Acute Leukemia: Diagnosis and Treatment

ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2019) 150950

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Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing

Acute Leukemia: Diagnosis and Treatment Lisa M. Blackburn, MS, RN, AOCNSÒ ,*, Sarah Bender, MS, RN, CNP, OCNÒ , Shelly Brown, MS, APRN-CNS, AOCNSÒ The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH

A R T I C L E

I N F O

Article History: Available online xxx Key Words: leukemia hematology hematopoiesis differentiation induction therapy consolidation therapy oncologic emergencies

A B S T R A C T

Objective: To provide an overview of acute leukemia, comparing incidence, presenting symptoms, diagnosis, prognosis, and treatment of the major subtypes. Data Sources: Review of articles dated 2010 to present in PubMed and CINAHL, and National Comprehensive Cancer Network Guidelines. Conclusion: The diagnosis of acute leukemia is comprised of a variety of hematopoietic neoplasms that are both complex and unique. Each subtype of acute leukemia has defining characteristics that affect prognosis and treatment. Implications for Nursing Practice: Nurses play an integral role in the care of the patient with acute leukemia during and beyond hospitalization. Therefore, baseline knowledge of these diseases is essential. Early symptom recognition is central in the management of oncologic emergencies. © 2019 Elsevier Inc. All rights reserved.

Introduction The term leukemia is derived from the Greek words “leukos” and “heima,” which refer to excess white blood cells (WBC) in the body. Leukemia, once considered a single disease, was first recognized around the 4th century.1 By the end of the 19th century, leukemia was classified into four subtypes: acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia, and chronic lymphocytic leukemia. Currently, the diagnosis of leukemia is known to be comprised of a variety of hematopoietic neoplasms that are both complex and unique. Each subtype can be further distinguished by morphologic differences, cytogenetic abnormalities, immunophenotype, and clinical features.1 These distinguishing characteristics affect both prognosis and selection of optimal treatment. This review will focus only on those classified as acute leukemia. Acute Myeloid Leukemia Etiology/incidence Acute myeloid leukemia (AML) is a disorder of hematopoietic progenitor cells characterized by an increased number of immature myeloid cells in the bone marrow.1,2 AML is the most common acute leukemia in *Address correspondence to: Lisa M. Blackburn, MS, RN, AOCNSÒ , Clinical Nurse Specialist, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, 460 W. 10th Ave., Columbus, OH 43210. E-mail address: [email protected] (L.M. Blackburn). https://doi.org/10.1016/j.soncn.2019.150950 0749-2081/© 2019 Elsevier Inc. All rights reserved.

adults, with an incidence of 2.7 per 100,000 people, or about 21,000 cases per year in the US.3 There are 14 new cases of leukemia per 100 people per year and roughly 1.6% of men and women will be diagnosed during their lifetime.3 The median age at diagnosis is 68 years, with 55.54% of patients diagnosed at 65 years or older.3 Although it varies by subtype and other risk factors, the 5-year survival rate is 62.7%.3 With the aging population, the incidence of AML has been rising 2.2% per year over the past 10 years.1 The cause of AML remains largely unknown. The following environmental factors have been associated with the diagnosis: ionizing radiation, benzene, chemotherapy drugs, and tobacco.2 Other disorders involving myeloid and nonmyeloid cells, such as chronic myelogenous leukemia, primary myelofibrosis, essential thrombocytosis, polycythemia vera, paroxysmal nocturnal hemoglobinuria, and aplastic anemia, can evolve into AML. Bloom syndrome, Diamond-Blackfan syndrome, Down syndrome, Fanconi anemia, neurofibromatosis, and Noonan syndrome are all genetic conditions associated with AML.2 There is an increased risk of treatment-related AML in survivors of childhood and young adult cancers.4 The exact incidence of treatmentrelated AML is unknown, but it is estimated that therapy-related AML may occur in 5% to 20% of patients with AML.4 The rate of therapyrelated AML is higher among patients treated for breast and gynecologic cancers and non-Hodgkin and Hodgkin lymphoma. This is likely because of the cytotoxic agents commonly used to treat these cancers (eg, anthracyclines, topoisomerase inhibitors, and alkylating agents).4 Clinical Presentation As with other leukemias, patients often present to their primary care clinician, local urgent care, or emergency department with non-specific

