ACUTE LEUKEMIA IN ADULTS
Acute Myeloid Leukemia
• Diagnosis is made on 20% blasts or more; in patients with t(8;21) (q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), or t(15;17)(q22;q12) AML diagnosis is made even with less than 20% blasts.
• Separate entities are recognized based on specific chromosomal/molecular abnormalities.
• Presence of increased promyeloblasts facilitates diagnosis of acute promyelocytic leukemia.
• Presence of dysplastic eosinophils assists in the diagnosis of acute myeloid leukemia with inv(16)/t(16;16).
• Acute myeloid leukemia presentation is grouped based on presence of myelodysplastic changes, prior exposure to chemotherapy or radiotherapy, the presence of myeloid sarcoma, or Down syndrome.
• Acute myeloid leukemia with multilineage dysplasia is divided into subgroups based on prior history of myelodysplastic syndrome.
Acute Myeloid Leukemia
• Treatment is divided into induction and post-remission therapy.
• Standard induction therapy for patients who have de novo acute myeloid leukemia and are younger than 60 years include combination therapy with cytarabine (cytosine arabinoside, ara-C [Cytosar]) and an anthracycline.
• All-trans-retinoic acid (tretinoin [Vesanoid]) and arsenic trioxide (Trisenox) are the new standard induction treatment for acute promyelocytic leukemia.
Acute Lymphoblastic Leukemia
• There is no agreed-upon lower limit of blast percentage required for diagnosing acute lymphoblastic leukemia. Many treatment
protocols use 25% blasts as the cut-off for diagnosis and in general, a diagnosis of acute lymphoblastic leukemia should be avoided if there are less than 20% blasts.
• The diagnosis includes B-lineage, T-lineage, and unspecified acute lymphoblastic leukemia.
• B-lineage, but not T-lineage categories are recognized as separate entities based on the presence of specific chromosomal or molecular abnormalities.
Acute Myeloid Leukemia
The age-adjusted incidence rate for acute myeloid leukemia (AML) is 4.5 per 100,000 men and women per year. The incidence increases with age and the median age at diagnosis is 67
Exposure to chemicals including benzene, petroleum products, herbicides, pesticides, and tobacco are associated with increased risk of AML. About 10% of patients exposed to chemotherapy or radiotherapy eventually develop therapy-related AML. Warfare and occupational exposure to ionizing radiation predispose to AML.
The pathophysiology of AML consists of maturation arrest at the blast level and activation of genes through several mechanisms (e.g., epigenetic silencing). One of the reasons for treatment failure in AML is the inability of current chemotherapy to kill the leukemia stem cells. These cells are quiescent, can self-renew, and have extensive proliferative capacity and the ability to give rise to differentiated progeny in a hierarchical pattern. Most of the chemotherapeutic
agents traditionally used to treat AML are cell-cycle–active agents that primarily target dividing cells. These agents are highly unlikely to be effective against the quiescent leukemia stem cells. Therefore, new agents are being studied that target the leukemia stem cell.
Secondary AML, defined as AML following antecedent hematologic disorder or therapy for another disease, is associated with very poor outcome.
Smoking cessation and avoiding exposure to offending agents, such as benzene, can prevent AML.
Patients might complain of fatigue or weakness, anorexia, or weight loss. Patients can also present with fever with or without source of infection, bleeding tendency, and sometimes bone pain, cough, or diaphoresis. Seldom patients present with soft tissue masses, called myeloid sarcoma, with or without bone marrow involvement.
On physical examination, fever, hepatosplenomegaly, lymphadenopathy, and evidence of infection and hemorrhage can be detected. Bleeding because of disseminated intravascular coagulopathy is more characteristic of acute promyelocytic leukemia. Infiltration of the gingiva, soft tissues, skin or meninges is more characteristic of monocytic leukemia. Patients with very high numbers of circulating blasts can develop signs of leukostasis such as headache, confusion, and dyspnea.
