Key Clinical Updates in Acute Leukemia
Patients with a FLT3 mutation benefit from the addition of the FLT3 kinase inhibitor midostaurin to their regimen.
Patients with secondary AML (evolved from prior myelodysplastic or myeloproliferative disorders) or treatment-associated AML should receive the drug Vyxeos (a liposomal formulation of daunorubicin and cytarabine).
Patients > 75 years of age who are not treated with initial curative intent can derive benefit from newer targeted agents, including the bcl2 inhibitor venetoclax added to a hypomethylating agent or low-dose cyatarabine, enasidenib (targeting IDH2 mutations), ivosidenib (targeting IDH2 mutations), or glasdegib.
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.
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, gastrointestinal 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 PML-RAR-alpha, 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 genome-wide 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 “core-binding factor” leukemias. These patients have a higher chance of achieving both short- and long-term 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 mutations 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 very poor prognosis in the setting of wild type NPM1. Other mutations 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 FLT3-ITD mutations and includes mutations of nucleophosmin 1 (NPM1) or carries CEBPA biallelic mutations.
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 non-chemotherapy treatments. APL is characterized by the cytogenetic finding of t(15;17) and the fusion gene PML-RAR-alpha. It is a highly curable form of leukemia (over 90%) with integration of all-trans-retinoic 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) (TEL-AML1), 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 lineage-specific 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.
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.
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%).
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.
Hyperuricemia may be seen. If DIC is present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin degradation products or fibrin D-dimers 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 needle-like inclusion in the cytoplasm, is a characteristic of AML (though sometimes seen in APL, high-grade 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).
Acute promyelocytic leukemia (APL), bone marrow aspirate films. A: Leukemic promyelocytes, which are mononuclear cells several with numerous cytoplasmic reddish-purple 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 reddish-purple granules in the cytoplasm. The cells vary in nuclear-to-cytoplasmic ratio, here ranging from high to intermediate. In addition, the nuclei have various shapes, some characteristic of myelocytes or metamyelocytes. Note the needle-like Auer rod in the left lower clefted promyelocyte, characteristic of APL (as well as of AML, high-grade 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. McGraw-Hill, 2016.)
AML must be distinguished from other myeloproliferative disorders, CML, and MDS. Acute leukemia may also resemble a left-shifted 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.
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.
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 treatment-associated AML should receive the drug Vyxeos (a liposomal formulation of daunorubicin and cytarabine). Patients with a FLT3 mutation benefit from the addition of the FLT3 kinase inhibitor midostaurin to their regimen. Post-remission 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 intermediate-risk 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 high-risk 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 low-dose cytarabine, enasidenib (targeting IDH2 mutations), ivosidenib (targeting IDH2 mutations), or glasdegib. Some of these patients can still benefit from a reduced-intensity 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 long-term disease control.
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 chromosome-positive ALL (or bcr-abl-positive 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 central nervous system 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 high-dose 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 high-risk 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 antibody-drug conjugate inotuzumab ozogamicin targeting CD22 have shown remarkable activity and are considered superior to traditional chemotherapy options. Tisagenlecleucel is a therapy utilizing autologous T cells engineered to express an anti-CD-19 antigen receptor (CART-19) and is FDA-approved for the treatment of children and young adults with relapsed/refractory B-ALL.
Approximately 70–80% of adults with AML under age 60 years achieve complete remission and ~50% are cured using risk-adapted post-remission 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 post-remission chemotherapy.
Patients younger than 39 years with ALL have excellent outcomes after undergoing chemotherapy followed by risk-adapted 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%).
All patients should be referred to a hematologist.
Most patients with acute leukemia will be admitted for treatment.
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