13-29 - Acute Leukemia

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Current Medical Diagnosis & Treatment 2023
1329: Acute Leukemia
Lloyd E. Damon; Charalambos Babis Andreadis
ESSENTIALS OF DIAGNOSIS
ESSENTIALS OF DIAGNOSIS
Short duration of symptoms, including fatigue, fever, and bleeding.
Cytopenias or pancytopenia.
Blasts in peripheral blood in 90% of patients.
More than 20% blasts in the bone marrow.
GENERAL CONSIDERATIONS
Acute leukemia is a malignancy of the hematopoietic progenitor cell. Malignant immature cells proliferate in an uncontrolled fashion and replace
normal bone marrow elements. Most cases arise with no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition, a
number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other alkylating agents, and etoposide) may cause leukemia. The
leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in
chromosomes 5 and 7. Those related to etoposide or anthracyclines may have abnormalities in chromosome 11q23 (MLL locus).
Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cells. Less common
manifestations result from organ infiltration (skin, GI tract, meninges). Acute leukemia is potentially curable with combination chemotherapy.
The myeloblastic subtype, AML, is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced
age. Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17), which produces the fusion gene PMLRARalpha,
leading to a block in differentiation that can be overcome with pharmacologic doses of retinoic acid. The lymphoblastic subtype of acute leukemia,
ALL, comprises 80% of the acute leukemias of childhood. The peak incidence is between 3 and 7 years of age. It is also seen in adults, causing
approximately 20% of adult acute leukemias.
CLASSIFICATION OF THE LEUKEMIAS
A. Acute Myeloid Leukemia (AML)
AML is primarily categorized based on recurrent structural chromosomal and molecular abnormalities. The cytogenetic abnormalities can be
identified on traditional karyotyping or metaphase fluorescence in situ hybridization (FISH) and the molecular abnormalities are identified by either
targeted or genomewide sequencing of tumor DNA. Favorable cytogenetics such as t(8;21) producing a chimeric RUNX1/RUNX1T1 protein and inv(16)
(p13;q22) are seen in 15% of cases and are termed the “corebinding factor” leukemias. These patients have a higher chance of achieving both short
and longterm disease control. Unfavorable cytogenetics confer a very poor prognosis. These consist of chromosomal translocations [t(6;9), t(3;3) or
inv (3), t(v;11q23)], isolated monosomy 5 or 7, the presence of two or more other monosomies, or three or more separate cytogenetic abnormalities
and account for 25% of the cases. The majority of cases of AML are of intermediate risk by traditional cytogenetics and have either a normal karyotype
or chromosomal abnormalities that do not confer strong prognostic significance. However, there are several recurrent gene pathogenic variants with
prognostic significance in this subgroup. On the one hand, internal tandem duplication in the gene FLT3 occurs in ~30% of AML and is conditionally
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associated with a poor prognosis in the setting of wild type NPM1. Other pathogenic variants conferring a poor prognosis occur in RUNX1, ASXL1,
1329: Acute Leukemia, Lloyd E. Damon; Charalambos Babis Andreadis Page and
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TP53. On the other hand, a relatively favorable group of patients has been identified that lacks FLT3ITD pathogenic variants and includes variants of
nucleophosmin 1 (NPM1) or carries CEBPA biallelic variants.
(p13;q22) are seen in 15% of cases and are termed the “corebinding factor” leukemias. These patients have a higher chance of achieving both short
Universidad Peruana de Ciencias Aplicadas
and longterm disease control. Unfavorable cytogenetics confer a very poor prognosis. These consist of chromosomal translocations [t(6;9), t(3;3) or
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inv (3), t(v;11q23)], isolated monosomy 5 or 7, the presence of two or more other monosomies, or three or more separate cytogenetic abnormalities
and account for 25% of the cases. The majority of cases of AML are of intermediate risk by traditional cytogenetics and have either a normal karyotype
or chromosomal abnormalities that do not confer strong prognostic significance. However, there are several recurrent gene pathogenic variants with
prognostic significance in this subgroup. On the one hand, internal tandem duplication in the gene FLT3 occurs in ~30% of AML and is conditionally
associated with a poor prognosis in the setting of wild type NPM1. Other pathogenic variants conferring a poor prognosis occur in RUNX1, ASXL1, and
TP53. On the other hand, a relatively favorable group of patients has been identified that lacks FLT3ITD pathogenic variants and includes variants of
nucleophosmin 1 (NPM1) or carries CEBPA biallelic variants.
B. Acute Promyelocytic Leukemia (APL)
In considering the various types of AML, APL is discussed separately because of its unique biologic features and response to nonchemotherapy
treatments. APL is characterized by the cytogenetic finding of t(15;17) and the fusion gene PMLRARalpha. It is a highly curable form of leukemia (over
90%) with integration of alltransretinoic acid (ATRA) and arsenic trioxide (ATO) in induction, consolidation, and maintenance regimens.
