Acute Leukemias in Adults

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Acute Leukemias in Adults

Frederick R. Appelbaum

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 AML Who Are Not Candidates for Intensive Therapy

• Low-dose cytarabine is a generally accepted therapy for patients with AML who are not candidates for intensive therapy. Recent alternatives include decitabine, azacitidine, or clofarabine.

Patients With APL

• Induction therapy should include all-trans-retinoic acid (ATRA) alone with an anthracycline and, for higher-risk patients, cytarabine. The inclusion of arsenic trioxide during consolidation therapy appears to prolong survival.

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.

Patients With Ph+ ALL

• A tyrosine kinase inhibitor (imatinib, nilotinib, or dasatinib) should be included as part of induction and consolidation therapy. Allogeneic transplantation is recommended in first remission if an appropriate donor is available.

Mature B-cell ALL

• Therapy should include, along with the usual drugs used for remission induction, high doses of fractionated cyclophosphamide, high-dose methotrexate and cytarabine, and rituximab.

Introduction

Normal hematopoiesis involves the tightly regulated proliferation and maturation of pluripotent hematopoietic stem cells to become mature myeloid and lymphoid peripheral blood cells. Acute leukemia is the result of a series of mutational events occurring in an early hematopoietic precursor that prevent the progeny of that precursor from maturing normally but allow them to proliferate in an uncontrolled fashion. The result is the rapid expansion of an immature population of myeloid (in acute myeloid leukemia [AML]) or lymphoid (in acute lymphocytic leukemia [ALL]) cells that replace the normal bone marrow, leading to the loss of production of normal red cells, white cells, and platelets. Eventually, the leukemic cells escape from the marrow into the bloodstream and accumulate in lymph nodes, the spleen, and normal organs. If untreated, acute leukemia is usually fatal within a few months. However, with modern therapies, survival following the diagnosis of acute leukemia can be markedly prolonged and many patients can now be cured.

Epidemiology

According to the American Cancer Society, there will be 13,780 new cases of AML and 6050 cases of ALL in the United States in 2012, resulting in 10,200 deaths from AML and 1440 from ALL.1 The incidence of AML has a bimodal pattern with a modest peak among infants, a decline in childhood, and then an exponential rise with advancing age (Figure 98-1). ALL likewise has a bimodal pattern, but the initial peak occurs among children aged 1 to 4, with a decline between ages 20 and 60, and a more modest rise in advanced years.2 The rates for all forms of acute leukemia are higher in males than females, and tend to be higher in non-Hispanic whites, with the exception of higher rates of acute promyelocytic leukemia (APL) and B-cell ALL among Hispanic whites.2

Etiology

Genetic Predisposition

The concordance rate of acute leukemia in identical twins is virtually 100% if one twin develops leukemia during the first year of life, but then declines with age. “Pure familial leukemia” is a term used to describe those rare syndromes caused by a single mutation that leads to leukemia without other manifestations; to date, three have been described involving RUNX1, CEBPA, and GATA2.3,4 The incidence of acute leukemia is also increased in primary bone marrow failure syndromes, such as Diamond-Blackfan, Shwachman-Diamond, and dyskeratosis congenita, as well as in syndromes involving defective DNA repair, such as Fanconi anemia and Bloom syndrome. Acute leukemia is also increased in some of the syndromes associated with loss of tumor suppressor gene function such as Li-Fraumeni syndrome, and in syndromes caused by abnormal chromosomal numbers, including 21+ and XXY.3 Aside from these rare syndromes, there does not appear to be any familial aggregation of acute leukemia; that is, first-degree relatives of patients with acute leukemia are not at increased risk for developing the disease.5

Prior Therapy

Although the exact percentage is uncertain, as much as 10% of AMLs and a smaller percentage of ALLs are thought to be the consequence of prior exposure to chemotherapy or radiation for a primary malignancy or autoimmune disorder.8 Treatment-related leukemias can be grouped into several syndromes. AML developing after alkylating agent therapy has a latency of 5 to 7 years, often first appears as a myelodysplastic syndrome (MDS), and is frequently associated with abnormalities involving the long arms of chromosomes 5 or 7. All alkylating agents are likely leukemogenic, with an increased incidence of leukemia observed after prolonged exposure, following the use of dose-intense regimens, or when used in certain combinations. Treatment-related AML is also seen following exposure to topoisomerase II inhibitors, such as etoposide, teniposide or anthracyclines. These leukemias develop relatively rapidly, often within 2 years of exposure, are not generally preceded by a myelodysplastic phase, and frequently have rearrangements involving 11q23, the locus for MLL (the mixed-lineage leukemia gene) or 21q22. A number of other drugs have also been implicated in the subsequent development of acute leukemia, including bimolane, an agent used to treat psoriasis, and recently, lenalidomide, an agent used in the treatment of myeloma or myelodysplasia.9 Patients with lymphoma who receive autologous hematopoietic cell transplants are at increased risk for the development of leukemia, which may, in part, be predicted by the therapy received before the transplant.

Not all treatment-related leukemias fall into the discrete categories described here. Secondary leukemias with inv(16), t(9;22), and abnormalities involving 3q21 have been reported. Although there remains some debate, in general, patients with treatment-related leukemias do not fare as well as patients with de novo leukemia, even after adjusting for known risk factors.10

Antecedent Hematologic Malignancies

A number of hematologic malignancies can eventually evolve into a disease indistinguishable from acute myeloid leukemia. This is a common occurrence for the myelodysplastic syndromes, and sometimes occurs with polycythemia vera, idiopathic myelofibrosis, and rarely with essential thrombocythemia. Antecedent hematologic malignancies are present in 3% to 4% of cases of AML in patients younger than age 60, and in as many as 15% of cases in patients older than age 60. The term “secondary AML” is sometimes used to describe both therapy-related AMLs and those arising from an antecedent hematologic malignancy. There are certain common features, including tri-lineage dysplasia and a high incidence of unfavorable cytogenetic changes. The current WHO classification schema distinguishes between the two, with separate definitions for therapy-related myeloid neoplasms and AML with myelodysplasia-related changes.

Pathobiology

Clonality and Clonal Architecture

The acute leukemias are clonal disorders, with all leukemic cells in a given patient descending from a common precursor. The initial proof of clonality in leukemia came from studies of the disease in females who were heterozygotic for the x-linked glucose-6-phosphate dehydrogenase isoenzyme. In normal heterozygotic women, because of random x-linked inactivation, any single blood cell will express one or the other isoenzyme, and hematopoietic cells overall will be a 50 to 50 mix. Leukemia cells in G6PD heterozygotic females, however, were found in every case to be all of one isoenzyme or the other, indicating their origin from a single precursor.

Recent genome-wide analysis of leukemia has demonstrated considerable complexity with a number of recurrent potential “driver” mutations, perhaps up to 10, and a much larger number of random “passenger” mutations in each individual case. Thus overt leukemia is not the result of a single mutation. Careful studies in both AML and ALL have further found considerable variability in the mutations among the individual leukemic cells in any single case. The pattern of variability suggests that the development of leukemia is not a simple progressive accumulation of mutations in an essentially linear direction but rather is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection.11,12

The Leukemic Stem Cell

Within the clonal populations of cells in patients with acute leukemia, there must be a subpopulation of cells capable both of self-renewal and proliferation. Such cells have been termed “leukemia stem cells.” Although there is no gold standard for their identification, the ability of human leukemic cells to engraft long-term in immunodeficient NOD/SCID mice is generally accepted as a marker for a leukemia stem cell. In human AML, the subpopulation of cells capable of long-term engraftment in immunodeficient mice is within the CD34++CD38– CD 123+ fraction and comprises only a small percent (0.2 to 100/106) of the leukemic cells present.13 However, many cases of AML do not engraft even in the more permissive NOD/SCID/IL2R immunodeficient mouse, including almost all cases of acute promyelocytic leukemia (APL), and thus the ability of leukemic cells to grow in an immunodeficient mouse is not a true assay for the leukemia stem cell.

Morphology

AML cells are typically 12 to 20 µm in diameter with large nuclei, multiple nucleoli, and azurophilic granules in the cytoplasm. ALL cells are typically smaller than AML blasts and are devoid of granules (Figure 98-2). For more than 3 decades, the French-American-British (FAB) system was used to describe and classify morphologic subtypes of AML and ALL. Morphologic subclassification of acute leukemia adds little prognostic or therapeutic information beyond that provided by cytogenetic and mutational categorization, but still remains part of the overall World Health Organization (WHO) classification schema.