AML is diagnosed if at least 20% blasts are present in the blood or bone marrow; except in patients with t(8;21)(q22;q22), inv(16)(p13q22), t(16;16)(p13;q22), or t(15;17)(q22;q12), where the diagnosis is made even with less than 20% blasts. Increased promyeloblasts are associated with t(15;17) and dysplastic eosinophils are characteristics of inv(16)/t(16;16). Auer rods, representing abnormal condensation of cytoplasmic granules, may be observed in myeloblasts.
AML presentation is grouped based on presence of myelodysplastic changes, prior exposure to chemotherapy or radiotherapy, the presence of myeloid sarcoma, or Down syndrome. AML with multilineage dysplasia is grouped into specific subtypes with or without the presence of prior multilineage dysplasia.
The AML blasts are characteristically myeloperoxidase-positive. If they are negative, expression of myeloid markers on their surface such as CD13 and CD33 is diagnostic. Blasts carrying t(8;21) often express lymphoid markers (e.g., CD19, PAX5, and cytoplasmic CD79a) and promyeloblasts with t(15;17) commonly express CD2.
The main alternative diagnosis is acute lymphoblastic leukemia (ALL).
Factors associated with worse outcome include older age (inability to survive induction either due to comorbidities or because of chemoresistance due to multidrug-resistance proteins), secondary presentation (prior chemotherapy for an unrelated disease or history of antecedent hematologic disorder), elevated white blood cell count (WBC >100 × 109/L), and poor performance status.
Karyotype aberrations (structural and numerical) assign patients into favorable, intermediate, and unfavorable subgroups (Table 1). In patients with normal karyotype, submicroscopic genetic aberrations further assign subgroups. NPM1 mutations are found in 46% to 62% of AML patients, and they are associated with improved outcome if they are solely present. Detection of internal tandem duplications
within the juxtamembrane domain of the FLT3 gene, reported in about a third of the normal karyotype AML patients, predicts poor outcome, especially if the FLT3-ITD/FLT3-wild type allelic ratio is high. The deleterious prognostic significance of FLT3 point mutations was demonstrated in younger patients; FLT3-ITD loses its prognostic effect in patients older than 70 years of age. Additional, less frequent, aberrations such as biallelic mutations of CEBPA, are associated with improved outcome, and partial tandem duplication of the MLL gene, WT1 mutations, and overexpression of BAALC, ERG and MN1 genes are associated with worse outcome in normal karyotype AML.
Submicroscopic genetic aberrations in the KIT gene adversely affect the outcome of t(8;21) and inv(16)/t(16;16).
New AML Standardized Reporting
|Genetic Group Subset1|
Biallelic CEPBA (NK)
|Intermediate-I||NPM1+/FLT3-ITD NPM1-/FLT3-ITD NPM1-/FLT3-WT|
Others not favorable or adverse
|Adverse||3q21-26, t(6;9), 11q23, -5, -7, abn(17p) complex|
Complete remission is defined as less than 5% blasts in the marrow, blood neutrophil count of at least 1 × 109/L, and platelet count at least 100 × 109/L without circulating blasts and disappearance of extramedullary disease, if such was present. Complete remission is necessary to achieve long-term survival or cure.
Induction therapy for patients with newly diagnosed AML, in the absence of a clinical trial, consists of the combination of ara-C (Cytosar) at 100 to 200 mg/m2/day for 7 days as continuous infusion along with an anthracycline (e.g., daunorubicin [Cerubidine] or idarubicin [Idamycin]) administered intravenously over the first 3 days. Attempts to escalate ara-C during induction results in longer disease-free survival in some studies, and escalating anthracyclines improves complete remission rate and overall survival in patients younger than 65 years. Adding etoposide (Toposar)1 can improve remission duration.
Multilumen right atrial catheters should be used to administer medications, fluid, and transfusions and to draw blood. Induction treatment can result in tumor lysis syndrome, characterized mainly by elevated uric acid. Therefore, allopurinol (Zyloprim) and hydration should be initiated early.
