CHAPTER 97 ACUTE LYMPHOBLASTIC LEUKEMIA
CHAPTER 97 ACUTE LYMPHOBLASTIC LEUKEMIA
Definition and History
Etiology and Pathogenesis
Acquired Genetic Changes
Signs and Symptoms
Diagnosis and Cell Classification
Course and Prognosis
Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates in a single B- or T-lymphocyte progenitor. The proliferation and accumulation of blast cells in the marrow results in suppression of hematopoiesis and, thereafter, anemia, thrombocytopenia, and neutropenia. Extramedullary accumulations of lymphoblasts may occur in various sites, especially the meninges, gonads, thymus, liver, spleen, or lymph nodes. The disease is most common in children but can occur at any age. ALL has many subtypes and can be classified using morphologic, immunologic, cytogenetic, and molecular genetic methods. These approaches can identify biologic subtypes that require different treatment approaches. These differences include the specific drug combination, drug dosages, and duration of treatment required to achieve optimal results. For example, childhood ALL with a hyperdiploid karyotype responds well to extended treatment with methotrexate and 6-mercaptopurine, while cases with adverse genetic changes, such as MLL-AF4 fusion, require intensive treatment with genotoxic agents. The relative lack of therapeutic success in adult ALL corresponds to a high frequency of cases with unfavorable genetic lesions, such as the BCR-ABL oncogene resulting from the rearrangement of chromosomes 9 and 22. This poor outlook in adults is improving, however, as a result of better drug combinations and the use of allogeneic stem cell transplantation. Currently, 80 percent of children and 35 percent of adults can expect long-term leukemia-free survival, and probable cure, following intensive therapy on contemporary protocols. As cure rates increase, new approaches are required to prevent second malignancies, cardiotoxicity, growth stunting, and other severe side effects that may accompany long-term survivors.
Acronyms and abbreviations that appear in this chapter include: ACTH, adrenocorticotrophic hormone; ALL, acute lymphoblastic leukemia; CD, clusters of differentiation; CSF, cerebrospinal fluid; PEG, polyethylene glycol; RT-PCR, reverse transcriptase-polymerase chain reaction; TCR, T-cell antigen receptor.
DEFINITION AND HISTORY
Acute lymphoblastic leukemia is a neoplastic disease that results from somatic mutation in a single lymphoid progenitor cell at one of several discrete stages of development. The immunophenotype of the leukemic cells at diagnosis reflects the level of differentiation achieved by the dominant clone. The clonal origin of ALL has been established by cytogenetic analysis and analysis of restriction fragments in females who are heterozygotes for polymorphic X chromosome-linked genes (Chap. 8). These female patients have both alleles expressed in normal tissue cells but only a single active parental allele is expressed in leukemic lymphoblasts. Also, analysis of T-cell receptor gene or immunoglobulin gene rearrangements has documented the monoclonal nature of the disease.1 The leukemic cells divide more slowly and take a longer time to synthesize DNA than do their normal hematopoietic counterparts,2 but they accumulate relentlessly, competing successfully with normal hematopoietic cells and resulting in anemia, thrombocytopenia, and neutropenia. At diagnosis, the leukemic cells not only have replaced normal marrow cells but have disseminated to various extramedullary sites. Studies suggest that the activation of telomerase in leukemic cells contribute their growth advantage and to disease progression.3,4
The earliest report of leukemia is generally credited to Velpeau, writing in 1827,5 although it was not until 1845 that Virchow,6 Bennett,7 and Craigie,8 in separate reports, recognized this condition as a distinct entity. In 1847, Virchow coined the term leukemia, applying it to two distinct types of the disease, splenic and lymphatic, that could be distinguished from each other on the basis of splenomegaly and enlarged lymph nodes, as well as the morphologic similarities of the leukemic cells to those normally residing in the spleen and lymph glands.9 Ehrlich’s introduction of staining methods in 1891 allowed further distinction of leukemia subtypes.10 Splenic and myelogenous leukemias were soon recognized as the same disease. By 1913, leukemia could be classified as acute or chronic, and as lymphatic or myelogenous.11 The increased prevalence of acute leukemia in children, especially those between 1 and 5 years, was recognized in 1917.12