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chief complaints and may be treated for general symptom management. Symptoms are typically a result of the highly proliferative, malignant “blasts” (the immature leukemic cells) invading the bone marrow where healthy cells are normally produced. Anemia, leukopenia, and thrombocytopenia occur because of the lack of space for cells to grow and mature into healthy red cells, WBC, and platelets. With anemia comes fatigue, shortness of breath with normal activity, chest pain, dizziness, and pallor. Fever, frequent infections, and impaired wound healing are a result of WBC dysfunction and leukopenia.5 Patients with thrombocytopenia often present with bleeding that is difficult to stop, easy bruising, nose bleeds, petechiae, and females may also notice menstruation that lasts longer than usual.2,6 8 Patients may present with arthralgias as a result of leukemia infiltration into the bone marrow.2,7 Patients can also present with leukocytosis manifesting as lymphadenopathy, splenomegaly, and hepatomegaly.6,8 Signs and symptoms of AML are related to the underlying disruption in hematopoiesis because of the untreated disease. Patients may present with physical signs of extramedullary disease, such as skin lesions, gingival hypertrophy, or lymphadopathy.2 Hyperleukocytosis, a WBC > 100,000/mL, may also be seen on presentation. The incidence of hyperleukocytosis in AML ranges from 5% to 13%, and may lead to leukostasis.9 Patients with leukocytosis require close monitoring and care to prevent and minimize complications. Nurses can expect for these patients to receive aggressive intravenous (IV) fluids, laboratory testing every 6 to 8 hours, and hydroxyurea to help decrease the WBC count.10 In some cases leukocytosis can lead to leukostasis (a medical emergency characterized by decreased tissue perfusion). Leukostasis is caused by leukemic cells clumping in capillaries and is associated with early mortality if not treated appropriately.11 Although any organ system can be affected by leukostasis, the most common sites are the central nervous system (CNS) and the lungs.9 CNS symptoms can include confusion, dizziness, headache, tinnitus, vision changes, delirium, coma, and ataxia; while respiratory symptoms can include dyspnea, tachypnea, and hypoxia.9 A thorough physical nursing assessment can quickly identify a patient who might be developing leukostasis. Patients with leukostasis may require leukapheresis, which is a process to rapidly remove leukocytes by mechanical separation.10 Once a large-bore peripheral IV catheter or central line is placed, apheresis should be performed. One apheresis session can decrease circulating blasts by 20% to 50%.12 Diagnosis The first step in the diagnosis of AML typically involves evaluating the peripheral blood of patients for anemia, thrombocytopenia, and leukopenia. Although leukocytosis is possible, leukopenia can also occur.2 The diagnosis of leukemia then involves testing via bone marrow aspirate and biopsy, along with peripheral blood samples that allow for flow cytometry, immunophenotyping, and morphologic and genetic analysis.2,4,6,7 Bone marrow aspirate and biopsy results often reveal a hypercellular marrow with a small number of normal hematopoietic cells and a diffuse population of blasts.6 Flow cytometry is a test that uses a variety of dyes and chemical substances to classify leukemia cells.6 Immunophenotyping is determined by the pattern of surface proteins on the leukemic cells and allows for discerning between healthy cells and leukemia cells. Patterns of the cell surface proteins and the level of differentiation are associated with classification and diagnosis.13 A bone marrow biopsy or peripheral blood showing at least 20% myeloblasts confirms the diagnosis of AML.1 Flow cytometry, cytogenetics, and molecular studies should be completed on the bone marrow aspirate and will aide in determining risk stratification.1 Antigens commonly expressed on AML blasts include CD13 and CD33.14 Common cytogenetic abnormalities include t(15;17), t(8;21), t(6;16), and inv(16).1 Chromosomal changes can be detected via

fluorescence in-situ hybridization (FISH) testing.6 Molecular analysis may reveal abnormalities in NPM1, CEBP a, IDH1, IDH2, TP53, cKIT or FLT3 ITD or TKD.4 The diagnostic workup of a patient with suspected AML should also include a complete metabolic panel, liver function test, serum lactic acid dehydrogenase, and uric acid. Patients without contraindications to hematopoietic cell transplant require human leukocyte antigen typing. Other diagnostic testing, such as lumbar puncture or computed tomography scans, may be needed based on patient symptoms and presentation.7 Treatment for AML often includes an anthracycline, which will require an echocardiogram pretreatment. Prognosis There are both patient and disease-specific factors that are used for risk stratification in AML. Patient-specific factors that predict poorer performance include: age over 59 years; poor performance status; and co-existing medical conditions.1 Disease-specific factors that predict poorer performance include: high WBC at time of diagnosis; prior history of hematologic condition; cytogenetics; molecular markers; and disease related to prior chemotherapy, radiation, or immunotherapy.1 Molecular markers have been validated to correlate with outcomes: NPM1, CEBP a, FLT3-ITD, cKIT, FLT3-TKD, IDH1, IDH2, RUNX1, ASXL1, and TP53.14 16 See Table 1 for full cytogenetic and molecular prognostic factors. Treatment The National Comprehensive Cancer Network recommends participation in clinical trials, if available, for all patients diagnosed with AML.4 Standard-of-care treatment for AML is determined by the patient’s age, risk category, and baseline functional status.1 For adults less than 60 years old with favorable or intermediate-risk AML, or treatment-related AML, therapy often includes induction chemotherapy with cytarabine plus an anthracycline (daunorubicin or idarubicin). This regimen is typically referred to as 7+3.4 Patients with treatment-related AML or with a prior history of myelodysplastic syndrome can also receive a dual-drug liposomal encapsulation of daunorubicin and cytarabine.4 More recent evidence points to an added benefit in incorporating gemtuzumab ozogamicin in patients with favorable-risk AML as well. Patients with a FLT3 mutation may receive midostaurin as part of their 7+3 induction.17,18 A repeat bone Table 1 Cytogenetic and molecular prognostic factors in acute myelogenous leukemia (AML). Risk category

Cytogenetics

Molecular abnormalities

Favorable risk

t(8;21)(q22;q22.1) inv(16)(p13.1q22) or t (16;16)(p13.1;q22)