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Figure 98-2 Panel 1 shows the results of bone marrow aspirates (AG) or a marrow biopsy (H) in patients with different forms of acute myeloid leukemia (AML); Panel 2 shows the results of marrow aspirates in different categories of acute lymphocytic leukemia (ALL). Panel 1: A, Acute myeloid leukemia with no (FAB AML-M0) or minimal (FAB AML M-1) maturation. The cells are myeloblasts with dispersed chromatin and variable amounts of agranular cytoplasm. Some cells have medium-sized poorly defined nucleoli. B, Acute myeloid leukemia with maturation (FAB AML-M2). Some of the blasts contain azurophilic granules and promyelocytes are evident. Note the Auer rod (arrow). C, Acute promyelocytic leukemia (FAB AML-M3). All of the cells are promyelocytes containing coarse cytoplasmic granules, which sometimes obscure the nuclei. D, Acute myelomonocytic leukemia (FAB AML-M4). Promonocytes with indented nuclei are present with monoblasts. E, Acute monoblastic leukemia (FAB AML-M5a). These characteristic monoblasts have round nuclei with delicate chromatin and prominent nucleoli. Cytoplasm is abundant. Nonspecific esterase staining was intense (not shown). F, Acute monocytic leukemia (FAB AML-M5b). Most of the cells in this field are promonocytes. Monoblasts and an abnormal monocyte are also present. G, Acute erythroid leukemia (FAB AML-M6). Dysplastic multi-nucleated erythroid precursors with megaloblastoid nuclei are present. H, Acute megakaryoblastic leukemia (FAB AML-M7). In this marrow biopsy specimen, large and small blasts and atypical megakaryocytes can be seen. Panel 2, A, Acute lymphocytic leukemia (FAB ALL-L1). Cells are small in size and homogeneous. There is moderate basophilia and an increased nuclear/cytoplasmic ratio. Nucleoli are inconspicuous. B, Acute lymphocytic leukemia (FAB ALL-L2). Cells are pleomorphic and somewhat larger in size than L1. The nuclear/cytoplasmic ratio is not as high. There is abundant cytoplasm and prominent nucleoli. C, Acute lymphocytic leukemia (FAB ALL-L3). The cells are homogeneous of medium size with dispersed chromatin. Multiple nucleoli are present. The cytoplasm is deep blue with sharply defined vacuoles (Panel B courtesy John Anastasi, MD, from Hoelzer D, Gokbuger N. Acute lymphocytic leukemia in adults. In Hoffman R et al., editors. Hematology. 5th ed. Philadelphia: Churchill Livingstone; 2013.)

Immunophenotyping

Acute leukemias can be categorized according to the cell surface antigens they express as determined by their reactivity to a panel of monoclonal antibodies (Table 98-1). The cell surface antigens expressed largely reflect the level of differentiation of the leukemic cell, and this information provides some prognostic information, especially in ALL. In addition, the antigens on leukemia blasts are almost always present in abnormal combinations or concentrations, allowing for the detection of as few as 0.01% abnormal cells in an otherwise normal looking bone marrow using multidimensional flow cytometry.

Table 98-1

Immunophenotype of Acute Leukemia

AML  
Precursor stage CD34, CD117, HLA-DR
Granulocyte marker CD13, CD 33, cMPO
Monocytic marker CD14, CD15, CD11b, NSE
Megakaryocytic marker CD41a, CD61
Erythroid marker CD36, CD71
ALL  
Pro-B C19 or CD22+ CD10–
Common ALL CD10+
Pre-B Intracytoplasmic Ig+
Mature B Surface immunoglobulin
Early T CD7+ CD1a–, surface CD3–
Cortical T CD1a+, surface CD3–
Mature T Surface CD3+

Most cases of AML express antigens found on normal immature myeloid cells. CD34, CD117, and HLA-DR are expressed on the surface of the more immature forms of AML. CD13 and CD33 are pan-myeloid markers and are present on the surface of the majority of cases of AML. CD14, CD15, and CD11b are more associated with monocytic differentiation. Erythroid leukemias express CD36, CD71, and the blood group H antigen, whereas megakaryocytic leukemias express CD41a and CD61. In 10% to 20% of AML cases, the blasts express antigens usually restricted to lymphoid cells, including CD4, CD7, or CD19. Expression of lymphoid antigens in AML does not appear to influence the clinical behavior or prognosis of the disease. The European Group for the Immunologic Classification of Leukemias has designated five markers as classical myeloid: myeloperoxidase, CD13, CD33, CD65, and CD117. AML cases expressing all five (a so-called pan-myeloid phenotype) have a better clinical outcome than cases that express only a subset of these.

Adult acute lymphocytic leukemia can be divided into B-cell ALL (about 75% overall) and T-cell ALL (about 25%). Approximately 10% of all ALLs express the early B-cell antigens CD19 or CD22 without any more mature markers, and are defined as pro-B-cell ALL. In about 50% of cases, the ALL blasts express CD10 (the common ALL antigen or CALLA). In about 10% of cases, the B-cell ALLs express cytoplasmic immunoglobulin but not surface immunoglobulin (pre-B cell ALL), whereas in 5% of cases surface immunoglobulin is also present (mature B-cell or Burkitt leukemia). T-cell ALL can be categorized as early T-precursor ALL, expressing CD7 but not CD1a or CD3, thymic (or cortical) T-ALL, expressingCD1a, but not cell-surface CD3, and mature T-ALL, expressing surface CD3. Thymic T-ALL makes up about half of T-ALLs and has a more favorable prognosis than either early-precursor or mature T-ALL, which each comprises about 25% of T-ALLs.

A small percentage of cases of acute leukemia express characteristics of both lymphoid and myeloid cells, and have recently been defined by the WHO as mixed-phenotype acute leukemia (MPAL).14 To fulfill the WHO criteria, the leukemia must express the myeloid-specific marker myeloperoxidase (either by flow cytometry or cytochemistry), and either a strictly specific T lymphoid marker (cytoplasmic CD3) or a B lymphoid marker (strong expression of CD19 or weak expression of CD19 together with expression of at least three other B-cell-associated markers). Many of these patients will have rearrangements of BCR/ABL or MLL or have complex cytogenetics. The median survival for this rare group of patients appears to be short, in the range of 18 months, and they should be considered as a high-risk group when selecting appropriate therapy.

Cytogenetics

Cytogenetic analysis of human leukemia has been central to the identification of the genetic events involved in leukemogenesis. In addition, cytogenetics remains the most important diagnostic factor in acute leukemia. Conventional cytogenetics involves the staining of metaphase cells and thus requires dividing cells. Because malignant cells in the marrow are more frequent and have a higher mitotic rate, marrow is preferred over peripheral blood as the source of cells for analysis. Typically 20 metaphases are examined. Fluorescent in situ hybridization (FISH) techniques involve hybridization of single-stranded DNA probes to homologous single-stranded sequences in chromosomes of metaphase or interphase cells. FISH has the advantage of being able to analyze large numbers of dividing (metaphase FISH) or nondividing (interphase FISH) cells with relatively little effort. Only those abnormalities targeted by the specific probe being applied will be detected. Thus FISH is very useful for monitoring the disappearance or reappearance of a known specific abnormality, but is not a substitute for conventional cytogenetics in the initial evaluation of acute leukemia. Polymerase chain reaction (PCR) is a method capable of amplifying selected regions of DNA through repeated cycles of DNA synthesis, denaturation, and hybridization. Standardized PCR analyses of several of the more common translocations have been developed and are being used for monitoring minimal residual disease.

For AML, the Southwest Oncology Group (SWOG) and the Medical Research Council (MRC) each developed and adopted cytogenetic risk classifications over two decades ago based on the outcomes of large prospective clinical trials.15,16 The resulting classifications, though similar, are not identical. For example, as shown in Table 98-2, in the SWOG categorization, patients with clonal abnormalities not recognized as within one of the three major groups are assigned to a fourth category with a predicted treatment outcome somewhere between the intermediate- and unfavorable-risk groups. And there are minor differences between classification schemas in the distinction between intermediate and unfavorable risk cytogenetics. More recently, in 2010, the MRC revised their classification system, with the major change being the movement of patients with various translocations involving chromosome 11 (with the exception of t(9;11) and t(11;19)) from the intermediate-risk group into the unfavorable group.17 Although these classification schemas differ slightly, they are each able to distinguish three major groups of patients. Among patients age <65 treated with standard chemotherapy, those with a favorable karyotype have complete response (CR) rates in the 85% to 90% range and a 5-year overall survival (OS) of 50% to 60%. Those with intermediate-risk cytogenetics have CR rates of 65% to 75%, and a 5-yr OS of 35% to 45%. And for those with unfavorable-risk cytogenetics, a CR rate of 45% to 55% and a 5-yr OS of 10% to 20% can be expected.