Shortly after the recognition of leukemia as a discrete disease entity, physicians began to use chemicals as palliative therapy for this disorder. The first advance came with the use of a 4-amino antimetabolite of folic acid (aminopterin), prompted by Farber’s observation that folic acid might have accelerated the proliferation of leukemic cells. The results were striking! For the first time, children achieved complete clinical and hematologic remissions that lasted for several months.13 A year after the report of aminopterin-induced clinical remissions, a 1949 conference revealed that a newly isolated adrenocorticotrophic hormone (ACTH) also could induce prompt though brief remissions in patients with leukemia.14 Almost concurrently, Hitchings and Elion15 synthesized antimetabolites that interfere with purine and pyrimidine synthesis, leading to the introduction of 6-mercaptopurine, 6-thioguanine, and allopurinol into clinical use. The decade from 1950 to 1960 witnessed the introduction of many new antileukemic agents and occasional cures. A “total therapy” approached devised by Pinkel at St. Jude Children’s Research Hospital in 1962 consisted of four treatment phases: remission induction, intensification or consolidation, therapy for subclinical central nervous system leukemia (or preventive meningeal treatment), and prolonged continuation therapy. By the early 1970s, it was clear that as many as 50 percent of children could be cured with this innovative strategy.16,17 During the same period, a better understanding of the genetics of human histocompatibility and wider use of HLA typing culminated in the successful use of bone marrow transplantation to treat children with relapsed leukemia.18 It was eventually recognized that ALL is a broad term encompassing a heterogeneous group of diseases—clinically, immunologically, and genetically19,20—setting the stage for risk-directed therapy.
Progress in the treatment of ALL has been incremental, beginning with the development of effective therapy for central nervous system disease, followed by intensification of early treatment, especially for patients at high risk of relapse. The current cure rates of nearly 80 percent in children (Fig. 97-1) and 30 to 40 percent in adults attest to the steady progress that has been made in treating this disease.21 The development of genetic probes to the genotype as well as the phenotype of leukemic lymphoblasts has improved the selection of therapy and the estimation of individual disease.
FIGURE 97-1 Kaplan-Meier analysis of event-free survival in 2255 children with ALL treated in 13 consecutive Total Therapy studies at St. Jude Children’s Research Hospital. Early intensification of systemic as well as intrathecal chemotherapy in the 1990s has boosted the event-free survival estimate to 81 plus or minus 8 (SE) %. (From Pui and Evans.21)
ETIOLOGY AND PATHOGENESIS
The initiation and progression of ALL is driven by successive mutations that differ according to the developmental stages of the affected blast cells. Thus, specific subtypes of ALL appear to have genetically distinct origins linked to different causative mechanisms. Environmental agents, such as ionizing radiation and chemical mutagens, have been implicated in the induction of ALL in some patients. However, the vast majority of cases lack discernible etiologic factors. The favored concept is that leukemogenesis reflects the interaction between multiple genetic and environmental factors, a model that needs to be confirmed in well-designed population and molecular epidemiologic studies.
ALL represents about 12 percent of all leukemias diagnosed in the United States, and 60 percent of all cases occur in persons younger than 20 years.22 ALL is the most common malignancy diagnosed in patients under the age of 15 years, accounting for one-fourth of all cancers and 76 percent of all leukemias in this age group.23 Age-specific incidence patterns are characterized by a peak between the ages of 2 and 5 years, followed by falling rates during later childhood, adolescence, and young adulthood (Fig. 97-2).22 The incidence rates rise again, beginning in the sixth decade and reaching a second, smaller peak in the elderly. The sharp incidence peak of ALL during childhood has only been observed since the 1930s in the United Kingdom and the United States.24 In the United States, the peak first appeared in children of European descent and was subsequently observed in children of African descent in the 1960s. The age peak is absent in many developing or underdeveloped countries, suggesting a leukemogenic contribution from factors associated with industrialization. With the exception of a slight female predominance in infancy,25 males of European descent are affected by ALL more often than females in all age groups; a similar frequency distribution has been noted among those of African descent.22 In most age groups, the incidence of ALL is higher in those of European descent than in those of African descent, especially among children from 2 to 5 years of age.