Intermediate risk

T(9;11)(p21.3;q23.3) Cytogenetic abnormalities not in other category

Poor risk

T(6;9)(p23;q34.1) T(v;11q23.3) T(9;22)(q34.1;q11.2) inv(3)(q21.3q26.2) or t(3;) (q21.3;q26.2) -5 or del(5q); -7; -17/abn (17p)

RUNX1-RUNX1T1 CBFB-MYH11 Mutated NRM1 w/o FLT3ITD or with FLT3-ITDlow Biallelic mutated CEBPA Mutated NPM1 and FLT3ITDhigh Wild-tpye NPM1 w/o FLT3-ITD or with FLT3ITDlow MLLT3-KMT2A DEK-NUP214 KMT2A rearranged BCR-ABL1 GATA2, MECOM(EVI1) Complex karyotype Wild-type NPM1 and FLT3-ITDhigh Mutated RUNX1 Mutated ASXL1 Mutated TP53#

Data from Estey,14 Rockova et al,15 and O’Donnell.16

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marrow is typically done on day 14 to confirm a hypoplastic marrow, and then again at the time of count recovery to assess the response to the chemotherapy. Complete remission (CR) is defined as neutrophils  1,000/mL with platelets  100,000/mL, and <5% blasts in the bone marrow. Complete remission with incomplete recovery (CRi) is defined as neutrophils  1,000/mL or platelets  100,000/mL, and <5% blasts in the bone marrow.1 Patients in CR or CRi go on to receive consolidation chemotherapy. Favorable-risk patients receive consolidation with high-dose cytarabine for three to four cycles followed by observation; intermediate-risk patients receive high-dose cytarabine, sometimes followed by allogeneneic stem cell transplant if a suitable donor exists; and high-risk patients receive consolidation followed by an allogenic stem cell transplant or alternative donor transplant.1 As shown in Table 2, patients over 60 years of age with an Eastern Cooperative Oncology Group (ECOG) status19 of 0 to 2 may receive induction chemotherapy or a lower-dose treatment with a hypomethylating agent (decitabine or azacitidine), or a targeted therapy, depending on their cytogenetic risks and molecular features.20 Induction typically includes cytarabine plus daunorubicin or idarubicin, as above. Doses of these drugs are often reduced for patients over 60 years of age. Treatment options for patients unfit for intensive therapy or those who choose not to receive it include hypomethylating agents with or without venetoclax, low-dose cytarabine in combination with venetoclax or glasdegib, low-dose cytarabine alone, or single-agent gemtuzumab ozogamicin.4 Treatment options for patients with relapsed or refractory disease include salvage induction chemotherapy, hypomethylating agents, novel targeted agents, or clinical trials, depending on the patient’s age, ECOG status, and disease risk. No salvage regimen has proven most effective; therefore, therapy should be tailored to each patient.1 Recent drug approvals for patients with relapsed or refractory AML include gemtuzumab,21 enasidenib for those with IDH2 mutation,22 gilteritinib for those with FLT3 mutation,23 and ivosidenib for those with IDH1 mutation.24 Acute Promyelocytic Leukemia Acute promyelocytic leukemia (APL), a rare subtype of AML, was once considered the most fatal form of AML because of its significant propensity for bleeding and the subsequent high mortality rate associated with early hemorrhagic death.25 However, advances in the understanding of the disease process and improvements in the available therapies over the past four decades have led to it now being considered the most curable.6 APL makes up 5% to 10% of all cases of AML1,6 and appears to be more common in patients of Latin American descent, representing up to 20% to 25% of AML cases in Latin countries.1,26 Within the United States, the incidence of APL diagnoses is estimated to be between 600 and 800 cases per year. A diagnosis of APL is considered to be highly unlikely in children and is most commonly seen in adults ranging from 20 to 50 years of age.27 Table 2 ECOG performance status. Grade

ECOG

0

Fully active, able to carry on all pre-disease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light housework, office work) Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair Dead

1

2 3 4 5

Data from Oken.19 Abbreviation: ECOG, Eastern Cooperative Oncology Group.

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A key characteristic of APL is the presence of atypical promyelocytes, both in the bone marrow and in the peripheral blood. The promyelocytes show characteristic findings of bi-lobed nuclei and azurophilic cytoplasmic granules. These granules can form elongated bodies called Auer rods.28 This disease is distinguished from other forms of AML by the cytogenetic translocation of the long arms of chromosomes 15 and 17.29 One of the genes responsible, the promyelocyte leukemia or PML gene, is on chromosome 15 and is thought to be responsible for apoptosis and tumor suppression. The other gene responsible, the retinoic acid receptor-alpha or RARa, is on chromosome 17 and is mostly responsible for myeloid differentiation. The translocation of genetic material that occurs between these two chromosomes creates a fusion between parts of the PML gene to parts of the RAR-a gene.28 This chromosomal translocation causes neither the PML nor the RAR-a protein to act in its original capacity. Because of this morphology of chromosomes, blood cells cannot differentiate past the promyelocyte phase, which results in both the bone marrow and the peripheral blood being filled with promyelocytes. Clinical Presentation The clinical presentation of APL, like that of AML, can be rather nondescript, with many patients experiencing days to weeks of nonspecific symptoms followed by the occurrence of bleeding and thrombosis.28 Symptoms can include infections, bruising, bleeding, fevers, excessive sweating, fatigue, and tachycardia. Patients often present through an emergency department. Misdiagnosis may occur because of an underlying infectious process or bleeding. This can lead to negative clinical outcomes because relatively quick treatment is imperative. Advances in treatment options have increased the incidence of both disease-free survival and CR, but there is still a high mortality rate in the first month of diagnosis. This occurs because APL is highly malignant in the initial stage when patients have severe coagulopathies requiring emergent treatment.29