C. Acute Lymphoblastic Leukemia (ALL)
ALL is most usefully classified by immunologic phenotype as follows: common, early B lineage, and T cell. Hyperdiploidy (with more than 50
chromosomes), especially of chromosomes 4, 10, and 17, and translocation t(12;21) (TELAML1), is associated with a better prognosis. Unfavorable
cytogenetics are hypodiploidy (less than 44 chromosomes), the Philadelphia chromosome t(9;22), the t(4;11) translocation (which has fusion genes
involving the MLL gene at 11q23), and a complex karyotype with more than five chromosomal abnormalities.
D. Mixed Phenotype Acute Leukemias
These leukemias consist of blasts that lack differentiation along the lymphoid or myeloid lineage or blasts that express both myeloid and lymphoid
lineagespecific antigens. This group is considered very high risk and has a poor prognosis. The limited available data suggest that an “acute
lymphoblastic leukemia–like” regimen followed by allogeneic stem cell transplant may be advisable; addition of a tyrosine kinase inhibitor in patients
with t(9;22) translocation is recommended.
CLINICAL FINDINGS
A. Symptoms and Signs
Most patients have been ill only for days or weeks. Bleeding (usually due to thrombocytopenia) occurs in the skin and mucosal surfaces, with gingival
bleeding, epistaxis, or menorrhagia. Less commonly, widespread bleeding is seen in patients with disseminated intravascular coagulation (DIC) (in APL
and monocytic leukemia). Infection is due to neutropenia, with the risk of infection rising as the neutrophil count falls below 500/mcL (0.5 × 109/L).
Common presentations include cellulitis, pneumonia, and perirectal infections; death within a few hours may occur if treatment with appropriate
antibiotics is delayed. Fungal infections are also commonly seen.
Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. The most dramatic presentation is hyperleukocytosis,
in which a markedly elevated circulating blast count (total white blood count greater than 100,000/mcL [100 × 109/L]) leads to impaired circulation,
presenting as headache, confusion, and dyspnea. Such patients require emergent chemotherapy with adjunctive leukapheresis since mortality
approaches 40% in the first 48 hours.
On examination, patients appear pale and have purpura and petechiae; signs of infection may not be present. Stomatitis and gum hypertrophy may be
seen in patients with monocytic leukemia, as may rectal fissures. There is variable enlargement of the liver, spleen, and lymph nodes. Bone tenderness
may be present, particularly in the sternum, tibia, and femur.
B. Laboratory Findings
The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts (eFigure 13–28). However, blasts may be absent from the
peripheral smear in as many as 10% of cases (“aleukemic leukemia”). The bone marrow is usually hypercellular and dominated by blasts (greater than
20%).
eFigure 13–28.
Peripheral blood changes in leukemias. In most cases of leukemia, the peripheral blood is involved. Both A and B show a marked increase in the
number of leukocytes. In A, which represents chronic lymphocytic leukemia (CLL), the cells resemble small lymphocytes. In B, which is acute
1329: Acute Leukemia, Lloyd E. Damon; Charalambos Babis Andreadis Page 2 / 7
lymphoblastic leukemia (ALL), the cells are larger and resemble the lymphoblasts seen in early stages of lymphocytic differentiation. Note the
fragmentation of the fragile leukemic cells, which is a common finding in peripheral blood smears of patients with acute leukemia. (Modified and
reproduced, with permission, from Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998
peripheral smear in as many as 10% of cases (“aleukemic leukemia”). The bone marrow is usually hypercellular and dominated by blasts (greater than
20%).
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eFigure 13–28.
Peripheral blood changes in leukemias. In most cases of leukemia, the peripheral blood is involved. Both A and B show a marked increase in the
number of leukocytes. In A, which represents chronic lymphocytic leukemia (CLL), the cells resemble small lymphocytes. In B, which is acute
lymphoblastic leukemia (ALL), the cells are larger and resemble the lymphoblasts seen in early stages of lymphocytic differentiation. Note the
fragmentation of the fragile leukemic cells, which is a common finding in peripheral blood smears of patients with acute leukemia. (Modified and
reproduced, with permission, from Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998
by The McGrawHill Companies, Inc.)
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Hyperuricemia may be seen. If DIC is present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin degradation products or
fibrin Ddimers present. Patients with ALL (especially T cell) may have a mediastinal mass visible on chest radiograph. Meningeal leukemia will have
blasts present in the spinal fluid, seen in approximately 5% of cases at diagnosis; it is more common in monocytic types of AML and can be seen with
ALL.