Table 98-2

Cytogenetic Classification of AML

Risk Status SWOG15 MRC (1998)16 MRC (2010)17
Favorable t(15;17), t(8;21), inv(16)/t(16;16)/del(16q) t(15;17), t(8;21), inv(16)/t(16;16)/del(16q) t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22)
Intermediate Normal, +8, +6, -Y, del(12p) Normal, 11q23 abn, +8, del(9q), del(7q), +21, +22, all others Abnormalities not classified as favorable or unfavorable
Unfavorable abn(3q), del(5q)/-5, -7/del(7q), t(6;9), t(9;22), 9q, 11q, 20q, 21q, 17p, complex (≥ 3 unrelated abnormalities) abn(3q), del(5q)/-5, -7, complex (≥ 5 unrelated abnormalities) abn(3q) [excluding t(3;5)(q21~25;q31~35)], inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/ del(5q)/-5, add(7q)/del(7q)/-7, t(6;11) (q27;q23), t(10;11)(p11~13;q23), t(11q23) [excluding t(9;11)(p21~22;q23) and t(11;19) (q23;p13)],t(9;22)(q34;q11), -17/ abn(17p),complex (≥ 4 unrelated abnormalities)
Unknown All other abnormalities Category not recognized Category not recognized

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In some cases of AML, multiple unrelated cytogenetic abnormalities will be seen in a single karyotype. If there are a sufficient number of abnormalities, such cases are defined as having “complex” cytogenetics. If these multiple abnormalities accompany one of the favorable-risk translocations (inv 16 or t(8 : 21)), CR rates and overall survival are slightly poorer than seen with the favorable-risk translocations alone, but still better than would be expected with intermediate risk or unfavorable risk. Thus cases with inv(16) or t(8;21) and multiple abnormalities remain within the favorable-risk group and are not considered as “complex” in most discussions. All other cases with complex cytogenetics are defined as unfavorable, and make up between a third and half of all cases of unfavorable-risk disease, or 10% overall. In the recent MRC revision of their classification system, they found that those with four abnormalities did worse than those with three, and those with five or more did worse than those with four. In the SWOG analysis, they further found that those with complex cytogenetics but without involvement of either chromosomes 5 or 7 had a CR rate of 50% and an overall survival of 20% compared with those with complex cytogenetics and involvement of chromosomes 5 and/or 7 who had a CR rate of 37% and only 3% OS.

The finding of a single monosomy is a relatively common finding in AML, with monosomy 7 being the most frequent. The presence of a single monosomy (excluding loss of a sex chromosome) is associated with a negative outcome, with a 12% OS at 4 years in the Dutch experience.18 Patients with two or more distinct monosomies, or a single monosomy but with an additional structural abnormality, have an even worse prognosis, with a predicted 4-year survival of less than 4%.18 Thus this category of patient (two monosomies or one plus an additional structural abnormality) has been defined as having a “monosomal karyotype” and identifies a group of patients with a very dismal prognosis if treated with conventional chemotherapy. There is obvious overlap among patients with unfavorable, complex, and monosomal karyotypes. All patients with complex karyotypes fall within the unfavorable-risk group and comprise between a third and half of the total, and almost all patients with a monosomal karyotype are within the complex category, accounting for about two-thirds of those patients.

As in AML, cytogenetic analysis plays an important role in the evaluation of patients with ALL (Table 98-3). The most common abnormality in ALL, seen in 20% to 30% of cases, is t(9;22)(q34;q11), which results in the Philadelphia chromosome. Other common translocations in adult B-cell ALL include t(4;11)(q21;q23), which is seen in 7% of cases, involves the MLL and AF4 gene and is associated with a poor prognosis, and t(8;14)(q24.1;q32), which is seen in 2% to 4% of adult B-cell ALL, involves c-MYC and the immunoglobulin heavy chain, and is the translocation associated with Burkitt lymphoma. T-cell ALLs often have translocations involving chromosomes 7 or 14 at T-cell receptor enhancer gene sites. The other most common cytogenetic changes seen in adult ALL involve del(9p) seen in 5% to 9% of cases, del(6q) seen in 5% to 7% and del(13q) seen in 3% to 5%. Abnormalities in chromosome number are also common. High hyperdiploidy (51 to 65 chromosomes) is seen in as many as 10% of cases, whereas low hypodiploidy (30 to 39 chromosomes)/near triploidy (60 to 78 chromosomes) is seen in 4%. Approximately 5% will have a complex karyotype. Compared with those cases of ALL with normal cytogenetics, those with del(9q) or high hyperdiploidy appear to have a more favorable outcome, whereas those with t(4;11), t(8;14), and del(6q), low hypodiploidy/near triploidy, or complex cytogenetics do worse (Figure 98-3).19

Table 98-3

Major Cytogenetic Categories in Adult ALL

  Incidence (%)
FAVORABLE  
High hyperdiploidy 10
del 9p 9
UNFAVORABLE  
t(9;22) 19
t(4;11) 7
t(8;14) 2
Low hypodiploidy/near triploidy 4
Complex 5

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Mutational Events

The identification of recurrent chromosomal abnormalities in acute leukemia, including translocations, point mutations, and gene duplications, followed by the cloning of the involved genes, has provided important insights into the pathogenesis of the disease. These initial studies have since been supplemented by a number of techniques, including whole genome sequencing, which have allowed for the identification of additional nonrandom mutations not recognizable by conventional cytogenetics. In AML, along with routine cytogenetic analysis, assays for the mutational status of CEBPA, NPM1, and FLT3 have entered standard clinical practice.

AML-Associated Mutations

Retinoic Acid Receptor Alpha Translocations

Acute promyelocytic leukemia (APL), which accounts for approximately 8% of adult AML cases, is almost always associated with t(15;17)(q22;q11.2), a translocation that fuses the promyelocytic leukemia gene (PML) on chromosome 15 to the retinoic acid receptor alpha (RARa) gene on chromosome 17. The resultant PML/RARa fusion protein acts as a dominant negative inhibitor of normal PML function and of the function of RXRa, an important heterodimeric partner of RARa. PML/RARa recruits a nuclear co-repressor (NCoR) and the molecules sin3 and histone deacetylase (HD) (Figure 98-4). HD deacetylases histones, a process that in turn inhibits binding of transcription factors, thus inhibiting the expression of genes required for hematopoietic differentiation. The unique activity of all-trans-retinoic acid (ATRA) in APL appears to be explained by its ability to bind to the PML/RARa fusion, changing its configuration and releasing the attached nuclear co-repressor. This then allows subsequent transcription and gene expression with subsequent maturation of the APL blasts. A number of other translocations, including t(5;17) and t(11;17), involve RARa and result in an APL-like phenotype. These leukemias are, however, generally unresponsive to ATRA because clinically achievable concentrations of the drug do not result in release of the NCoR-HD complex.

Core Binding Factor Translocations

Core binding factor is a heterodimeric transcription factor made up of two subunits, CBFα (also known as RUNX-1) and CBFβ. CBF plays a role in the transcriptional activation of a number of genes required for normal hematopoietic differentiation. The t(8;21) abnormality seen in approximately 8% of adult AML cases results in the fusion of the RUNX1 gene on chromosome 21 to the MTG8 gene on chromosome 8. The RUNX1/MTG8 fusion protein acts as a dominant negative inhibitor of the wild-type RUNX-1 gene (Figure 98-5). AML characterized by t(8;21) has a favorable prognosis. Similarly, inv(16)(p13;q22) and t(16;16)(p13;q22) both result in the fusion of CBFβ at 16q22 to the smooth-muscle myosin heavy chain (MYH11) gene at 16p13. As in the case of t(8;21), the resultant fusion protein acts as a dominant negative regulator of transcription. AML cases with involvement of 16q22 account for approximately 9% of adult AML cases, have a unique myelomonocytic morphology, and like t(8;21) leukemias have a favorable prognosis.

Tyrosine Kinase Receptor Mutations

FLT1, FLT3, FMS, KIT, and PDGF are members of a family of genes encoding receptor tyrosine kinases, each with an extracellular ligand-binding domain, transmembrane and juxtamembrane domains, and an intracellular domain with tyrosine kinase activity. Ligand binding of the receptor causes receptor dimerization and autophosphorylation, which in turn activates an adaptive protein such as GRB2, with subsequent activation of RAS and other proteins. FLT3 is mutated in 30% to 35% of patients with AML. The majority of these are internal tandem duplications, but approximately one-fourth of the mutations are in the form of point mutations. Both forms of mutation are activating. The incidence of FLT3 mutations appears to increase with age and is associated with high white counts at diagnosis and poorer clinical outcomes. The negative impact of FLT3 mutations increases with increasing size of the duplication and with higher allelic ratios of mutated to wild-type genes in leukemic blasts. Clinical trials of small molecule FLT3 inhibitors are being performed. Mutations in other receptor tyrosine kinase genes are also sometimes seen in AML. Point mutations in FMS are present in perhaps 10% of cases, whereas point mutations, deletions, or insertions of KIT have also been seen in a small percentage of patients.

