Acute Leukemias in Adults
Summary of Key Points
Incidence
• There were 13,780 new cases of acute myeloid leukemia (AML) and 6,050 new cases of acute lymphocytic leukemia (ALL) in the United States in 2012, resulting in 10,200 deaths from AML and 1440 from ALL. The incidence of AML is relatively low until age 35 and then rises almost exponentially, whereas ALL peaks in incidence in young children. Risk factors for the development of acute leukemia include exposure to benzene, ionizing radiation, or previous chemotherapy.
Biological Characteristics
• The acute leukemias are clonal disorders, with all leukemic cells in a given patients descending from a common precursor. Recent genomewide analyses of leukemia have demonstrated considerable complexity with a number of recurrent potential “driver” mutations and a much larger number of random “passenger” mutations in individual cases.
Diagnosis and Classification
• The diagnosis of acute leukemia is generally made by bone marrow examination. In the past, the classification of acute leukemia depended heavily on morphologic examination of the leukemic cells. This is no longer the case, and currently the most important elements of classification are the immunophenotype (to distinguish AML from ALL), cytogenetics, and mutational analyses. In AML, three primary-risk groups are recognized. Favorable-risk patients are those with CBF translocations, and those with normal cytogenetics and either NMP1 or CEBPA mutations without mutations in FLT3-ITD. Unfavorable-risk patients are those with abnormalities of 3q, 5 or 7, and those with complex cytogenetics. The intermediate-risk group includes all those not classified as favorable or unfavorable. Acute promyelocytic leukemia, characterized by t(15;17), is a separate entity and requires specific therapy. In ALL, the favorable-risk group includes those with high hyperdiploidy, and del9q. The unfavorable-risk group includes t(4;11), low hypodiploidy/near triploidy, and those with complex cytogenetics. All others comprise the intermediate-risk group. Patients with t(9;22) (Ph+ ALL) and mature B-cell ALL including Burkitt leukemia comprise separate categories of ALL that require specific treatment.
Treatment
Patients With AML Who Are Candidates for Intensive Therapy
• Induction chemotherapy that includes an anthracycline plus cytarabine will result in a complete remission in approximately 70% of patients. Postremission therapy depends on the risk group. Favorable-risk patients are generally treated with three or four cycles of consolidation chemotherapy, including high-dose cytarabine. With such treatment, approximately 50% of patients will be cured. Patients with intermediate-risk disease should undergo allogeneic transplantation while in first remission if they have a matched sibling or matched unrelated donor. The use of partially matched donors in this setting is less agreed on. Allogeneic transplantation using matched siblings, matched unrelated donors, or partially matched cord blood is recommended for patients with unfavorable-risk disease in first remission.
Patients With ALL Who Are Candidates for Intensive Therapy
• Induction therapy in ALL includes a combination of vincristine, prednisone, an anthracycline, and asparaginase, with cyclophosphamide sometimes included. With such regimens, 75% to 90% of patients will achieve a complete remission. Postremission therapy generally involves six to eight courses of intensive consolidation therapy, several of which contain high-dose methotrexate, cytarabine, and asparaginase, and several of which include the same drugs used for initial remission induction. Some form of central nervous system (CNS) prophylaxis is required, as is low-dose maintenance therapy. High-risk patients should receive an allogeneic transplant in first remission if at all possible. The role of allogeneic transplantation for patients with standard-risk disease is more controversial.
1. A 39-year-old man presents with pallor, easy bruising, and is found to have an elevated white blood cell count of 45,000/mm3 of which >60% are myeloid blasts. A bone marrow examination shows AML, and chromosomal analysis shows normal cytogenetics in 20 of 20 metaphases. The patient is treated with induction chemotherapy and achieves a complete remission. He has an HLA-identical brother. Further testing of the leukemia blasts looking for mutations in which of the following genes would be most important in determining whether or not transplantation while in first complete remission would be indicated?
2. A 28-year-old woman presents with bone pain and fatigue, and is found to have a white blood count of 18,000/mm3 with 75% lymphoblasts. A bone marrow shows acute lymphocytic leukemia; immunophenotype characterizes the leukemia as pro-B cell; cytogenetics show t(4:11) in 18 of 20 metaphases. A lumbar puncture is negative. The patient is treated with a regimen of daunorubicin, vincristine, prednisone, and l-asparaginase and achieves a complete remission by day 28. She is an only child. Which of the following is most appropriate?
A Treat with several rounds of consolidation chemotherapy
B Treat with several rounds of consolidation chemotherapy followed by at least 2 years of maintenance chemotherapy
C Treat with several rounds of consolidation chemotherapy followed by an autologous hematopoietic cell transplant
D Begin search for unrelated or cord blood donor and refer for allogeneic transplant.
3. A 48-year-old man presents with a 3-week history of fatigue, malaise, and over the last week, bleeding gums after brushing his teeth. His peripheral counts reveal a white count of 34,000/mm3 and a platelet count of 22,000/mm3. A bone marrow exam shows acute myeloid leukemia, and cytogenetics reveal t(8;21) along with –y and +8 in 19 of 20 metaphases. The patient is treated with induction chemotherapy and achieves a first remission. He has a healthy HLA-matched brother. Which of the following is the most appropriate next step?
A Treat with several rounds of consolidation chemotherapy including high-dose cytarabine.
B Treat with several rounds of consolidation chemotherapy including high-dose cytarabine followed by maintenance therapy with dasatinib.
C Treat with several rounds of consolidation chemotherapy followed by an autologous hematopoietic cell transplant.
D Treat with one cycle of consolidation chemotherapy followed by an allogeneic hematopoietic cell transplant from his HLA-matched brother.
1. Answer: D. AML with normal cytogenetics fall into the intermediate-risk category by classical cytogenetic-based schemas. Studies have shown that patients with normal cytogenetics can be further divided into those with mutations in NPM1 or CEBPA without mutations in FLT3, and all others. In a prospective trial, patients with mutations in NPM1 or CEBPA without mutations in FLT3 had a much better outcome after chemotherapy than the other subgroups, and did not further benefit from allogeneic transplant in first remission. In contrast, patients without mutations in NMP1 or CEBPA, or those with mutations in FLT3, did much worse and benefited from undergoing transplant while in first remission.
2. Answer: D. t(4:11) and having complex cytogenetics constitute the very high-risk category of patients with ALL. The outcomes of such patients are sufficiently unfavorable if treated with conventional chemotherapy that they should be considered for allogeneic hematopoietic cell transplantation if a donor can be identified.
3. Answer: A. Patients with AML with inv(16) or t(8;21) comprise the favorable-risk category of AML. Additional cytogenetic abnormalities involving loss of a sex chromosome or addition of 8 (8+) are frequently seen with t(8;21) and do not appear to change the overall prognosis. If four or five abnormalities are present, the overall outcome may be somewhat worse, but not sufficiently so to change the overall therapeutic approach. In prospective trials, there did not appear to be any advantage for allogeneic transplantation in first remission for patients with favorable risk AML.