The Auer rod, an eosinophilic needlelike inclusion in the cytoplasm, is a characteristic of AML (though sometimes seen in APL, highgrade MDS, and
myeloproliferative disorders) (see an example of an Auer rod in eFigure 13–29). The phenotype of leukemia cells is usually demonstrated by flow
cytometry or immunohistochemistry. AML cells usually express myeloid antigens such as CD13 or CD33 and myeloperoxidase. ALL cells of B lineage will
express CD19, and most cases will express CD10, formerly known as the “common ALL antigen.” ALL cells of T lineage will usually not express mature T
cell markers, such as CD3, CD4, or CD8, but will express some combination of CD2, CD5, and CD7 and will not express surface immunoglobulin. Almost
all cells express terminal deoxynucleotidyl transferase (TdT).
eFigure 13–29.
Acute promyelocytic leukemia (APL), bone marrow aspirate films. A : Leukemic promyelocytes, which are mononuclear cells several with
numerous cytoplasmic reddishpurple granules. Note at the top right the promyelocyte with a cleft nucleus, highlighting the frequent variations in
nuclear shape in promyelocytic leukemia. B : Leukemic promyelocytes, several of which have numerous reddishpurple granules in the cytoplasm. The
cells vary in nucleartocytoplasmic ratio, here ranging from high to intermediate. In addition, the nuclei have various shapes, some characteristic of
myelocytes or metamyelocytes. Note the needlelike Auer rod in the left lower clefted promyelocyte, characteristic of APL (as well as of AML, highgrade
MDS, and myeloproliferative disorders). A cell on the left appears to have matured to a neutrophilic myelocyte. (Reproduced, with permission, from
Lichtman MA, Shafer MS, Felgar RE, Wang N. Lichtman's Atlas of Hematology. McGrawHill, 2016.)
numerous cytoplasmic reddishpurple granules. Note at the top right the promyelocyte with a cleft nucleus, highlighting the frequent variations in
nuclear shape in promyelocytic leukemia. B : Leukemic promyelocytes, several of which have numerous reddishpurple granules in the cytoplasm. The
cells vary in nucleartocytoplasmic ratio, here ranging from high to intermediate. In addition, the nuclei have various shapes, some characteristic of
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myelocytes or metamyelocytes. Note the needlelike Auer rod in the left lower clefted promyelocyte, characteristic of APL (as well as of AML, highgrade
MDS, and myeloproliferative disorders). A cell on the left appears to have matured to a neutrophilic myelocyte. (Reproduced, with permission, from
Lichtman MA, Shafer MS, Felgar RE, Wang N. Lichtman's Atlas of Hematology. McGrawHill, 2016.)
DIFFERENTIAL DIAGNOSIS
AML must be distinguished from other myeloproliferative disorders, CML, and MDS. Acute leukemia may also resemble a leftshifted bone marrow
recovering from a previous toxic insult. If the diagnosis is in doubt, a bone marrow study should be repeated in several days to see if maturation has
taken place. ALL must be separated from other lymphoproliferative disease such as CLL, lymphomas, and hairy cell leukemia. It may also be confused
with the atypical lymphocytosis of mononucleosis and pertussis.
TREATMENT
Acute leukemia is considered a curable disease, especially among younger patients without significant comorbidities. The first step in treatment is to
obtain complete remission, defined as normal peripheral blood with resolution of cytopenias, normal bone marrow with no excess blasts, and normal
clinical status. The type of initial chemotherapy depends on the subtype of leukemia.
1. AML
Most patients with AML who are treated with a curative intent receive a combination of an anthracycline (daunorubicin or idarubicin) plus cytarabine,
either alone or in combination with other agents (eg, gemtuzumab ozogamicin). This therapy will produce complete remissions in 80–90% of patients
under age 60 years and in 50–60% of older patients (see Table 39–2). Patients with secondary AML (evolved from prior myelodysplastic or
myeloproliferative disorders) or treatmentassociated AML should receive the drug Vyxeos (a liposomal formulation of daunorubicin and cytarabine).
Patients with a pathogenic variant of FLT3 benefit from the addition of the FLT3 kinase inhibitor midostaurin to their regimen. Postremission therapy
options include additional chemotherapy and allogeneic stem cell transplantation. Patients with a favorable genetic profile can be treated with
chemotherapy alone or with autologous transplant with cure rates of 60–80%. For intermediaterisk patients with AML, cure rates are 35–40% with
chemotherapy and 40–60% with allogeneic transplantation. Patients who do not enter remission (primary induction failure) or those with highrisk
genetics have cure rates of less than 10% with chemotherapy alone and are referred for allogeneic stem cell transplantation.