ALL-associated Mutations

BCR-ABL Translocations

As noted under “Cytogenetics” above the most common translocation in ALL involves the movement of most of the ABL protooncogene from chromosome 9 to the 5′ portion of the BCR gene on chromosome 22. The breakpoints on chromosome 22 occur within two regions, the major breakpoint cluster region (M-bcr), and the minor breakpoint cluster region (m-bcr). BCR-ABL rearrangements involving the minor breakpoint result in a smaller 190-kilodalton fusion protein, whereas those involving the major breakpoint result in a 210-kilodalton fusion protein. In chronic myelogenous leukemia (CML), virtually all cases involve the major breakpoint, whereas in Ph+ ALL, rearrangements involve the minor and major breakpoints with about equal frequency. Prior to the availability of specific tyrosine kinase inhibitors (TKIs), Ph+ ALL had a very poor prognosis, an outcome that is changing with incorporation of TKIs into front-line therapy.

Nonrandom Mutations in B-cell ALL

Cytogenetic studies of B-cell ALL reveal that a portion of cases are associated with the translocation of the MYC gene on chromosome 8 and immunoglobulin enhancer response genes on chromosomes 14 or 22. High-resolution single nucleotide polymorphism array analysis of B-cell ALL has found that in more than 40% of B-cell ALLs, deletion, amplication, point mutation, or structural rearrangements of gene encoding regulators of B cell development can be found.20 The two most frequently involved genes are PAX5, which is altered in about 30% of cases, and IKZF1 (IKAROS5), altered in approximately 25% of cases. Only a limited number of studies have been conducted analyzing the association of alterations in these genes with outcome. Available data suggest that mutations in IKZF1 may be linked with a poor prognosis.

Nonrandom Mutations in T-cell ALL

Cytogenetic studies of T-cell ALL show that the disease is often characterized by translocations involving chromosomes 7 or 14 at the sites of T-cell receptor enhancer genes on those chromosomes. More recent studies have found recurrent mutations in NOTCH1 or FBXW7 in sizable subsets of T-cell ALL patients.21 NOTCH1 is located on chromosome 9q34 and plays a key role in cell fate choice. NOTCH1 appears to be mutated in anywhere from 34% to 71% of T-ALL cases; the impact of NOTCH1 mutations on treatment outcome is not yet clear. FBXW7, located at 4q31.3, codes for a component of the ubiquitin ligase complex, and is mutated in 10% to 15% of T-cell ALL cases. The prognostic impact of mutations in FBXW7 is not yet clear. A variety of other genes including FLT3, BCL11B, and PTPN2 have been found to be mutated in occasional cases of T-cell ALL, but no prognostic importance has been identified with their presence.22

Gene and MicroRNA Expression

The mutational events that underlie acute leukemia result in aberrant gene and microRNA expression.23 Abnormal expression of a number of single genes, including BAALC, MN1, ERG, and EVI1, is commonly seen in AML and has been tied to prognosis. Distinct clusters of AML and ALL based on genomewide expression signatures have been described. These clusters tend to be associated with specific cytogenetic or molecular alterations. MicroRNAs are noncoding RNAs that hybridize to imprecisely complementary mRNA of protein-coding genes, leading to their downregulation. Aberrant expression of multiple microRNAs has recently been reported in acute leukemia. Studies of alternations in gene and microRNA expression have contributed to our understanding of normal and altered hematopoiesis, but they have not yet advanced to the point of affecting clinical practice.

Classification of Acute Leukemia

The World Health Organization classification of acute leukemia is based on clinical, morphologic, immunophenotypic, cytogenetic, and molecular features (Table 98-4).24 Though comprehensive, this classification system is not organized according to prognosis and is not widely used in the development of treatment guidelines.

B LYMPHOBLASTIC LEUKEMIA/LYMPHOMA T LYMPHOBLASTIC LEUKEMIA/LYMPHOMA

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Among the most broadly used classifications schemas for AML is one developed by the European Leukemia Net (ELN) (Table 98-5).25 This classification system combines the already well-established cytogenetic risk categories illustrated in Table 98-2 with newer mutational analyses. Briefly, the favorable category continues to include the core binding factor leukemias, t(8;21) and inv(16), but adds those with a normal karyotype and with either mutated CEBPA or with mutated NPM1 without FLT3/ITD. The intermediate category is split into intermediate-I and intermediate-II. The intermediate-I category includes all those with a normal karyotype except those in the favorable subgroup, whereas intermediate-II includes all of those with cytogenetic abnormalities not defined as favorable or unfavorable. The unfavorable group remains essentially the same as in the traditional cytogenetic schemas. A recent retrospective study analyzed survival in 1550 AML patients according to the suggested ELN definitions.26 Figure 98-6, A and B, present the survival of newly diagnosed AML patients younger than (A) or older than (B) age 60 according to ELN categorization. In both age groups, those in the favorable group have the best overall survival; those with intermediate-II disease appear to do somewhat better than those with intermediate-I disease; whereas those in the unfavorable category have a very poor outcome. More complex systems attempting to integrate additional mutations or mutations and gene expression markers have been published, but none of these systems has gained wide usage as yet.27,28

Table 98-5

ELN Risk Stratification for Adult AML

Genetic Group Subsets
Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD (normal karyotype)
Mutated CEBPA (normal karyotype)
Intermediate-I Mutated NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 without FLT3-ITD (normal karyotype)
Intermediate-II t(9;11)(p22;q23); MLLT3-MLL
Cytogenetic abnormalities not classified as favorable or adverse
Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); MLL rearranged
−5 or del(5q); −7; abnl(17p); complex karyotype

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The WHO classification schema for ALL defines subcategories of the disease according to immunophenotype and specific translocations, and as for AML, does not create categories of disease according to prognostic risk. A large number of clinical groups have developed their own definitions of risk categorization. These definitions vary, but in general, most have settled on three risk categories: standard risk with an estimated 5-year survival of around 50%, intermediate risk with an estimated survival of approximately 30%, and high risk with an estimated survival of less than 20% (Table 98-6).29 These schemas typically define a number of risk factors, and patients with no risk factors make up the standard risk group, those with one or two factors make up the intermediate-risk group and those with three or more comprise the high-risk group. Risk factors vary between studies, but typically include age >35, high WBC at diagnosis (>30,000/mm3 for B-cell ALL and >100,000/mm3 for T-cell ALL), cytogenetics with t(4;11), t(9;22), MLL rearrangements, or low hypodiploidy/near triploidy, or CD10-negative pro-B phenotype, and in some studies, slow initial response with greater than 4 weeks required to obtain first remission.

Clinical Manifestations

The initial clinical manifestations of acute leukemia usually relate to the diminished production of normal blood cells. Most patients complain of fatigue and malaise. Anemia is often present, causing fatigue, pallor, headache, and in the predisposed patient, angina. Thrombocytopenia is common, and when asked, patients will often note easy bruising, bleeding gums, epistaxis, or other evidence of bleeding. Patients may present with nonhealing skin wounds, recurrent minor infections, or in some cases, significant infection, most commonly bacterial in origin.

AML tends to develop more gradually, often over weeks to months. Chloromas, which are local collections of blasts, can present as rubbery, fast-growing, soft tissue masses. Gingival hyperplasia due to leukemic infiltration of the gums is sometimes seen, particularly with M5 AML (Figure 98-7). AML sometimes infiltrates the skin and results in a raised, nonpruritic rash termed leukemia cutis (Figure 98-8). Although uncommon, an occasional AML patient (1% to 2%) may present with meningeal signs or cranial neuropathies (most often affecting cranial nerves IV or VII) because of infiltration of the central nervous system (CNS) with leukemia, and another 2% will have unsuspected involvement if a diagnostic lumbar puncture is performed.

In contrast to AML, ALL generally manifests without a prodromal syndrome. Patients commonly report bone pain. Approximately 50% of patients with ALL will have enlarged lymph nodes, hepatomegaly, or splenomegaly, a much higher incidence than seen in AML. As in AML, leukemia cutis is sometime seen. Approximately 5% of patients with ALL will have symptomatic involvement of the CNS at the time of diagnosis, and another 2% will have asymptomatic involvement. T-cell ALL is commonly associated with male sex, a mediastinal mass, and disseminated lymph node involvement.