Diagnosis Diagnostics for APL, as with AML, should include a bone marrow aspirate and biopsy, complete blood count, metabolic panel, uric acid, and lactate dehydrogenase. A screen for disseminated intravascular coagulation (DIC) should be added for the diagnosis of APL. Preliminary testing of a complete blood count will show an increased WBC and decreased red cells and platelets. The WBC differential may show an increased percentage of promyelocytes. The bone marrow will be screened for presence of the PML-RARa gene, reverse-transcription polymerase chain reaction (or RT-PCR), but full results may take up to a week. Cytogenetic testing identifies where genetic abnormalities have occurred and FISH identifies the PML-RARa translocation. FISH on peripheral blood for cytogenetic abnormalities can usually confirm the diagnosis in less than 24 hours. Patients with APL are divided into three prognostic groups (see Table 3)4 based on their WBC and platelet count, with patients at highest risk being those with a WBC of > 10,000/mL at presentation (no matter their associated platelet count).1,29

Table 3 APL risk stratification. Risk status

WBC

Platelets

Low risk Intermediate risk High risk

 10,000/mL  10,000/mL  10,000/mL

>40,000/mL <40,000/mL -

Abbreviations: APL, acute promyelocytic leukemia; WBC, white blood cell. Data from the National Comprehensive Cancer Network.4

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Treatment Because of the bleeding complications caused by APL, the diagnosis is considered a medical emergency and treatment should be initiated as soon as it is suspected. Once APL is suspected, based on the review of the peripheral smear and presenting signs and symptoms of the patient, treatment with all-trans retinoic acid (ATRA) should be initiated immediately.28 This differs from other forms of acute leukemia in that treatment should be started before a bone marrow biopsy is obtained and cytogenetic results are available. ATRA has minimal toxicity and can be discontinued if the diagnosis of APL is later abandoned. Conversely, delaying the administration of ATRA can lead to serious complications, such as fatal hemorrhage.27 For both low- and intermediate-risk APL, induction treatment involves both ATRA and arsenic trioxide (ATO).4 ATRA helps resolve coagulopathy in a unique manner. Instead of destroying the offending promyelocytes, it assists in differentiating the malignant promyelocytic blasts into granulocytes, which begins induction therapy.25 ATO works by degrading the PML-RARa gene, which leads to differentiation and cell death.25,30 ATRA and ATO have a synergistic effect when used together and should be given daily until patients achieve both hematologic and molecular remission. The combination of ATRA and ATO is an effective treatment for APL, while avoiding the long-term effects of cytotoxic agents.28 Since the initiation of ATRA/ ATO therapy, CR rates have improved to > 90% in patients newly diagnosed with APL and 5-year disease-free survival rates have improved to 74%.28,31 Patients who are high risk at diagnosis may require both ATRA and anthracycline-based chemotherapy.4,27 For these patients, idarubicin and ATRA are given until both hematologic and molecular remissions occur, unless the patient is elderly or has concomitant heart disease that would restrict the use of an anthracycline.4,30 Alternative regimens now include gemtuzumab ozogamicin in high-risk patients to reduce the risk of anthracycline-induced cardiomyopathy and secondary malignancies years later.32 Patients with APL require consolidation treatment to destroy any undetectable leukemia cells that survive induction therapy. Consolidation consists of additional ATO and ATRA for maintenance therapy, and possibly 6mercaptoprurine and methotrexate given for an additional 1 to 2 years, depending on the regimen used.25 Disseminated Intravascular Coagulation Coagulopathic disorders are very common in patients with APL, with almost 85% of patients experiencing them.28 Bleeding is frequently the presenting symptom in patients with APL. Because these complications are so frequently seen, it is imperative that clinicians successfully identify potentially fatal conditions and react quickly and succinctly. Researchers have found patients with APL to carry an early death rate of 17%, with early death being defined as death within 1 month of APL diagnosis.25,29 Other researchers have found the early death rate to be somewhat higher, with a rate of 29% reported within the first month of APL treatment.25,30 Greater than 60% of early death is caused by coagulopathy within the population of patients with APL.31,33 Nursing interventions should include assessing the patient for airway, breathing, circulation, and level of consciousness changes, as well as obvious signs of bleeding, petechiae, purpura, and other signs of thrombotic events.10 Laboratory tests include complete blood count, coagulation values (including fibrinogen, prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT), and D-dimer) should be obtained with assessments every 4 to 6 hours.1 Aggressive supportive treatment with blood products is essential. This includes platelet transfusions to maintain platelet levels > 30,000/mL, cryoprecipitate to maintain fibrinogen above 100 to 150 mg/dl, as well as fresh frozen plasma to correct abnormal PT/ INR and PTT values, plus red blood cells as necessary.27 Blood product