Patients who are allergic to allopurinol, who are unable to take oral medications, or who have uric acid nephropathy may be treated with rasburicase (recombinant uric acid oxidase, Elitek) or hemodialysis.
Aggressive supportive care during the period of granulocytopenia and thrombocytopenia are necessary for the success of this treatment. Using recombinant growth factors has been reported to shorten median time to neutrophil recovery, but it has not resulted in improved outcome. Therefore, their use is controversial and should be restricted to clinical trials or according to published guidelines.
Platelet transfusions should maintain a platelet count greater than 10 ×109/L unless the patient has active bleeding or disseminated intravascular coagulation, when it may be necessary to maintain higher platelet counts. Similarly, red blood cell transfusions should maintain hemoglobin of greater than 8 g/dL unless patients have active bleeding, disseminated intravascular coagulopathy, or history of cardiovascular or pulmonary disease. All blood products should be leukodepleted by filtration and irradiated to prevent alloimmunization, fever, and transfusion-associated graft-versus-host disease.
Infections remain the most important cause of morbidity and mortality. Prophylactic antibiotics should be based on institutional antibiograms, and prophylactic antifungal and antiviral medications are highly recommended. Fever should be treated as resulting from bacterial and fungal infections.
After achieving complete remission, further treatment depends on the patient’s age and prognostic factors. For example, high-dose ara-C is more effective than standard-dose ara-C in younger AML patients, especially for those with t(8;21) and inv(16)/t(16;16) and those with normal karyotype AML.
Acute Promyelocytic Leukemia
Acute promyelocytic leukemia (APL), characterized by t(15;17) and its product PML/RARα, should be treated with all-trans retinoic acid (tretinoin [Vesanoid]), which induces differentiation of the leukemic blasts. During this differentiation process, the promyeloblasts lose their characteristic granules that can release enzymes causing disseminated intravascular coagulopathy. The most important side effect of tretinoin is the differentiation syndrome, characterized by increasing leukocyte counts, fever, shortness of breath, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxia. Treatment for this complication includes steroids, chemotherapy, and supportive care.
Tretinoin and arsenic trioxide (Trisenox) represent the new treatment for APL. Because arsenic trioxide also exerts its effect through induction of differentiation, steroids are recommended for all patients preemptively. Approximately 90% of APL patients achieve complete remission, and this regimen results in prolonged disease- free survival.
Once relapse occurs, patients are rarely cured with standard chemotherapy. Patients should be offered allogeneic stem cell transplantation in either first relapse or second remission; the outcome following second remission seems better. Second complete remission is more likely if the first remission lasted longer than 12 months and patients achieved complete remission following one induction course. The long-term disease-free survival following an allogeneic stem cell transplant in relapsed patients is about 40%.
Relapse in APL, in the absence of clinical trials, can respond to the combinations of tretinoin, arsenic trioxide, and an anthracycline.1
Novel Approaches and Future Directions
Novel approaches and future directions include targeted therapies for patients with FLT3 and KIT mutations with specific tyrosine kinase inhibitors and targeting aberrant DNA methylation or histone deacetylation (or both) resulting in epigenetic silencing of structurally normal genes. Current hypomethylating agents approved for myelodysplastic syndromes (5-azacitidine [Vidaza]1 and decitabine [Dacogen]1) are being studied in AML. The proteasome inhibitor bortezomib (Velcade)1 is also being explored in AML.
Allogeneic stem cell transplantation reduces the relapse risk, but this beneficial effect is offset by its treatment-related mortality.
Therefore, this approach should be reserved for patients with high- risk features such as intermediate and adverse karyotypes; those with high white blood cell counts at diagnosis; secondary AML; patients who do not achieve remission after standard induction treatment; and those in second remission and beyond.
Detection of minimal residual disease following complete remission by reverse-transcriptase polymerase chain reaction (PCR) of PML/RARα transcript predicts relapse. Therefore, sequential monitoring of PML/RARα is standard in APL. Detection of minimal residual disease in other types of AML is lagging behind, even though other fusion genes, such as t(8;21) and inv(16)/t(16;16), are available.