Laboratory Manifestations

Peripheral blood counts are abnormal in virtually every case of newly diagnosed acute leukemia. Patients with AML are usually thrombocytopenic, with 50% having platelet counts below 50,000/mm3 and 25% less than 20,000/mm3. Most patients are granulocytopenic, but the total white blood cell (WBC) count is more variable, with 25% having very high counts (greater than 50,000/mm3), and approximately 25% having counts less than 5,000/mm3. Blasts can usually be seen in the peripheral blood. Bone marrow examination generally reveals a hypercellular marrow containing 20% to 100% blast cells largely replacing the normal marrow. The partial thromboplastin and prothrombin times can be prolonged, and in APL reduced fibrinogen and other evidence of disseminated intravascular coagulation (DIC) are frequent. Blood chemistries are usually normal, although in patients presenting with very aggressive disease, there can be some evidence of tumor lysis syndrome at presentation. This syndrome more often manifests after therapy is initiated and can be rapidly fatal if untreated.

Like patients with AML, those with ALL are significantly thrombocytopenic (<50,000/mm3) in about half of cases, and WBCs can be high (greater than 50,000/mm3) in about 25% or low (<5000/mm3) in roughly the same percentage. Patients with ALL, as compared with those with AML, are less often neutropenic. Bone marrows are typically hypercellular and in the large majority of cases, blasts make up more than 50% of cells. DIC is rare at diagnosis, but increased uric acid and early evidence of tumor lysis is not uncommon.

Pretreatment Evaluation

The evaluation of patients with suspected acute leukemia includes a history and physical examination, a complete blood count, and a bone marrow examination. The marrow should be examined by morphology, cytogenetics, and immunophenotyping. If the diagnosis is AML, then evaluation for mutations involving FLT3, NPM1, and CEBPA should be performed. Prothrombin and partial thromboplastin times and fibrinogen levels should be measured, as should serum electrolyte and uric acid levels. Patients with ALL should have a diagnostic lumbar puncture, although if there are high numbers of circulating blasts and no neurological symptoms, this can be postponed until after induction. Patients with AML without CNS symptoms do not require a lumbar puncture. Patients should have a cardiac scan if there is any reason for concern about cardiac function. HLA typing should be performed, except for patients with a major contraindication to hematopoietic cell transplantation.

Therapy

Preparing the Patient for Treatment

The initial therapy of leukemia is usually intensive and can result in significant complications. Therefore patients who are candidates for intensive therapy should be stabilized to the extent possible before treatment begins. Bleeding resulting from thrombocytopenia usually responds to platelet transfusions. If patients have evidence of DIC and APL is suspected, patients should be started on ATRA without waiting for molecular confirmation of the diagnosis; DIC secondary to APL responds rapidly to ATRA, and if the patient turns out not to have APL, the drug can always be discontinued. Patients with fever and neutropenia should have blood cultures taken but should be placed on broad-spectrum antibiotics empirically. Sufficient fluid to guarantee urine production of 100 mL/hour throughout initial treatment should be maintained to reduce the danger of uric acid formation. In addition, patients should receive allopurinol (300 to 600 mg/d) to reduce the likely of developing urate nephropathy. Allopurinol blocks the enzyme xanthine oxidase, which generates uric acid from xanthine. An alternative to allopurinol is rasburicase, which catalyzes the oxidation of uric acid to allantoin. Because rasburicase can reduce high uric acid levels faster than allopurinol, it is the preferred drug in patients with very high counts who are at risk for the development of tumor lysis syndrome.

Patients with AML presenting with very high white cell counts (>100,000/mm3) are also at risk for hemorrhage or microinfarctions of small vessels, presumably due to leukostasis. Lung involvement can result in pulmonary infiltrates and hypoxia, whereas CNS leukostasis can lead to mental status changes, seizures, and sudden death. Pulmonary or CNS leukostasis is a medical emergency requiring intravenous hydration and measures to lower the blast count immediately. Although oral hydroxyurea is often used, whether it lowers counts faster than intravenous cyclophosphamide or other drugs is unknown. Leukapheresis is of short-term benefit, but should not be used in patients with suspected APL. Patients with CNS symptoms should be given whole-brain irradiation emergently. Leukostasis has been associated with the expression of the adhesion molecule CD14 on malignant blasts, which might explain why the syndrome is rarely seen in lymphoid leukemias, which lack this antigen.

The diagnosis of leukemia causes a profound shock to the patient and family and has far-reaching implications. Thus in addition to stabilizing the patient medically, many practitioners find it valuable to have a formalized conference at which the patient and family can be instructed about the nature of leukemia, the immediate plans for therapy, and the likely consequences of treatment.

Acute Myeloid Leukemia

Many treatment guidelines for AML provide separate suggestions for patients younger or older than an arbitrary age cutoff, usually around 60 years, based on the implicit assumption that younger patients can tolerate more intensive therapy than their older counterparts. This assumption was recently questioned by examining the outcome of therapy in 3365 patients with AML; a multicomponent model that accurately predicted treatment related mortality was created and included age, performance status, platelet count, and whether patients had primary versus secondary disease among other factors.30 Although age was a component of the model, eliminating age from the model only minimally affected the model’s accuracy. Thus recommendations for initial induction therapy should be based on whether patients are eligible for intensive therapy or not, and not on age per se. In general, intensive therapy is appropriate for patients at least up to age 70 if they have good performance status and limited comorbidities.

Remission Induction

Standard induction therapy includes a combination of an anthracycline and cytarabine. Prospective randomized trials have shown that higher doses of daunorubicin (60 to 90 mg/m2/d for 3 days) or idarubicin (12 mg/m2/d for 3 days) are superior to a lower dose of daunorubicin (45 mg/m2/d for 3 days).31;32 There does not appear to be any advantage to doses of cytarabine higher than 200 mg/m2/d by continuous infusion for 7 days.33 A bone marrow examination should be performed approximately 7 days after completing initial chemotherapy, and if residual leukemia is present, the induction cycle should be repeated. With this approach, 65% to 80% of patients will achieve an initial remission. Approximately 5% of patients die of bleeding or infection during the period of profound myelosuppression that follows induction therapy, and approximately 20% will have persistent leukemia despite intensive induction therapy. Attempts to improve the outcome of induction therapy by adding other agents have not convincingly improved outcomes, although there are some recent encouraging results with the use of gemtuzumab ozogamicin.

Postremission Chemotherapy

If no further therapy is given after patients enter remission, all will inevitably relapse and will do so rapidly, on average in about 4 months, and thus further therapy is needed. Three types of therapy are available, chemotherapy, allogeneic hematopoietic cell transplantation (allogeneic HCT), or autologous HCT. The best form of chemotherapy is unsettled. One trial showed that four cycles of high-dose cytarabine administered at 3 g/m2 every 12 hours on days 1, 3, and 5 yielded superior outcome compared with less-intensive cytarabine therapy given at either 100 mg/m2 or 400 mg/m2 by continuous infusion for 5 days.34 The survival benefit with the high-dose arm was largely restricted to patients with AML with favorable-risk cytogenetics. More recently, consolidation with intermediate-dose cytarabine (1 g/m2 every 12 hours days 1 to 6) was compared with high-dose cytarabine (3 g/m2 every 12 hours days 1 to 6); no advantage was seen with the higher-dose regimen.35

Leukemic recurrence occurs in the CNS in less than 10% of adults with AML. Randomized trials have found no evidence that CNS prophylaxis improves either disease-free or overall survival of adults with AML. Whether a subgroup of patients at higher risk for CNS involvement (i.e., those with high blast counts at diagnosis and with CD56+ disease) might benefit for CNS prophylaxis is unknown.

Allogeneic Hematopoietic Cell Transplantation

Multiple prospective studies have been conducted in which younger AML patients, generally those under age 55, who have achieved a complete remission are assigned to allogeneic HCT if they have a matched sibling or to aggressive chemotherapy or autologous HCT if they lack a donor. Several meta-analyses have been conducted of such studies and show that survival is improved with allogeneic transplant in first remission.36 When examined by cytogenetic risk category, the survival advantage is lost for patients with favorable-risk disease and is most marked for patients with unfavorable-risk disease.