replacements are continued until the patient no longer shows signs of coagulopathy.33 The early initiation of ATRA, even before a confirmed diagnosis, should be anticipated by the nurse and may have a great impact on the emergence of fatal bleeding disorders.28,33 Differentiation Syndrome Differentiation syndrome (DS), also referred to as retinoic acid syndrome, is a potentially fatal development in patients with APL who are undergoing induction therapy with ATRA or ATO.33 DS is characterized by an elevated WBC, weight gain, unexplained fever, respiratory distress, interstitial pulmonary infiltrates, pulmonary edema, pericardial effusion, unexplained hypotension, and acute renal failure.31 In a patient exhibiting one or more of these signs and symptoms, absent of other causes, DS should be considered and early intervention should take place to avoid life-threatening complications.1 Diagnosis can be challenging because signs and symptoms can be very nonspecific or parallel those of other complications, such as septic shock. About 50% of patients with APL treated with ATRA develop DS.31 Although variable, onset generally takes place between 2 and 21 days into therapy. Patients receiving ATRA and ATO in combination have a lower incidence of DS (16%) as opposed to patients who receive ATRA or ATO alone (25% to 31%).31 Predictors of severe DS include serum creatinine > 1.4 mg/dL and a WBC count > 5,000/mL at time of diagnosis. In comparison, a WBC count of 10,000/mL at time of diagnosis predicts moderate DS.1 Treatment for APL causes differentiation and maturation of malignant promyelocytes, and these maturing leukocytes invade tissues and organs such as the lungs and kidneys.1 Production of inflammatory chemokines and adhesion molecules promote local inflammation and leukocyte adhesion to alveolar epithelial cells.1 Oncology nurses must be attentive to the early signs of DS, such as increased work of breathing, cough, shortness of breath, decreased oxygen saturation, hypotension, weight gain, fever, or decreased urinary output. These symptoms can usually be correlated with a rise in the total WBC during DS.33 Treatment with IV dexamethasone should begin as soon as the initial signs and symptoms of DS are recognized and should be continued for at least 3 days or until the resolution of symptoms.31 Early intervention is vital; corticosteroids started in the early stages of DS better inhibit production of alveolar chemokines, lessening the migration of differentiating APL cells to the alveolar space. Depending on the degree of patient symptoms, ATRA and ATO might be stopped and re-started with symptom resolution.31 ATRA and ATO may be resumed at a full or reduced dose, but close monitoring for recurring DS is critical.2 Because DS can be so severe, and yet is also very steroid-responsive, some APL treatment regimens include the use of prophylactic steroids upfront.31 Acute Lymphocytic Leukemia Acute lymphocytic leukemia (ALL), also referred to as acute lymphoid leukemia and acute lymphoblastic leukemia, is a malignancy of immature lymphocytes. Lymphocytes are a type of mature WBC that is an integral part of the immune system. Lymphoblasts, a type of immature WBC, grow and mature into lymphocytes that are found in the blood as well as the lymphatic system. Abnormal or malignant lymphoblasts are also called leukemic cells. These leukemic cells divide and replicate, crowding out healthy cells in the bone marrow.34 As ALL progresses, lymphoblasts spill out of the bone marrow and accumulate in various areas, including the spleen, thymus, lymph nodes, liver, testicles of men, and the brain and spinal cord.34,35 Malignant lymphoblasts do not go through the maturation process to become lymphocytes, nor do they function as they should, and therefore the body’s infection-fighting capabilities are compromised. These

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malignant cells block the production and development of healthy cells and, unfortunately, grow and live longer than normal cells.34,36 At diagnosis, the ALL subtype is determined by which lymphocyte is affected. There are three main types of lymphocytes: B lymphocytes (B cells) make antibodies; T lymphocytes (T cells) fight infections by activating the immune system, destroy infected and diseased cells, and assist B cells;34 36 and natural killer cells fight cancer cells and microbes.35 Incidence It is estimated that in 2019, close to 6,000 people (children and adults) in the United States were diagnosed with ALL.36 The incidence in European countries is very similar to the rates noted in the US.7 with whites and Hispanics being more likely to develop ALL than African Americans.35,36 ALL accounts for 60% to 74% of all leukemias diagnosed in people under the age of 20,35 with children under 5 years of age having the highest risk.7,35 Approximately 20% of patients diagnosed with ALL are over 55 years of age.37 In those diagnosed with ALL across all age groups, 75% to 88% will have the B-cell subtype; 15% to 25% have the T-cell subtype; and the natural killercell subtype of ALL is extremely rare.35