Patients who are not treated with initial curative intent (those older than 75 years or with significant comorbidities) can derive benefit from newer
targeted agents, including the bcl2 inhibitor venetoclax added to a hypomethylating agent or lowdose cytarabine, enasidenib (targeting IDH2
mutations), ivosidenib (targeting IDH2 mutations), or glasdegib. Some of these patients can still benefit from a reducedintensity allogeneic transplant
if they achieve good disease control.
Once leukemia has recurred after initial chemotherapy, the prognosis is poor. For patients in second remission, allogeneic transplantation offers a 20–
30% chance of cure. Targeted therapies described above are useful for selected patients and can offer longterm disease control.
2. ALL
Adults with ALL are treated with combination chemotherapy, including daunorubicin, vincristine, prednisone, and asparaginase. This treatment
produces complete remissions in 90% of patients. Those patients with Philadelphia chromosomepositive ALL (or bcrablpositive ALL) should receive
a tyrosine kinase inhibitor, such as dasatinib or ponatinib, added to their initial chemotherapy. Remission induction therapy for ALL is less
myelosuppressive than treatment for AML and does not necessarily produce prolonged marrow aplasia. Patients should also receive CNS prophylaxis
so that meningeal sequestration of leukemic cells does not develop.
After achieving complete remission, patients may be treated with either additional cycles of chemotherapy or highdose chemotherapy and stem cell
transplantation. Treatment decisions are made based on patient age and disease risk factors. Adults younger than 39 years have uniformly better
outcomes when treated under pediatric protocols. For older patients, minimal residual disease testing early on can identify highrisk patients who will
not be cured with chemotherapy alone and who will do better with allogeneic transplantation. For patients with relapsed disease, the bispecific
Adults with ALL are treated with combination chemotherapy, including daunorubicin, vincristine, prednisone, and asparaginase. This treatment
produces complete remissions in 90% of patients. Those patients with Philadelphia chromosomepositive ALL (or bcrablpositive ALL) should receive
a tyrosine kinase inhibitor, such as dasatinib or ponatinib, added to their initial chemotherapy. Remission induction therapy for ALL is less
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myelosuppressive than treatment for AML and does not necessarily produce prolonged marrow aplasia. Patients should also receive CNS prophylaxis
so that meningeal sequestration of leukemic cells does not develop.
After achieving complete remission, patients may be treated with either additional cycles of chemotherapy or highdose chemotherapy and stem cell
transplantation. Treatment decisions are made based on patient age and disease risk factors. Adults younger than 39 years have uniformly better
outcomes when treated under pediatric protocols. For older patients, minimal residual disease testing early on can identify highrisk patients who will
not be cured with chemotherapy alone and who will do better with allogeneic transplantation. For patients with relapsed disease, the bispecific
antibody blinatumomab targeting CD19 and the antibodydrug conjugate inotuzumab ozogamicin targeting CD22 have shown remarkable activity and
are considered superior to traditional chemotherapy options. Chimeric antigen receptor T cell therapy targeting CD19 is an additional option for
patients with relapsed or refractory BALL but is currently used as a bridge to allogeneic transplantation.
PROGNOSIS
Approximately 70–80% of adults with AML under age 60 years achieve complete remission and ~50% are cured using riskadapted postremission
therapy. Older adults with AML achieve complete remission in up to 50% of instances. The cure rates for older patients with AML have been very low
(approximately 10–20%) even if they achieve remission and are able to receive postremission chemotherapy.
Patients younger than 39 years with ALL have excellent outcomes after undergoing chemotherapy followed by riskadapted intensification and
transplantation (cure rates of 60–80%). Patients with adverse cytogenetics, poor response to chemotherapy, or older age have a much lower chance of
cure (cure rates of 20–40%).
WHEN TO REFER
All patients should be referred to a hematologist.
WHEN TO ADMIT
Most patients with acute leukemia will be admitted for treatment.
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Muffly L et al. Pediatricinspired protocols in adult acute lymphoblastic leukemia: are the results bearing fruit? Hematology Am Soc Hematol Educ
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Sekeres MA et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv.
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Osman AEG et al. Treatment of acute promyelocytic leukemia in adults. J Oncol Pract. 2018;14:649.
[PubMed: 30423270]
Rytting ME et al. Acute lymphoblastic leukemia in adolescents and young adults. Cancer. 2017;123:2398.
[PubMed: 28328172]
Sekeres MA et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv.
2020;4:3528.
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Smith CC. The growing landscape of FLT3 inhibition in AML. Hematology Am Soc Hematol Educ Program. 2019;2019:539.
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Swaminathan M et al. Novel therapies for AML: a roundup for clinicians. Expert Rev Clin Pharmacol. 2020;13:1389.
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Tasian SK et al. Philadelphia chromosomelike acute lymphoblastic leukemia. Blood. 2017;130:2064.
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