Based on these analyses, currently patients with favorable-risk AML are generally treated with multiple cycles of consolidation chemotherapy with allogeneic HCT employed only if patients relapse. As noted earlier, patients with intermediate-risk cytogenetics can be further categorized according to mutational analyses. Those with normal cytogenetics but mutations in either NPM1 or CEBPA without FLT3/ITD constitute a more favorable group, whereas the remainder makes up a less favorable group. A prospective analysis was conducted in 872 patients with cytogenetically normal (CN)-AML in first remission.37 Among the 135 patients with mutant NPM1 without FLT3/ITD, there was no benefit for having a donor and presumably proceeding to allogeneic HCT (which 80% of patients did), as compared with the no-donor group (hazard ratio for relapse or death during CR, 0.92; 95% CI, 0.47 to 1.81). Conversely, there was a clear benefit for having a donor and proceeding to allogeneic HCT in the remaining patients with CN-AML (hazard ratio, 0.61; 95% CI, 0.40 to 0.94).

The benefit of allogeneic HCT is most marked for patients with unfavorable-risk cytogenetics. However, only about a third of all patients will have a matched sibling to serve as a donor. With the development of unrelated donor registries, it is now possible to find a matched unrelated donor (URD) for many patients. Data from single centers, and more recently from transplant registries, show that the outcomes of transplants from matched siblings and matched unrelated donors are very similar.38 For example, in a study from the Center for International Blood and Marrow Transplant Research (CIBMTR), transplantation for high-risk AML in 226 recipients of matched related HCT was compared to that in 358 recipients of matched URD HCT.38 OS at 3 years was 45% with matched related donors versus 37% for matched URDs. In multivariate analysis, these outcomes were indistinguishable (RR = 1.06). Although matched unrelated donors can be found for many patients, for others no such donors are available. This is a particular problem for blacks, Hispanics, and patients of mixed racial background. In the study from the CIBMTR, outcomes were significantly worse with the use of partially matched unrelated donors. Recently, the results of transplantation from matched related donors, matched unrelated donors, and partially matched double cord blood transplants were compared in a study from Seattle and Minnesota.39 Although transplant-related mortality was higher with double cord transplants, relapse rates were less, leading to equivalent overall survival using matched siblings, matched unrelated donors, and double cord transplants.

The CIBMTR and Seattle/Minnesota study suggest that if a matched related donor is not available for a younger patient with unfavorable-risk AML, consideration should be given to proceeding to either a matched unrelated or cord blood transplant. However, these were retrospective studies and considerable patient selection bias could have influenced results. Recently, the results of AMLHD98A from the German-Austrian group were published.40 In this study, 844 patients were enrolled and 267 were determined to be high risk either by virtue of having high-risk cytogenetics and achieving a CR (n = 51), or not achieving a CR with initial induction therapy (n = 216). Attempts were made to transplant all high-risk patients and, in fact, 61% were actually transplanted. Among high-risk patients, the 5-year OS rates were 6.5% in those not transplanted, versus 25.1% in those receiving a transplant. There was no difference in outcome using matched related and matched unrelated donors.

Based on the data from these studies, allogeneic hematopoietic cell transplantation is generally not recommended for younger patients with favorable-risk AML, defined as t(8;21), inv(16), or normal cytogenetics with mutated NMP1 or CEBPA without FLT3-ITD. Allogeneic transplantation using a matched sibling donor, matched unrelated donor, or cord blood should be considered for all other categories of AML in younger, fit patients.

The role of transplantation for fit, but older, patients is less clear. There have been essentially no sufficiently sized prospective trials yet reported where older patients have been followed from diagnosis and the outcomes of transplantation versus chemotherapy compared. The largest retrospective trial comes from the Japanese National Cancer Center who examined the outcome of 1036 patients aged 50 to 70 with AML who achieved a first CR and were treated with either allogeneic HCT (n = 152) or chemotherapy (n = 884).41 Both overall survival and relapse-free survival were significantly improved in the HCT group, but patient selection bias could have a major potential impact on the study results.

Autologous Hematopoietic Cell Transplantation

In the decade between 1989 and 1998, six prospective randomized trials were performed in which patients with AML in first remission were randomized to receive either autologous HCT with bone marrow as the source of stem cells or further chemotherapy. A meta-analysis of these trials showed that autologous HCT was associated with better disease-free survival but similar overall survival. In the decade since the completion of these trials, there have been at least three similar studies conducted using peripheral blood rather than marrow as the stem cell source. The general conclusions of these more recent studies were similar to those using marrow, and a meta-analysis of all trials comparing autologous HCT to chemotherapy published through 2010 concluded that autologous HCT is associated with improved disease-free survival but no benefit in overall survival. Based on these outcomes, an evidence-based review of the field conducted by the American Society for Blood and Marrow Transplantation concluded that for patients with AML first remission “there is no significant advantage for autologous HCT over chemotherapy.”42

Treatment of Recurrent AML

The majority of patients with AML treated with conventional chemotherapy will either not go into complete remission (so-called primary induction failure) or will recur with their disease. Patients who fail to achieve a complete remission with standard induction have almost no chance of being cured if treated with alternative chemotherapy. However, if a suitable allogeneic donor can be found, allogeneic HCT should be considered. Although the posttransplant relapse rate is high, approximately 20% of patients can be cured if transplanted for primary induction failure according to registry data from the CIBMTR.

For patients who relapse after achieving a first complete remission, the likelihood of achieving a second remission after retreatment is higher in patients with a longer duration of first remission. With the use of drugs similar to those used for induction (an anthracycline and cytarabine), second complete remissions can be expected in 50% to 70% of patients whose first remission lasted longer than 18 months compared to only 15% to 20% of those who relapse within 6 months of obtaining their initial remission. Thus for those patients with a long first remission (>18 months), retreatment with an anthracycline and cytarabine is a reasonable approach. For those with shorter first remissions, alternative therapies such as clofarabine-containing combinations should be considered.

Occasionally, second remissions can last for periods beyond 3 years; such long second remissions are restricted to the rare patients with favorable risk cytogenetics who had a long first remission. Generally, however, second remissions are short, with an average duration of 6 months. A prognostic index for overall survival of patients with AML in first relapse identified the duration of first remission, age, and cytogenetics as the three most important predictors, with the best overall survival seen in younger patients with a longer first remission and favorable risk cytogenetics.43 No matter the risk category, improved survival was seen in those patients who were able to receive an allogeneic HCT.

Treatment of AML in Patients Not Candidates for Intensive Therapy

As noted earlier, the definition of “not a candidate for intensive therapy” is influenced by many factors. The patient’s own perspective, of course, plays a central role, with some patients placing a higher premium on short-term quality of life than on the possibility of longer survival. The objective risk of immediate mortality associated with intensive chemotherapy, as measured for example in multicomponent models, plays an important role. In addition, the anticipated outcome of therapy enters into the discussion: if the likelihood of complete response and long-term survival with intensive therapy are high in those who survive treatment, then one might broaden the definition of who is eligible, but if the benefits of intensive therapy are marginal even if patients tolerate the immediate toxicities, then exposing less healthy patients to aggressive therapy might not be in their best interests.

If the choice is made to not pursue aggressive treatment, the proven therapeutic options for patients with AML are limited. Palliative care alone may be an appropriate choice for patients with substantial comorbidities. In a randomized trial, low-dose cytarabine was found to be superior to hydroxyurea. Single-agent clofarabine has been studied in a cohort of 112 patients older than age 60 and resulted in an encouraging complete response rate of 42% in patients with unfavorable-risk cytogenetics. Azacitidine and decitabine have both been found to have activity in this population of patients. In an interesting recently published trial, Fenaux et al. asked physicians to pick one of three approaches as their “standard therapy,” either supportive care alone, low-dose cytarabine, or standard daunorubicin plus cytarabine, and then randomized 113 patients to either the selected standard care or azacitidine.44 Median OS for the azacitidine group was 24.5 months compared with 16 months in the conventional treatment group. In the small subset of patients with unfavorable-risk cytogenetics (27 total), those treated with azacitidine had a median survival of 12 months, compared to 5 months when treated with conventional care. The longer survival did not depend on achieving a CR.

Treatment of Acute Promyelocytic Leukemia

APL is a distinct subtype of AML, accounting for 5% to 15% of cases (average, approximately 10%), with unique clinical, morphologic, and cytogenetic features.45 Compared with most patients with AML, patients with APL tend to be somewhat younger (median age, 30 to 40 years), rarely have a myelodysplastic prodrome, and usually have a lower white blood cell count at the time of diagnosis. Compared to other subtypes of AML, APL appears to be overrepresented among Hispanics. Although many of the clinical and laboratory features are similar to other forms of AML, APL almost always presents with some elements of a hemorrhagic syndrome, including hypofibrinogenemia, decreased normal coagulation factors, elevated fibrin degradation products, and increased platelet consumption. These findings are the result of both DIC and primary fibrinolysis. As noted earlier, leukemic blasts virtually always have the characteristic translocation t(15;17)(q22;q11.12).