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and deoxynucleotide transferase.39 Wright-Giemsa stained bone marrow aspirate smears, hematoxylin and eosin-stained core biopsy and clot sections are used for morphologic evaluation.34 Chromosomal changes in ALL often involve translocation of chromosome 9 and 22, called Philadelphia chromosome positive (Ph-positive) disease.35,36,39 The incidence of this particular translocation, which results in a BCR-ABL fusion gene, increases from 3% in children up to more than 50% occurrence in adults over the age of 50.2 A translocation of chromosomes 12 and 22 with TEL-AML1 fusion gene is frequently found in children.35 A newer subtype of ALL, Ph-like ALL, exhibits gene expression similar to Ph-positive ALL, but without the translocation of chromosomes 9 and 22. In addition to translocations, there are genetic changes that result in an abnormal number of chromosomes. Instead of having the normal number of chromosomes (46), hyperdiploidy means there are more than 50 chromosomes per leukemia cell and hypodiploidy indicates there are less than 45 chromosomes per leukemia cell. Hyperdiploidy is considered a favorable cytogenetic factor and hypodiploidy is an adverse cytogenetic factor.2 Prognosis

The cause of ALL has yet to be determined, but there is thought that the DNA changes found with ALL are not inherited from a parent.36 However, genetic syndromes are linked to a higher risk. Genetic abnormalities such as Down syndrome, Bloom syndrome, ataxia teleangiectasia, Klinefelter syndrome, Fanconi anemia, and Wiskott-Aldrich pose a higher risk of developing ALL.35 Genetic changes in utero are the same genetic changes seen years after birth, when a diagnosis of ALL has been confirmed.35

Even though significant improvement in survival has been on the rise over the past 2 decades for the adult population, there remains a wide chasm between the overall survival of pediatric patients compared with adults. The 5-year survival rate for people diagnosed with ALL under the age of 20 is 89%, yet this same 5-year survival milestone is only obtained by 35% of those who are 20 years of age and older.35 Having minimal residual disease detected after induction suggests a poor prognosis.1 Patients diagnosed with Ph-like ALL have a very high risk of relapse and the overall survival rate is poor.37 However, the presence of the Ph chromosome allows for the use of novel targeted therapies that may be changing the course of Ph+ ALL.40

Clinical Presentation

Standard Treatment

Patients typically present to their primary care provider, local urgent care, or emergency department with the same presenting symptoms described for AML. Symptoms of anemia, thrombocytopenia, and ongoing infections are often what lead a person to seek care. Some unique presenting symptoms of ALL are a direct result of the subtype. Patients with B-cell ALL can present with CNS disease, while lytic bone lesions, extramedullary disease, mediastinal mass and high calcium levels may be noted more frequently in those with T-cell ALL.2

CR is the treatment goal of induction therapy, and treatment options are determined by risk stratification (Ph status and age). Many other factors should also be considered, such as the subtype and classification of ALL, the patient’s current health status, treatment side effects, and the patient’s goals. Multi-agent systemic chemotherapy regimens with drugs that cross the blood-brain barrier, such as high-dose cytarabine and methotrexate, along with intrathecal chemotherapy for CNS prophylaxis are standard treatments for ALL.1 Systemic treatment regimens also include various combinations of anthracyclines, vincristine, steroids, and cyclophosphamide.34 Philadelphia chromosome-positive disease is the largest subset of patients with ALL in the older population.37 Ph-like ALL is treated with the same regimens as Ph-positive ALL because even though the Philadelphia chromosome is not present in the Ph-like subtype of ALL, the genetic changes in the leukemia cells mimic those of the Philadelphia chromosome.35 While Ph-positive ALL has often been thought of as a high-risk disease, the addition of tyrosine kinase inhibitors (TKIs) has improved remission rates.37 TKIs disrupt the signaling process of the abnormal fusion gene (BCR-ABL) that promotes leukemia cell growth.36 Imatinib, dasatinib, and nilotinib are a few TKIs that target Ph-positive ALL.35 Targeted therapies include not only TKIs, but drugs such as nelarabine that can be prescribed for Tcell ALL.21 Other therapies that can be prescribed include: nelarabine for T-cell ALL; ponatinib, which can target Ph-positive disease; rituximab, which can be added to chemotherapy to treat B-cell ALL if there is significant expression of CD20; or blinatumuab and inotuzamab ozogamicin.35 Blinatumomab directs the body’s own T cells to target and destroy cells with the CD19 protein on the surface of B-cell lymphocytes. Blinatumomab is now approved by the US Food and Drug Administration for the treatment of minimal residual disease after

Etiology

Diagnosis Diagnosis of ALL involves testing via bone marrow aspirate and biopsy, along with peripheral blood samples that allow for flow cytometry and immunophenotyping, morphologic and genetic analysis as described.34 36,38 Bone marrow aspirate and biopsy results often reveal a hypercellular marrow with a small number of normal hematopoietic cells and a diffuse population of lymphoblasts. Flow cytometry and immunophenotyping aides in determining if the ALL is derived from the B-cell or T-cell lymphocyte.35,36,38 Patterns of the cell surface proteins and the level of differentiation are associated with classification and diagnosis.37 B-cell ALL can be further segmented into additional subtypes based on the differentiation of the B cell, such as precursor B-cell ALL, intermediate or “common B-ALL”, and pre B-cell, which is the most mature.2 Precursor Bcell ALL cells most often express CD10, CD19, and CD34 proteins on the cell surface, along with nuclear terminal deoxynucleotide transferase.39 Mature B-cell ALL, also called Burkitt cell leukemia,2 has a male predominance and often a bulky extramedullary disease presentation.2,37 T-cell ALL cells typically express CD2, CD3, CD7, CD34,