FIGURE 97-2 Age-specific incidence rates for ALL by race and sex. (From SEER data, 1991 to 1995.22)
There are substantial geographic differences in the incidence of ALL. Higher rates are evident among populations in Northern and Western Europe, North America, and Oceania, with lower rates apparent in Asian and African populations.26 In Europe, the highest rates of ALL among males are found in Spain and the highest rates among females in Denmark. In the United States, the highest rates for both genders are among Latinos in Los Angeles. A survey by the Surveillance, Epidemiology, and End Results Program indicated that during the period 1973 to 1995, the age-adjusted incidence of childhood ALL in the United States increased from 2.7 to 3.3 cases per 100,000 children aged 0 to 14 years.22 However, changes in diagnostic specificity from the mid-1970s to later eras, resulting in the recognition of not-otherwise-specified forms of lymphoid leukemia as ALL, could account for this apparent increase in incidence.27 Indeed, a recent survey showed a plateau of the incidence curve.22
Despite the paucity of knowledge of factors that increase the risk of ALL, a minority (5 percent) of cases are associated with inherited, predisposing genetic syndromes, often involving genes whose encoded proteins affect genomic stability and DNA repair.28 A variety of normal inherited genetic polymorphisms may also contribute indirectly to the risk of leukemia, for example, those involving enzymes important in carcinogen metabolism and detoxification and those affecting the regulation of immune responses.29
Children with Down syndrome have a 10- to 30-fold increased risk of leukemia. Acute megakaryoblastic leukemia predominates in patients younger than 3 years and ALL in older age groups. Down syndrome cases are more likely to have B-cell precursor ALL, and their leukemic cells lack adverse genetic abnormalities.30 Autosomal recessive genetic diseases associated with increased chromosomal fragility and a predisposition to ALL include ataxia-telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome.31 The lymphocytes and leukemic cells of patients with ataxia-telangiectasia frequently have chromosomal rearrangements involving bands 7p13-p14, 7q32-q35, and 14q11 (sites of the T-cell receptor gamma, beta, and alpha/delta genes respectively), as well as band 14q32 (site of the immunoglobulin heavy-chain gene). The mutation of ataxia-telangiectasia patients may allow a large increase in production of translocations at the time of V(D)J recombination, leading to an increased predisposition to ALL.31 Patients with other constitutional or acquired immunodeficiency diseases, such as congenital X-linked agammaglobulinemia, immunoglobulin A deficiency, and variable immunodeficiency, are also at increased risk for this disease.32 Although impaired immune surveillance contributes to the increased risk of Epstein-Barr-virus-related malignancies in patients with acquired immunodeficiencies, there is no compelling evidence that defective immunity contributes to the predisposition to ALL in patients with ataxia-telangiectasia or other congenital immunodeficiency syndromes.