Flow cytometry is being studied as a means to monitor minimal residual disease in AML.
The main risk following successful AML treatment is late development of secondary myelodysplastic syndromes and AML.
Acute Lymphoblastic Leukemia
The age-adjusted incidence rate is 1.77 per 100,000 population per year. The median age at diagnosis is 14 years of age; about 60% of cases are diagnosed in patients younger than 20 years.
Genetic predisposition to ALL is associated with Down syndrome, Fanconi’s anemia, Bloom syndrome, neurofibromatosis type 1, and ataxia telangiectasia.
The theories about the origin of the leukemia-initiating cell in ALL vary. Some relate it to an already committed B- or T-lineage cell, and others propose that—at least in some ALL subtypes—the leukemia blasts might arise from a more phenotypically primitive hematopoietic stem cell. The most recent challenge to the leukemia- initiating cell theory is the report that B precursor blasts in various stages of differentiation displayed self-renewal capability, suggesting that leukemic lymphoid progenitors might not lose their self-renewal capability with maturation or are able to “move backward” in differentiation.
Secondary ALL, defined as ALL following another malignancy, irrespective whether patients received prior therapy, is rare. As in secondary AML, the outcome is extremely poor.
Data suggest that early aspects of lifestyle and environment are associated with a decreased risk for ALL in children. For example, prolonged breast-feeding, daycare attendance, and early community-acquired infections are associated with a reduced incidence of childhood ALL. In the United States, ALL incidence rates are lower in rural communities compared with metropolitan areas. Finally, some data suggest that Haemophilus influenzae type b vaccine might reduce ALL risk.
The symptoms are not significantly different from those of patients with AML. Central nervous system (CNS) involvement is detected in approximately 10% of the cases and is more prevalent in T-cell ALL.
The blasts range in size from homogeneous small cells with a high nuclear-to-cytoplasmic ratio and inconspicuous nucleoli to more- pleomorphic cells. Burkitt leukemia is characterized by medium-sized homogeneous cells with dispersed chromatin, multiple nucleoli, and a moderate amount of deep blue cytoplasm with clearly defined vacuoles. The “starry sky” appearance is composed of the tinted body macrophages (the stars) scattered among sheets of dark blue blasts (the sky).
ALL is characterized by blasts that are myeloperoxidase-negative and terminal deoxynucleotide transferase (TdT)-positive. CD10, CD19, cytoplasmic CD22, cytoplasmic CD79a, and PAX5 with variable expression of CD20 characterize B-lineage ALL, whereas CD1a, cytoplasmic CD3, CD7, CD4, and CD8 characterize T-lineage ALL.
The presence of myeloid markers does not exclude the diagnosis of ALL.
Burkitt leukemia is characterized by B-cell–associated antigens and moderate to strong levels of membrane immunoglobulin M (IgM) with light chain restriction; the cells are TdT-negative and more than 99% Ki-67 positive. Burkitt’s leukemia is a subtype of ALL whose hallmark is the t(8;14)(q24;q32) and its variants, t(2;8)(p12;q24) and t(8;22)(q24;q11). In these cases, MYC, located on 8q24, is activated and expressed at high levels, leading to uncontrolled cell proliferation.
However, MYC translocations are not specific for Burkitt leukemia.
The main diagnosis in the differential is AML. The leukemia blasts can resemble hematogones, the normal lymphoid progenitors.
Morphologic distinction between hematogones and residual ALL can be difficult. However, hematogones display the continuum of B-cell markers whereas the leukemic blasts overexpress or underexpress specific markers. For example, ALL with myeloid markers can be relatively easily distinguished from hematogones because the latter lack myeloid markers. Leukemia of ambiguous lineage includes biphenotypic leukemia, describing a single blast population expressing antigens from more than one lineage, and bilineage leukemia describing separate populations of blasts from more than one lineage. The two most common examples are those with t(9;22) and 11q23/MLL translocations.