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initial induction treatment in ALL, which is a paradigm-shifting approach that may be improving our ability to achieve very deep remissions and hopefully improve outcomes without the need for riskier treatments like allogeneic stem cell transplantation. Because of the higher remission rates in children than adults, adolescent and young adult regimens routinely given to young children have been adopted for the adult population in the 15- to 39-year-old age range. Depending on the patient’s age at diagnosis, regimens for Phnegative ALL may include induction, consolidation, delayed intensification, and maintenance format. Chemotherapy drugs for these regimens may include anthracyclines, vincristine, steroids, cytarabine, cyclophosphamide, pegaspargase, cyclophosphamide along with 6-mercaptopurine, and thioguanine. Treatment regimens for this population are close to 2 years in length for females and almost 3 years for males. Patients with either Ph-positive or Ph-negative disease can be treated with an allogeneic stem cell transplant, although the timing is still unclear.34 The CNS can act as a sanctuary for leukemia cells and which may be seen at diagnosis of mature B-cell ALL.7 Some systemic chemotherapies, intrathecal chemotherapy, and radiation therapy can be used prophylactically to decrease the potential of CNS involvement.34 If the patient’s CNS is positive for disease at any point, intrathecal chemotherapy may be increased to twice weekly administrations until the CNS is clear. While CNS disease is seen in <10% of patients with ALL at diagnosis, a presentation of infiltration into the CNS has been reported in 50% or higher if CNS prophylaxis is not provided.36 Oncologic Emergencies: The Nurses Role One of the hallmark roles of a seasoned, knowledgeable oncology nurse exists in the arena of prevention and early identification of oncologic emergencies.41 Oncologic emergencies are defined as potentially life-threatening conditions related to cancer-treatment modalities or the disease itself. Most have early subtle symptoms that could be easily confused with common symptoms of cancer or its treatment, but if left unrecognized can quickly progress to conditions that greatly increase morbidity and mortality for the cancer patient. Tumor Lysis Syndrome Tumor lysis syndrome (TLS) is considered an oncologic emergency and is caused by the quick destruction of tumor cells. TLS is frequently observed in patients with highly proliferative hematologic malignancies, including acute leukemias.42 TLS occurs when tumor cells release their content into the bloodstream, either spontaneously or after the invitation of treatment, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.43 These electrolyte imbalances can lead to cardiac arrhythmias, gastrointestinal disturbance, neurologic and neuromuscular abnormalities, and acute renal failure.42 Early identification of TLS can prevent life-threatening multi-organ failure. Optimal management of TLS involves preservation of renal function.43 This involves aggressive hydration with IV fluids to achieve high urine output (2 mL per kg per hour).44 If this cannot be achieved with IV fluids only, loop diuretics may also be utilized.43,44 Hyperuricemia is managed with the use of allopurinol, and sometimes rasburicase. Allopurinol prevents the formation of further uric acid while rasburicase is effective at rapidly reducing uric acid levels. Patients with hyperkalemia or hypocalcemia should be placed on cardiac monitoring and have frequent repeat checks. Standard therapies for symptomatic hyperkalemia include loop diuretics, insulin and glucose, polystyrene sulfate, and calcium gluconate. Asymptomatic hypocalcemia should not be treated with calcium administration and symptomatic hypocalcemia should be treated with the lowest dose possible because of the risk of increasing calcium phosphate deposition in the renal tubules.44 If severe kidney injury occurs, hemodialysis may be indicated.

Febrile Neutropenia and Sepsis Neutrophils, a type of WBC, are one of the primary cells that serve to protect the body against bacterial infections. Patients with acute leukemia can experience neutropenia as a result of the disease process and/or as a side effect of treatment. Because of the function of the infection fighter cells, when a patient becomes neutropenic there is significant risk of infection and increased mortality. Febrile neutropenia is not only a common complication but a medical emergency that can quickly escalate to sepsis. The National Comprehensive Cancer Network guideline defines a fever as a single temperature of 38.3°C (100.9°F) or a temperature of 38°C (100.4°F) sustained over a 1-hour period of time. This guideline also reports reference parameters for neutropenia as neutrophils that are <500/mL or <1,000/mL with a predicted decrease to <500 neutrophils/mL over the next 48 hours.45 When periods of neutropenia are expected, prophylactic antimicrobials are administered based on disease, regimen, risk factors, expected length of neutropenia, and institutional policy. It is imperative that nurses caring for hematology patients are aware that during periods of neutropenia, a single fever may be the only indication of infection.46 Neutropenic patients are often void of other infectious symptoms because of the decreased ability of the body to mount a normal inflammatory response. At the initiation of a febrile neutropenic episode, the nurse should expect to see orders for blood cultures, cultures or radiographic imagining that correspond to sites of potential infection, and an empiric broad-spectrum antibiotic if the organism has not already been identified. Per evidence-based guidelines, antibiotic should be started within 1 hour of the fever and after blood cultures are drawn and antibiotic administration should not be delayed while waiting on results.47 A febrile neutropenic episode can become a life-threatening sepsis situation when the impaired immune system cannot respond appropriately to an infection. Early intervention with fluid resuscitation is necessary to address tissue hypoperfusion. Acute organ dysfunction, decreased blood pressure, and increased serum lactate are the results of decreased tissue perfusion that occurs during the septic process. When aggressive fluid resuscitation does not improve hypotension and vasopressors are necessary, the mean arterial pressure target pressure should be 65 mm Hg.48 When caring for febrile neutropenic patients who have leukemia, nurses should be aware of the high risk for sepsis and the need to recognize even subtle changes in these patients’ vitals. Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) may be seen with all leukemia subtypes, but can be an especially prominent feature in patients with APL. DIC is often present in association with hyperleukocytosis in patients with AML. DIC is a systemic process in which activation of the coagulation cascade introduces the potential for simultaneous thrombosis and hemorrhage. Fibrin and platelets produce thrombi that can occur in the microvasculature and/or larger vessels. Extensive formation of thrombi in turn leads to consumption of endogenous coagulation factors, platelets, and anticoagulant factors.49 Fibrinolysis is then activated at sites of thrombus formation, with generation of fibrin degradation products that, when present in significant amounts, interfere with both fibrin clot formation and platelet aggregation. Tissue or organ damage may result from reduced perfusion, thrombosis, and/or bleeding. Often, contributions from DIC itself and the condition that precipitated it are intertwined. Organ failure may result in significant morbidity and mortality.49 Common bleeding manifestations include petechiae; ecchymoses; and blood oozing from wound sites, IV lines, catheters, and mucosal surfaces. The bleeding can be life-threatening if it involves the gastrointestinal tract, lungs, or CNS. Common thromboembolic manifestations of DIC include venous thromboembolism and arterial thrombosis