Reports of two or more leukemia cases in the same family are rare, reinforcing the notion that heredity plays only a minor role in the causation of this disease. Even so, fraternal twins and siblings of affected children have a twofold to fourfold greater risk of developing leukemia than do unrelated children during the first decade of life. When leukemia occurs in one identical twin, the other twin has a 20 percent chance of developing the disease. If leukemia develops in the index twin before the age of 1 year, the other twin almost invariably will develop leukemia, typically within a few months. Molecular studies have demonstrated that intrauterine metastasis from one twin to the other via their shared placental circulation is responsible for the concordant leukemia.33,34 The same route of transmission appears to operate in older twins, emphasizing the long latent period of ALL in some patients.35 This finding also supports speculation that many cases of ALL arise in utero, with the most aggressive forms presenting in infants and the remainder appearing in later childhood.27
In utero (but not postnatal) exposure to diagnostic X-rays confers a slightly increased risk for the development of ALL, which correlates positively with the number of exposures.36 The evidence for an association between the development of ALL and nuclear fallout; occupational, natural terrestrial, or cosmic ionizing radiation exposure; or paternal preconception radiation exposure is weak.28 Nonionizing radiation in the form of low-energy electromagnetic fields produced by residential power supply and appliances is not a factor in the development of childhood ALL according to a recent comprehensive study.37 Pesticide exposure (occupational or home use) and parental cigarette smoking before or during pregnancy have been suggested as causes of childhood ALL. Other proposed causes of childhood ALL include neonatal administration of vitamin K, maternal alcohol consumption during pregnancy, and increased consumption of dietary nitrites. However, each of these associations is controversial, and most have been refuted after careful, controlled investigation. An increased incidence of ALL has also been reported among women whose drinking water was contaminated with trichloroethylene and among smokers older than 60 years.24 Both of these findings require confirmation.
Despite numerous provocative clues, the instigating factors in most cases of ALL remain a mystery. Some researchers now believe that many childhood cases, especially those diagnosed between 2 and 5 years of age, result from rare abnormal responses to common infections occurring at a later time than was typical in the past.28,38 Such “delayed” exposures at a time when there is increased lymphoid cell proliferation would be expected to increase the chance of unfavorable genetic mutations and hence the development of leukemia. This theory is supported by the higher frequency of childhood ALL in industrialized as opposed to developing countries and in locations where large numbers of infected and uninfected persons come into contact with each other (e.g., new towns). Two large-scale epidemiologic studies now under way in the United States and the United Kingdom are designed to test this theory.
ACQUIRED GENETIC CHANGES
The lymphoblasts from virtually all cases of ALL have acquired genetic changes, at least two-thirds of which are nonrandom and, in all likelihood, contribute in major ways to the generation and expansion of leukemic clones.39 Such lesions include changes in both the number (ploidy) and structure of chromosomes. The latter comprise translocations (the most frequent abnormality), inversions, deletions, point mutations, and amplifications (see Chap. 10). These rearrangements affect gene expression in ways that subvert normal programs of cell differentiation, proliferation, and survival, and these factors likely act in concert with each other in multistep pathways leading to leukemic transformation.
There are two general mechanisms of leukemia induction. One depends on the activation of a proto-oncogene or the creation of a fusion gene with oncogenic properties. In both cases, genes that encode transcription factors are the most frequent mutational targets, reflecting the pivotal roles of these regulatory proteins in cell function.39 Transcription factors are usually classified by their shared structural motifs, denoting participation in similar regulatory processes (Table 97-1).
TABLE 97-1 GENES AFFECTED BY CHROMOSOMAL TRANSLOCATIONS
The second mechanism involves the loss or inactivation of one or more tumor suppressor genes (e.g., p53 and INK4a, encoding p16 and p19ARF). Wild-type p53 function can be inhibited by overexpression of the MDM-2 oncoprotein, a protein capable of complexing with p53.40 These tumor suppressors act at specific points in the cell cycle: p53 expression is increased by DNA damage, blocks cell division at G1 in the cell cycle to allow DNA repair, and is capable of stimulating apoptosis of cells that have irreparable DNA damage41; p16 and p19ARF negatively regulate the cell cycle by inhibiting cyclin-dependent kinase phosphorylation of retinoblastoma protein, decreasing the proportion of cells entering S-phase.42 Hence, the loss of tumor suppressor function either endows the leukemic cell with a proliferative advantage or prevents its normal programmed cell death. While p53 mutation occurs rarely in ALL, homozygous deletions of p15 and p16 have been detected in 20 percent to 30 percent of B-cell precursor ALL and 60 percent to 80 percent of T-cell ALL. Studies have shown that homozygous p15/p16 deletions are frequently acquired at relapse, suggesting that loss of function of the proteins encoded by these genes plays an important role in disease progression.43
The first mammalian antiapoptotic gene identified was BCL2, whose overexpression can render cells relatively resistant to a wide variety of insults and stimuli. Subsequently, a large family of related proteins was identified as either inhibiting (BCL2, BCLXL, MCL1, and A1) or promoting (BAX, BAD, BCLXS, BAK, BIK, and BID) cell death through interactions with the ICE protease.44,45 Several studies demonstrated increased BCL2 expression or mutations in the BAX gene in leukemic lymphoblasts,46,47 and 48 suggesting that members of the BCL2 family play a role in leukemogenesis or in the development of drug resistance. Elucidation of the complex interactions between BCL2 family members and other proteins, such as those binding the various caspases and those acting as receptors for members of the tumor necrosis family, is needed to define the fundamental mechanisms responsible for aberrant regulation of cell death in leukemic lymphoblasts.