Several factors are associated with worse outcome such as older age (inability to survive induction either owing to comorbidities or because of chemoresistance due to multidrug resistance proteins), secondary presentation (prior chemotherapy for an unrelated disease), elevated WBC count (>30 × 109/L in B-cell ALL; >100 × 109/L in T-cell ALL), immunophenotype (B-cell) CD20 expression and elevated lactate dehydrogenase, associated with CNS disease. Interestingly, persistence of normal residual hematopoiesis and intense leukemia cell mitotic index are associated with favorable outcome.
Recurring chromosomal abnormalities divide ALL into favorable, intermediate, and unfavorable subgroups (Table 2). Submicroscopic genetic aberrations further characterize the disease. For example, in T- cell ALL, activating somatic mutations in NOTCH1 are described in about 50% of cases. NOTCH1 protein, either normal or aberrant, is cleaved by the γ-secretase complex, leading to its translocation to the nucleus where it induces NOTCH1-target gene transcription. This pathway is currently being targeted in clinical trials with γ-secretase inhibitors. Lack of HOX11 expression and high ERG and BAALC expression predict adverse outcome in T-lineage ALL.
Karyotype Risk Groups in Acute Lymphoblastic Leukemia
|Risk Group Aberration|
|Favorable||del(12p) or t(12p), t(14)(q11-q13), hyperdiploid|
|Intermediate||Normal karyotype, +21, del(9p) or t(9p)|
|Unfavorable||t(9;22), -7, +8, t(4;11), hypodiploid, t(1;19)|
As in AML, achievement of complete remission is necessary to achieve long-term survival or cure. In addition, lack of cytoreduction on day 7 or 14 correlates with adverse prognosis in ALL.
The two most commonly used approaches in ALL include the BFM (Berlin-Frankfurt-Munster) and the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) regimens.
BFM-like regimens include induction with vincristine, prednisone,1 daunorubicin, and pegylated asparaginase (Oncaspar); early intensification with cyclophosphamide (Cytoxan), ara-C (Cytosar), 6- mercaptopurine (Purinethol), and vincristine; CNS prophylaxis with either cranial radiation or high-dose methotrexate and ara-C; late intensification with doxorubicin, vincristine, dexamethasone,1 cyclophosphamide, 6-thioguanine (Tabloid),1 and ara-C; and maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) for a total of 24 months.
The hyper-CVAD regimen consists of eight alternating courses of CVAD with methotrexate and high-dose ara-C. CNS prophylaxis includes, in addition to the high-dose cytarabine and methotrexate, intrathecal methotrexate. Maintenance is conducted with POMP to complete 24 months.
The outcome following these different approaches results in approximately 30% to 40% 5-year survival. Supportive care guidelines are similar to those described in the AML section.
A major breakthrough occurred with the introduction of imatinib mesylate (Gleevec) for the treatment of t(9;22) ALL and its product BCR/ABL. Imatinib functions though competitive inhibition at the adenosine triphosphate (ATP) binding site of the ABL kinase in the inactive conformation, which leads to inhibition of tyrosine phosphorylation of proteins involved in BCR/ABL signaling. It shows a high degree of specificity for BCR/ABL, the receptor for platelet- derived growth factor and KIT tyrosine kinases. Imatinib does not affect the normal hematopoietic progenitor cells. Combining imatinib with chemotherapy, either sequentially (aiming to reduce toxicity) or concurrently, resulted in a significant improvement in disease-free survival over chemotherapy-alone approaches.
Four mechanisms of resistance to imatinib have been described to date: gene amplification, mutations at the kinase site, decreased intracellular imatinib levels, and alternative signaling pathways functionally compensating for the imatinib-sensitive mechanisms.
Unique to ALL, kinase domain mutations can precede imatinib-based therapy and give rise to relapse in patients with de novo t(9;22) ALL. Alternating signaling pathways such as Src family kinase members— Lyn, Hck, and Fgr—have been shown to be elevated in hematopoietic cells of mice with t(9;22) ALL. Even in the presence of suppressed BCR/ABL, t(9;22) ALL cells can proliferate in the presence of stromal support.