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with tissue or organ ischemia.50 The detection of early, subtle signs of bleeding and clotting in at-risk patients with leukemia can result in early identification of DIC and therefore decreased morbidity and mortality. Coagulation profiles, including fibrinogen and measurements of fibrin degradation products, should be obtained at the time of leukemia diagnosis and at frequent intervals should DIC be suspected.50 Conclusion The diagnosis and treatment of leukemia is complex and the unique subtypes of the disease add to that complexity. Presenting symptoms, treatment, and prognosis vary by subtype. Because oncology nurses are at the forefront in the care provided to these patients, an understanding of the differences between subtypes is essential. Nurses can better provide treatment, support patients in crisis, and identify early warning signs of complications of acute leukemias when they are well versed in this complicated disease. References 1. Sallman DA, Chaudhury A, Nguyen J, Zhang L, List A. Handbook of hematologic malignancies. New York, NY: Springer Publishing; 2017. 2. Oxford American mini-handbook of hematologic malignancies. In: Lyman GH, ed. Oxford American mini-handbook of hematologic malignancies. New York, NY: Oxford University Press; 2010. 3. SEER Cancer Statistics Review. In: Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, eds. SEER Cancer Statistics Review 1975-2016. Bethesda, MD: National Cancer Institute; April 2019:92. Available at: https://seer.cancer.gov/csr/ 1975_2016/. based on November 2018 SEER data submission, posted to the SEER web site. (Accessed March 28, 2019) . 4. National Comprehensive Cancer Network. Clinical practice guidelines in oncology (NCCN guidelines): acute myeloid leukemia. 2018. Available at: https://www.nccn. org/professionals/physician_gls/pdf/aml.pdf. (Accessed April 8, 2019). 5. Meyers AU, Albitar CA, Estey M. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104:788–793. 6. Hematologic malignancies in adults. In: Olsen M, Zitella LJ, eds. Hematologic malignancies in adults. 1st ed. Pittsburgh, PA: Oncology Nursing Society; 2013. 7. Rose-Inman H, Kuehl D. Acute leukemia. Emerg Med Clin North Am. 2014;32:579–596. 8. Leukemia & Lymphoma Society. Acute lymphoblastic leukemia. Available at: https:// www.lls.org/leukemia/acute-lymphoblastic-leukemia/. (Accessed March 28, 2019). 9. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and leukapheresis: practice management. Blood Rev. 2012;26:117–122. 10. Blackburn LM, Bauchmire N, Bender S, Tomlinson-Pinkham K, Roberts S, Rosan S. Impact of an alert system on quality indicators in patients with acute promyelocytic leukemia. Clin J Oncol Nurs. 2016;20:523–527. 11. Ruggiero A, Rizzo D, Amato M, Riccardi R. Management of hyperleukocytosis. Curr Treat Options Oncol. 2016;17:7. 12. Jain R, Bansal D, Marsaha RK. Hyperleukocytosis: emergency management. Indian J Pediatr. 2013;80:144–148. 13. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405. 14. Estey E. Acute myeloid leukemia: 2016 update on risk-stratification and management. Am J Hematol. 2016;91:824–846. 15. Rockova V, Abbas S, Wouters BJ, et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood. 2011;118:1069–1076. 16. O’Donnell MR. Risk stratification and emerging treatment strategies in acute myeloid leukemia. J Natl Compr Canc Netw. 2013;11:667–669. 17. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a metaanalysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15:986–996. 18. Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2:444–453. 19. Oken M.Eastern Cooperative Oncology Group (ECOG) performance status. Available at: https://www.mdcalc.com/eastern-cooperative-oncology-group-ecog-per formance-status. (Accessed June 8, 2019).

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