SIGNS AND SYMPTOMS
The clinical presentation of ALL is variable. Symptoms may appear insidiously or acutely. The presenting features generally reflect the degree of marrow failure and the extent of extramedullary spread (Table 97-2).49,50,51,52,53 and 54 Approximately half the patients present with fever, which often is induced by pyrogenic cytokines released from the leukemic cells, including interleukin-1, interleukin-6, and tumor necrosis factor.55 In about a third of the patients, fever results from infection. Regardless of its origin, fever in leukemia patients resolves within 72 h after the start of induction therapy.49
TABLE 97-2 PRESENTING CLINICAL FEATURES IN CHILDREN AND ADULTS
Fatigue and lethargy are frequent manifestations of anemia in patients with ALL. In the older patient population, anemia-related dyspnea, angina, and dizziness may be the dominant presenting features.53 More than a fourth of the patients, especially young children, may present with a limp, bone pain, arthralgia, or refusal to walk, owing to leukemic infiltration of the periosteum, bone, or joint or to expansion of the marrow cavity by leukemic cells. Children with prominent bone pain frequently have nearly normal blood counts, which can contribute to a delay in diagnosis.56 In a small proportion of patients, marrow necrosis can result in severe bone pain and tenderness, fever, and a very high serum lactate dehydrogenase level.57 Arthralgia and bone pain are less severe in adult patients. Less common signs and symptoms include headache, vomiting, alteration of mental function, oliguria, and anuria. Occasional patients present with a life-threatening infection or bleeding (e.g., intracranial hematoma). Very rarely, ALL does not produce any signs or symptoms and is detected during routine examination.
Pallor, petechiae, and ecchymosis in the skin and mucous membranes and bone tenderness due to leukemic infiltration or hemorrhage that stretches the periosteum frequently are evident. Liver, spleen, and lymph nodes are the most common sites of extramedullary involvement, and the degree of organomegaly is more pronounced in children than in adults. An anterior mediastinal (thymic) mass is present in 7 to 10 percent of childhood cases and 15 percent of adult cases (Fig. 97-3). A bulky anterior mediastinal mass can compress the great vessels and trachea and possibly lead to the superior vena cava syndrome or the superior mediastinal syndrome.58 Patients with this syndrome present with cough, dyspnea, orthopnea, dysphagia, stridor, cyanosis, facial edema, increased intracranial pressure, and sometimes syncope. Such patients tolerate anesthesia poorly.
FIGURE 97-3 Chest x-ray of a 12-year-old black boy with T-cell ALL and an anterior mediastinal mass.
Painless enlargement of the scrotum can be a sign of a testicular leukemia or hydrocele, the latter resulting from lymphatic obstruction. Both conditions can be readily diagnosed by ultrasonography. Overt testicular disease is relatively rare and generally occurs in infants or patients with T-cell leukemia with hyperleukocytosis.59 Other uncommon presenting features include ocular involvement (leukemic infiltration of the orbit, optic nerve, retina, iris, cornea, or conjunctiva), subcutaneous nodules (leukemia cutis), enlarged salivary glands (Mikulicz’s syndrome), cranial nerve palsy, and priapism (due to leukostasis of the corpora cavernosa and dorsal veins or sacral nerve involvement). Epidural spinal cord compression is a rare but serious presenting finding that requires immediate treatment to prevent permanent paraparesis or paraplegia. In some pediatric patients, infiltration of tonsils, adenoids, appendix, or mesenteric lymph nodes leads to surgical intervention before leukemia is diagnosed.