Approaches to overcome these mechanisms of resistance include introduction of dasatinib (Sprycel), which is almost 300-fold more potent than imatinib, binds to the kinase domain in the open conformation, is resistant to most mutations, and is active against Src kinases. Dasatinib, as a single agent and in combination with chemotherapy, was tested in imatinib-resistant and imatinib-naïve t(9;22) ALL with encouraging results. Dasatinib and prednisone alone have been studied as front-line therapy in newly diagnosed t(9;22)1 ALL with encouraging results. Similarly, nilotinib (Tasigna)1 is about 30-fold more potent than imatinib, binds to the kinase domain in the inactive formation, and is resistant to most mutations. Nilotinib has promising activity in imatinib-resistant ALL as monotherapy. Recently, ponatinib (Iclusig) was approved for t(9;22) that failed prior treatment. Its unique role is in overcoming resistance generated by the presence of the T315I mutation, for which none of the other TKIs, have activity.
Nelarabine (Arranon) is a purine analogue shown to have significant activity in T-lineage ALL patients whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. In the adult clinical trial, the rate of complete remission was 31% and the overall response rate was 41%. The main toxicity was grade 3 to 4 neutropenia and thrombocytopenia. It is now going to be studied in newly diagnosed T-lineage ALL.1
Pediatric Regimens for Adolescents and Adults
Adolescents and young adults represent a challenging group for both pediatric and adult oncologists. Several groups have evaluated the outcome of patients aged 16 to 21 years based on their treatment on adult or pediatric protocols. Despite an assortment of treatment approaches among the different groups, the results of these retrospective analyses consistently demonstrated that adolescents and young adults treated on pediatric protocols had significantly better 5- year survival than those treated on adult protocols. Several reasons were suggested for these differences, including more-intensive use of non-myelosuppressive agents (e.g., steroids, L-asparaginase, vincristine), earlier CNS prophylaxis, and longer maintenance in the pediatric protocols. Moreover, protocol adherence and compliance, by both treating physicians and patients, was raised as a contributing factor to outcome differences. Therefore, most groups offer pediatric regimens to adolescents and young adults (up to age 30 years and beyond) with encouraging results.
The treatment of adult Burkitt leukemia underwent significant improvement when pediatric regimens, including repetitive cycles of fractional alkylating agents and aggressive CNS therapy, were employed. Because Burkitt leukemia is characterized by strong CD20 expression, two groups successfully included anti-CD20 antibody, rituximab (Rituxan),1 in their treatment regimens. In addition to the favorable outcome in these patients, concerns about increased infectious complications, due to the use of rituximab, were dismissed by these studies. This led to the addition of rituximab to CD20- positive ALL treatment protocol.
Allogeneic stem cell transplantation continues to represent an effective treatment approach for adult ALL. It is usually recommended to high-risk ALL patients in first remission and those in second remission and beyond. Offering allogeneic stem cell transplantation for standard-risk ALL is controversial.
Novel Approaches and Future Directions
The use of a bi-specific T cell–engaging antibody that directs cytotoxic T cells to CD19 expressing target cells resulted in a complete remission rate of 68% among relapsed or refractory ALL patients. In addition, a CD22 monoclonal antibody conjugated to calicheamicin has demonstrated a 50% overall response rate in relapsed or refractory ALL patients. Both studies are still ongoing, and plans to incorporate these novel approaches into the treatment armamentarium of newly diagnosed ALL are underway.
Minimal residual disease in ALL is one of the most powerful and informative parameters to guide clinical management. Two methods have been established to detect minimal residual disease: Flow cytometry relies on immunologic markers to identify residual leukemic cells, and PCR amplifies fusion transcript or uses antigen- receptor genes as targets to detect minimal residual disease.
The main risk following successful treatment of ALL is late development of secondary myelodysplastic syndromes and AML. Another complication is avascular necrosis due to steroid use.
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1 Not FDA approved for this indication.
1 Not FDA approved for this indication.