Unique features of APL are its sensitivities to treatment with ATRA and arsenic trioxide. As a single agent, ATRA results in complete response rates of 80% or more for patients with recurrent disease who have not previously been exposed to the drug. Similarly, arsenic trioxide, when used as a single agent, results in complete remission for 85% of patients with arsenic-naïve recurrent disease. The robust activity of these agents led to studies combining them with conventional chemotherapy as initial therapy for APL. Randomized trials have demonstrated that the addition of ATRA to conventional chemotherapy improves complete response rates to approximately 90% and decreases the incidence of bleeding complications. These trials also demonstrated a clear role for ATRA as maintenance therapy. More recently, a large randomized trial demonstrated that the use of arsenic trioxide during consolidation therapy further improves disease-free and overall survival.46 With current therapies, survival at 3 years from diagnosis can be expected for more than 85% of patients presenting with a WBC count of less than 10,000/mm3 and for 75% of those presenting with a WBC count of more than 10,000/mm3. A small fraction of patients with APL morphology will have a different translocation, for example, t(11;17), and respond poorly to ATRA and arsenic.

During induction therapy with either ATRA or arsenic trioxide, some patients will experience fever, weight gain, respiratory distress, pulmonary infiltrates, episodic hypotension, and renal failure. This condition is thought to be related to the sudden maturation of promyeloblasts and usually responds to dexamethasone. Treatment with arsenic trioxide has been complicated by a prolongation of the QT interval and, rarely, by sudden death. Thus before initiating treatment with arsenic trioxide, any electrolyte imbalances should be corrected, especially hypomagnesemia and hypocalcemia; other drugs that can prolong the QT interval should be discontinued.

Because modern therapy of APL is so effective, there are limited studies exploring the best way to treat those patients who do recur. If patients have not been exposed to ATO during their initial therapy, then second complete remissions can be expected in 80% to 90% if treated with this agent at a dose of 0.15 mg/kg/d until hematologic remission or for a maximum of 60 days. If patients have been previously exposed to both ATRA and ATO, retreatment with the combination can be successful if patients had a long first remission. If not, gemtuzumab ozogamicin is an effective agent in this disease. Although some patients might remain in second remission for some time if given effective salvage chemotherapy, most experts would recommend either autologous or allogeneic HCT for patients with APL in second remission. Data from the European Blood and Marrow Transplant Group show that for patients with APL in second remission, overall survival rates are 58% for allogeneic transplantation versus 40% for autologous transplantation. The choice of autologous or allogeneic HCT might be influenced by the status of the autologous stem cell source. In a small but provocative study, Meloni reported on 15 patients with APL in second remission undergoing autologous transplantation. Only one of eight patients transplanted with marrow that was PCR-negative subsequently relapsed, whereas all seven who were transplanted using PCR-positive marrow did so.

Measuring Minimal Residual Disease in AML

Measurement of minimal residual disease (MRD) can theoretically be used in AML to direct therapy after induction and to monitor response. There are two general approaches to measurement of MRD in AML, PCR-based methods and multidimensional flow cytometry (MFC).47 PCR-based techniques can be used in three settings. Approximately 30% of cases of AML are associated with a fusion gene, such as t(8;21), inv(16), or MLL translocations that can be assayed by PCR. In an additional 30% to 40% of cases, gene mutations in fusion-negative AML cases exist and can be monitored by PCR. Examples here include FLT3-ITD, NPM1, and CEBPA. Overexpression of a gene such as WT1 might also serve as a marker for a PCR-based assay of MRD. The advantages of PCR-based assays are their remarkable sensitivity and the relative ease of their performance. Their shortcomings include the fact that such assays are only available for perhaps 70% of the AML population; there are as yet no generally agreed-upon standardized assays and cutoffs, and for some mutations, there is a question about their longitudinal stability.

MFC relies on the fact that in greater than 90% of AML cases, the cells express a combination of cell surface antigens and/or flow cytometric physical abnormalities that are absent or very infrequent in normal bone marrow cells. This combination of features serves as a leukemic fingerprint. The sensitivity of MFC depends, in part, on the number of monoclonal antibody combinations used in the assay and the skill and experience of the laboratory, with recent evidence emerging that 6- to 9-color polychromatic assays can provide accurate detection of as few as 0.01% leukemic cells in a remission marrow. Advantages of MFC as an approach for measuring MRD include its wide applicability, rapid turnaround time, specificity, and its ability to provide quantitative results.

MRD measurements have generally been used in two ways, as a means of risk stratification after induction therapy, and as a method to follow patients for possible disease progression. Several groups have convincingly shown that the level of MRD as determined by MFC after induction therapy reliably predicts the subsequent chance of relapse, with increasingly higher relapse rates as the amount of MRD increased in the cohorts with less than 0.01%, 0.01% to 0.1%, 0.1% to 1%, and more than 1%. Most of the studies of MRD detection have used bone marrow as the source of cells for assay; some suggest that peripheral blood may also be used, although the cut-off levels for the risk categories may differ. How much measurement of MRD after induction adds to the information already available from pre-treatment cytogenetic and molecular assays is uncertain, although early data suggest that patients who are favorable and intermediate risk by standard criteria but who are MRD positive after induction have a very poor prognosis (15% relapse-free survival at 4 years). Similarly, patients with intermediate risk disease by conventional criteria who are MRD negative after induction may have a prognosis almost as good as patients with favorable-risk cytogenetics (60% relapse-free survival at 4 years). These early results require confirmation in larger prospective studies. The ultimate goal of this approach is to see if overall treatment outcome can be improved by using this potentially more robust approach to risk stratification to alter patient care decisions, for example, by using more intensive consolidation chemotherapy or allogeneic transplantation to treat good- and intermediate-risk patients who have MRD after induction, and perhaps using less intensive consolidation in patients with intermediate-risk disease but without MRD. Large prospective trials testing this approach have not yet been reported.

Another theoretical use of MRD measurement is to monitor patients for early disease recurrence, with the hope that by detecting early disease recurrence prior to the emergence of full-blown relapse, alternative interventions might be instituted. In the setting of APL and CBF leukemias, it has been shown that PCR assays can detect recurrence several months before clinical relapse, but there are no data as yet that this is a clinically useful approach.

Acute Lymphocytic Leukemia

Remission Induction

Similar to AML, the initial goal of therapy in ALL is to eliminate the vast majority of the leukemic cells allowing recovery of normal hematopoiesis. Most contemporary induction regimens include combinations of vincristine, prednisone, an anthracycline, and asparaginase, with cyclophosphamide sometimes included. With such regimens, complete response rates of 75% to 90% have been achieved.29,48 No one regimen has been convincingly demonstrated to be superior. However, the addition of cyclophosphamide and more intensive dosing of asparaginase are generally accepted as being beneficial, particularly for patients with T-cell ALL. As will be discussed, patients with Ph+ ALL and those with mature B-cell phenotype (Burkitt leukemia) require specific therapies. Patients who present with CNS leukemia are often treated with triple intrathecal therapy (methotrexate, cytarabine, and prednisone) biweekly until clearing of the CSF, followed by cranial irradiation.

Postremission Therapy

If no postremission therapy is given after achievement of complete remission, the duration of remission is invariably short. A variety of postremission regimens have been developed and are currently in use. There is no consensus about which is the best, but there are features that are common among most protocols. Therapy generally includes six to eight courses of intensive “consolidation” therapy, several of which contain high-dose methotrexate, cytarabine and asparaginase, and several of which contain the same drugs used for initial remission induction. In addition, some form of CNS prophylaxis is needed, because without it, CNS disease will develop in at least 35% of adults. Patients with a high leukemic blast count at diagnosis and an elevated LDH are at highest risk. With prophylaxis, CNS leukemia as an isolated source of relapse occurs in less than 10% of patients. CNS prophylaxis may consist of intrathecal methotrexate and cranial radiation. If consolidation includes repeated cycles of systemic high-dose cytarabine and methotrexate, the need for other CNS prophylaxis is diminished. Postremission consolidation therapy is usually followed by low-dose long-term maintenance consisting of daily oral mercaptopurine and weekly methotrexate for 2 years or longer. Maintenance therapy appears to be particularly important for patients with pro- and pre-B cell ALL, but less so for T-cell ALL and does not apparently benefit patients with mature B-cell ALL. With standard adult regimens, approximately 35% to 40% of patients will remain alive, in remission at 5 years from diagnosis. There are emerging data that adults up to age 40 may benefit from treatment using somewhat more intensive regimens, similar to those used for pediatric patients. With such regimens, event-free survival rates above 50% are being reported with some consistency.