Anemia, neutropenia, and thrombocytopenia are common findings in patients with newly diagnosed ALL, and their severity reflects the degree of marrow replacement by leukemic lymphoblasts (Table 97-3).49,50,51,52,53 and 54 Presenting leukocyte counts range widely, from 0.1 to 1500 × 109/liter (median, 10 to 12 × 109/liter), with hyperleukocytosis (>100 × 109/liter) occurring in 10 percent to 16 percent of patients. Profound neutropenia (<0.5 × 109/liter) is found in 20 percent to 40 percent of patients, rendering them at high risk for infection. Most patients have circulating leukemic blast cells. Hypereosinophilia, generally reactive, may precede the diagnosis of ALL by several months.60 Some patients, principally males, have ALL with the t(5;14)(q31;q32) chromosomal abnormality and a hypereosinophilia syndrome (pulmonary infiltration, cardiomegaly, and congestive heart failure). Activation of the interleukin-3 gene on chromsome 5 by the enhancer element of the immunoglobulin heavy-chain gene on chromosome 14 is thought to play a central role in leukemogenesis and the associated eosinophilia in these cases.61 In patients with anemia, there is a strong inverse relationship between the hemoglobin level and age at diagnosis.52 Occasionally, a child can present with a hemoglobin level as low as 1 g/dl.
TABLE 97-3 PRESENTING LABORATORY FEATURES IN CHILDREN AND ADULTS
Decreased platelet counts often are present at diagnosis (median, 48–52 × 109/liter). This finding differs from immune thrombocytopenia, since it is almost always accompanied by anemia and or leukocyte abnormalities.62 Severe bleeding is uncommon, even when platelet counts are as low as 20 × 109/liter, provided that infection and fever are absent.63 Occasionally patients, principally males, present with thrombocytosis (>400 × 109/liter).64 Pancytopenia followed by a period of spontaneous hematopoietic recovery may precede the diagnosis of ALL in rare cases (see Chap. 92).65 Coagulopathy, usually mild, can occur in 3 percent to 5 percent of patients, most of whom have T-cell ALL, and is only rarely associated with clinical bleeding.53,66 The serum lactate dehydrogenase level is elevated in most patients with ALL and correlates well with the size of the leukemic infiltrate and prognosis.67 Increased serum uric acid levels are common in patients with a large leukemic cell burden, reflecting an increased rate of purine catabolism. Patients with massive renal involvement can have increased levels of creatinine, urea nitrogen, uric acid, and phosphorus. Occasionally, patients with T-cell ALL present with acute renal failure, despite a relatively small leukemic infiltrate.68 Rarely, patients present with hypercalcemia due to the release of parathyroid hormonelike protein from lymphoblasts and leukemic infiltration of bone.69 Liver dysfunction due to leukemic infiltration occurs in 10 per cent to 20 percent of patients, is usually mild, and has no important clinical or prognostic consequences.49 Serum immunoglobulin levels (mostly IgA and IgM classes) are modestly decreased in approximately a third of children with ALL, reflecting the decreased number and impaired function of normal lymphocytes.70 Urinalysis may disclose microscopic hematuria and the presence of uric acid crystals.
A chest radiograph is needed to detect enlargement of the thymus or mediastinal nodes, with or without pleural effusion (Fig. 97-3). Although bony abnormalities, such as metaphyseal banding, periosteal reactions, osteolysis, osteosclerosis, or osteopenia, can be found in half of the patients, especially children with low presenting leukocyte counts,71 skeletal roentgenograms are not necessary for patient management. Spinal roentgenography is useful in patients suspected of having vertebral collapse.
