failure or allopurinol intolerance.43 Allopurinol affects only further production of uric acid; rasburicase, by contrast, can convert existing uric acid to allantoin, which is 5 to 10 times more soluble than is uric acid. The standard rasburicase dose is 0.2 mg/kg IV infusion over 30 minutes. The use of rasburicase is contraindicated in patients with G6PD deficiency because of the increased risk of oxidative hemolysis and methemoglobinemia.44
TLS-Associated Metabolic Derangements
Hyperphosphatemia results in a secondary hypocalcemia. Because calcium phosphate crystals can precipitate in the renal parenchyma and lead to renal failure, calcium correction should occur only in the context of clinically severe hypocalcemia (e.g., tetany, seizures) or after correction of hyperphosphatemia.37 If hypercalcemia is seen in the context of acute leukemia, the diagnoses of plasma cell leukemia or adult T-cell leukemia/lymphoma should be considered as alternate explanations.
Hyperkalemia should be monitored closely in the first 24 to 48 hours after initiation of chemotherapy (including hydroxyurea), when the risk of TLS is greatest. Potassium levels, however, should be interpreted with caution. Monocytic leukemias may present with significant hypokalemia due to renal tubular damage from high levels of muramidase (the lysozyme released by monoblasts), with subsequent renal potassium wasting.1 In addition, measurement of potassium in samples can be factitious: when blast counts are significantly high, metabolically active blasts up-take residual potassium from the serum if a blood specimen is left standing too long, resulting in pseudohypokalemia. Conversely, pseudohyperkalemia may be caused by in vitro blast lysis in the sample. Treatment of hyperkalemia should, therefore, be pursued only after obtaining a heparinized—and more truly diagnostic—plasma potassium level.45
Because chemotherapy destroys dividing cells, it disproportionately affects those cells with increased mitotic potential—in the bone marrow, oral cavity, GI endothelium, nails, and hair. Chemotherapy patients thus carry a high risk of oral mucositis and ulcers, as well as enteric ulcers, resulting in multiple potential portals of entry for gram-negative bacteria.
In patients with febrile neutropenia, treatment should include broad-spectrum antibiotics including coverage for Pseudomonas aeruginosa. Antifungal therapy is recommended in the event of persistent fevers despite 4 to 7 days of antibiotic coverage or in the event of persistent neutropenia. Treatment should continue throughout the duration of neutropenia until the ANC exceeds 500 cells/mm3.46 The use of granulocyte colony–stimulating factor varies by institution; most literature specific to AML shows no impact or mixed results on duration of neutropenia, infection, antibiotic usage, hospitalization, or survival.47,48
The selection of antiviral, antifungal, and antibiotic prophylaxis is dependent on local levels of invasive fungal infections and is often institution specific. The Infectious Disease Society of America recommends acyclovir prophylaxis for HSV seropositive patients.46 Posaconazole has been shown to significantly reduce fungal infections when compared to fluconazole and is increasingly being used in the leukemia population.49
Neutropenic colitis—termed typhlitis when only the ileocecal region is involved—typically occurs 10 to 14 days after initiation of chemotherapy and presents with neutropenia, right lower quadrant pain, and fever.50 Patients may also have nausea, vomiting, and watery or bloody diarrhea. The pathogenesis of neutropenic colitis is likely related to chemotherapy-induced mucosal injury with bowel wall edema, ulceration, and secondary intestinal microbial infiltration. The cecum is particularly vulnerable because of its low blood supply. Patients will typically demonstrate gram-negative bacteremia; up to 15% of patients will have fungus isolated in blood or bowel specimens.51 Along with testing and empirical treatment for Clostridium difficile, patients must undergo immediate CT imaging. Bowel wall thickening of >4 mm on imaging is consistent with the diagnosis.52 Despite aggressive treatment with broad-spectrum antibiotics, bowel rest, volume resuscitation, and surgical consultation, the mortality rate of typhlitis is as high as 30% to 50%.53
Differentiation Syndrome of APL
Differentiation syndrome occurs in 15% to 25% of patients receiving ATRA or arsenic trioxide (ATO) and can occur between 2 and 47 days after exposure to ATRA or ATO.54,55 Patients will present with cough, fever, or dyspnea and often with a white blood cell count of >10,000/μL. This cardiopulmonary syndrome is often mistaken for pulmonary edema or pneumonia. Patients must be monitored closely for hypoxia, pulmonary infiltrates, and pleural or pericardial effusions. In cases of APL with a WBC > 10,000/μL, or suspicion for differentiation syndrome, patients should receive dexamethasone 10 mg bid for 3 to 5 days with a taper over 2 weeks.35 Treatment should commence immediately, rather than after abnormalities appear on chest radiograph. If differentiation syndrome is suspected, ATRA and/or ATO should be discontinued and not resumed until resolution of all signs and symptoms; steroid therapy should be given concurrently.37
Cytoreductive Therapy in AML and ALL
AML treatment is divided into two stages: induction chemotherapy to induce a remission and subsequent consolidation (postremission) therapy. The goal of therapy is to achieve a complete response (CR)—defined as having <5% of blasts in a repeat bone marrow aspirate with a count of 200 nucleated cells. To date, the cure rates for AML excluding APL are low; only 40% of young adults and 10% of elderly patients will be cured.37 Treatment varies by institution; in patients who are transplant eligible (age <60 with good performance status), every effort should be made to enroll the patient into a clinical trial.
Induction chemotherapy has not changed considerably for over 30 years: it consists of anthracyclines such as daunorubicin (60 to 90 mg/m2 × 3 days) and cytarabine (100 to 200 mg/m2 continuous infusion × 7 days),56 known as the “3+7” strategy. Studies have shown that varying the doses of chemotherapy can improve CR rates but can also precipitate considerable toxicity. Patients who achieve remission proceed to consolidation (postremission therapy), typically with high-dose cytarabine. Treatment regimens, including subsequent hematopoietic stem cell transplant, are dependent on prognostic factors and type of leukemia.
Treatment of ALL includes multiagent chemotherapies divided into induction, consolidation, and maintenance phases of treatment, with all patients receiving CNS prophylaxis. Treatment will always include anthracyclines, vincristine, l-asparaginase, cyclophosphamide, methotrexate, cytrarabine, mercaptopurine, and corticosteroids, all of which can result in significant toxicity. Imatinib is added in those patients who are Philadelphia chromosome positive. Due to their significant exposure to steroids, patients must also receive prophylaxis for Pneumocystis jiroveci and are often placed on viral and fungal prophylaxis as well. Impressively, with this regimen, most children with ALL included in clinical trials have 5-year survival rates that approach 85%; in adults, only a 30% 5-year survival rate is achieved.57 Table 27.2 highlights the major toxicities associated with the standard chemotherapies used for AML, APL, and ALL.
TABLE 27.2 Selected Chemotherapy Drug Complications