Hematopoietic Cell Transplantation

The role of allogeneic HCT for adult patients with ALL is unsettled. There is general agreement that allogeneic HCT from a matched sibling is appropriate for patients with high-risk ALL, including those with Ph+ ALL, t(4;11) ALL, adverse immunophenotype or cytogenetics, CNS involvement, and higher leukocyte counts at diagnosis. Depending on the actual high-risk feature, cure rates of 15% to 25% are seen with standard chemotherapy, but are increased to 35% to 60% with transplantation. There is also general acknowledgment that outcomes using matched unrelated and cord blood donors approach those with matched siblings. There is less agreement about the role of allogeneic HCT for patients with standard-risk disease. A recent evidence-based review by the American Society of Blood and Marrow Transplantation led to the conclusion that new data indicates that myeloablative allogeneic HCT is an appropriate treatment for adult ALL in first remission for all disease groups. Allogeneic HCT provides a significant improvement in overall and leukemia-free survival in younger (<35 years), standard risk Ph- patients compared with less intensive chemotherapy regimens. In older (>35 years), standard risk Ph- ALL patients, a higher transplant-related mortality diminishes the significant survival advantage with allogeneic HCT.49

This statement does acknowledge that the chemotherapy regimens included in most of the comparative studies were “less intensive,” and with the use of pediatric-like regimens, the survival advantage seen with allogeneic HCT might no longer hold. There is no evidence that autologous HCT in first remission provides a survival benefit.

Ph+ ALL

Approximately 25% of adult ALLs have t(9;22), and this incidence increases with age. Prior to the development of specific tyrosine kinase inhibitors (TKIs), Ph+ ALL was considered to have among the worst prognoses of all subtypes, with a CR rate of 75% but only a 10% chance of cure if treated with conventional chemotherapy. With allogeneic HCT, cure rates could be improved to 50% in the pre-TKI era. Over the last decade, multiple studies have shown that TKIs can be safely combined with standard chemotherapy, resulting in an improvement in CR rates to 90%. Further, approximately 50% of patients will become negative for BCR/ABL by PCR, something that was almost never seen with conventional chemotherapy alone. There is no evidence as yet for the superiority of one TKI over any other when used in combination with chemotherapy. With a combination of a TKI and chemotherapy, overall survival at 2 years appears to be improved to as high as 50%, but the true proportion of patients who will be cured is still uncertain. Prior exposure to a TKI does not increase toxicity of subsequent allogeneic HCT, and in fact, the outcome of allogeneic HCT appears to be improved in patients who are in molecular remission at the time of transplant. Further, TKIs can be safely administered after transplantation in an effort to reduce the risk of recurrence. Currently, allogeneic HCT is still considered as the best curative option for younger patients with Ph+ ALL.

Elderly patients with Ph+ ALL, particularly those with significant comorbidities, may not be candidates for intensive combination chemotherapy. Imatinib, with or without corticosteroids, results in CR rates as high as 90%, and thus is a very reasonable initial option for such patients. Unfortunately, most patients will eventually relapse. Older patients may be better able to tolerate moderate-dose chemotherapy once they are in remission. Current studies often include intermediate-dose methotrexate, cytarabine, and asparaginase. Reduced-intensity allogeneic HCT may be an option for select patients.

Relapse of Ph+ ALL is frequently caused by mutations in the TKI-binding domain. Depending on the particular mutation, switching to an alternative TKI is sometimes effective.

Measuring Minimal Residual Disease in ALL

As in AML, there are two general approaches to measuring MRD in ALL, PCR-based approaches and those based on MFC.50 One PCR-based approach relies on the fact that during B-cell development, the V, D, and J segments of the immunoglobulin genes are randomly rearranged, creating a unique gene sequence for each cell and its progeny. A similar process occurs in the genes encoding the components of the T-cell receptor. Because ALL arises from a single lymphoid precursor, all the cells in any one case of ALL will have the same immunoglobulin or T-cell receptor rearrangement, which can be used to distinguish the malignant cells from normal. For measurement of MRD, the specific rearrangement must be sequenced in the case upfront, but once this is done, an assay exists that has a sensitivity as low as 0.001%. An alternative approach is to use PCR assays of gene fusions, such as BRC-ABL or MLL-AFF1. Although this technique is much less laborious and does not require the patient-specific primers needed with the immunoglobulin and T-cell receptor approach, gene fusions are present in no more than 50% of adult ALL cases, making this approach unavailable for most patients.

Similar to AML, in more than 90% of cases of ALL, the leukemic cells will express combinations of cell surface antigens and other flow-cytometric physical abnormalities not found on normal bone marrow or peripheral blood cells. With currently available technologies, MFC can detect ALL cells with a 0.01% sensitivity. Although PCR methods might be somewhat more sensitive, at levels of 0.01% or greater, MFC and PCR yield very similar results. Measurement of MRD after completion of induction chemotherapy provides prognostic information in addition to that available by routine pretreatment testing. Among patients with standard risk disease, those with no MRD after induction appear to have a very low risk of relapse, whereas those with MRD in excess of 0.01% have relapse rates in excess of 50%. Studies attempting to intervene based on the results of MDR testing after induction are only now being initiated. Retrospective observational studies suggest that the use of allogeneic HCT (but not autologous HCT) for patients with MRD after induction appears to overcome, at least to some extent, the negative prognostic impact of the finding. Similar to the situation in standard-risk ALL, measurement of MRD following induction in Ph+ ALL appears to be an independent predictor of relapse regardless of manifesting features. Further, any increase in levels of MRD in patients with Ph+ ALL in remission appears to be an ominous sign, with almost all patients subsequently relapsing.

Future Possibilities

Whole Genome Sequencing

The feasibility of conducting whole genome sequencing in individual cases of AML and ALL has now been convincingly demonstrated. These studies have identified a number of previously unrecognized mutations present in substantial subpopulations of patients. As increasing numbers of cases are sequenced, it will almost certainly be possible to use these mutational analyses to more accurately predict the response of patients to standard chemotherapy, and accordingly, assign those with higher risk disease to more aggressive chemotherapy or allogeneic transplantation. Perhaps more importantly, these studies will likely enable us to predict which patients benefit from specific elements of standard therapy. For example, although higher-dose anthracyclines are, in general, beneficial, are there subsets of patients who particularly benefit and others who do not? Similar questions will be answered for the use of high-dose cytarabine and for the addition of other agents, such as gemtuzumab ozogamicin. A number of the mutations revealed in whole genome sequencing of AML and ALL, including KIT, FLT3, RAS, IDH1/2, and NOTCH, are potential targets of novel small molecule inhibitors, and likely others will be as well. Although the first generation of such studies, for example those targeting FLT3 and RAS, have been disappointing, almost certainly more potent and specific inhibitors will be developed. And although one can be optimistic that these newer inhibitors will be more effective, this hope must be tempered by the mutational complexity of acute leukemia revealed in recent investigations studying the variability in individual cells in single cases of leukemia.

Minimal Residual Disease

Studies of minimal residual disease using PCR- of MFC-based technologies provide independent prognostic information above and beyond that provided by pretreatment cytogenetic and mutational analyses. Because MRD is an actual measure of the overall sensitivity of the specific leukemia to therapy, this is perhaps not surprising. MFC-based technologies in particular are broadly applicable, relatively simple, and have a rapid turnaround. What is currently lacking are the well-organized large trials demonstrating a clinical advantage using risk stratification based on an integrated assessment of pretreatment cytogenetic/molecular studies and MRD results after induction therapy. Multidimensional phospho-flow imaging is a technique in which leukemic cells are exposed to exogenous factors or chemotherapeutic agents and the cells’ response, including apoptotic responses, are imaged. Like measures of MRD, this approach is a measure of the integrated responses of the cell and may provide another approach to selecting optimal therapies.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation plays a major role in the treatment of patients with acute leukemia. From the 1990s to the 2000s, the mortality rate associated with HCT dropped by more than 50%. Further, techniques have been developed that allow transplantation to be safely applied to patients in their sixth and seventh decades. The expansion of the unrelated donor pool, as well as the development of cord blood transplantation mean that an allogeneic donor can now be found for almost every patient in need. The expansion of the donor pool, combined with more accurate identification of high-risk patients by genomic analysis and measures of MRD should allow transplantation to be applied to a larger number of patients in a timely fashion. Further, the development of small-molecule inhibitors that are not myelosuppressive provides an opportunity to suppress tumor regrowth during the posttransplant period, allowing time for the potentially powerful graft-versus-leukemia effect to take place. Already, the use of TKIs after allogeneic transplantation is changing the prognosis for patients with Ph+ disease.