Examination of the cerebrospinal fluid (CSF) is an essential diagnostic procedure. Leukemic blasts can be identified in as many as a third of childhood ALL patients at diagnosis, the majority of whom will lack neurologic symptoms.72 Traditionally, central nervous system (CNS) leukemia is defined by the presence of at least five leukocytes per microliter of CSF (with leukemic blast cells apparent in a cytocentrifuged sample) or by the presence of cranial nerve palsies. There are conflicting conclusions regarding the clinical importance of blast cells in diagnostic CSF samples containing fewer than five leukocytes per microliter.73,74,75 and 76 Some studies have shown that the presence of any leukemic blast cells in the CSF is an indication to intensify CNS-directed therapy to prevent subsequent CNS relapse.73,74 There are also different opinions on when the first lumbar puncture should be performed. Many leukemia therapists perform the procedure at diagnosis but do not instill intrathecal chemotherapy in the event a second diagnostic test is needed to verify the presence of leukemic cells. Others delay the examination because of concern that circulating leukemic cells from the peripheral blood will “seed” the CNS. A recent study has shown that contamination of the CSF by leukemic cells, due to a traumatic lumbar puncture at diagnosis, was associated with an inferior treatment outcome.77 However, this potential hazard must be weighed against the benefit associated with early intensification of intrathecal therapy.72 Thus, we perform lumbar puncture at diagnosis in all of our patients under deep sedation or general anesthesia and administer intrathecal therapy immediately after a CSF sample is obtained for examination.
DIAGNOSIS AND CELL CLASSIFICATION
Careful examination of marrow cells is essential to establishing the diagnosis of ALL because as many as 16 percent of patients lack blasts in the blood film at the time of diagnosis. Also, the morphology of leukemic cells in blood may differ from that in marrow. Fibrosis or tightly packed marrow can lead to difficulties with marrow aspiration, necessitating biopsy. A touch preparation of the biopsied tissue can be used for cytological diagnosis. Multiple marrow aspirations are sometimes needed to obtain diagnostic tissue from patients with marrow necrosis.
MORPHOLOGIC AND CYTOCHEMICAL ANALYSIS
The diagnosis of ALL begins with morphologic analysis of Romanowsky-stained (Wright-Giemsa or May-Grünwald-Giemsa) bone marrow smears. Lymphoblasts tend to be relatively small (ranging from the same size to twice the size of small lymphocytes) with scanty, often light-blue cytoplasm; a round, clefted or slightly indented nucleus; fine to slightly coarse and clumped chromatin; and inconspicuous nucleoli (Fig. 97-4). In some cases, the lymphoblasts are large with prominent nucleoli and moderate amounts of cytoplasms, with an admixture of smaller blasts (Fig. 97-5). Cytoplasmic granules are found in the lymphoblasts of some cases of ALL (Fig. 97-6); such granules are usually amphophilic (fuchsia) and readily distinguishable from the primary myeloid granules (deep purple). B-cell ALL blasts are characterized by intensely basophilic cytoplasm, regular cellular features, prominent nucleoli, and cytoplasmic vacuolation (Fig. 97-7).
FIGURE 97-4 Typical lymphoblasts with scanty cytoplasm, regular nuclear shape, fine chromatin, and indistinct nucleoli (Wright-Giemsa, ×1000).
FIGURE 97-5 ALL with large blasts showing prominent nucleoli and moderate amounts of cytoplasm, with an admixture of smaller blasts (Wright-Giemsa, ×1000).
FIGURE 97-6 ALL with cytoplasmic granules. Fuchsia-colored granules are present in the cytoplasm of many blasts. Such granules may lead to a misdiagnosis of acute myeloid leukemia; however, the granules are negative for myeloperoxidase and myeloid-pattern Sudan black B (Wright-Giemsa, ×1000).
FIGURE 97-7 B-lineage lymphoblasts. The blasts are characterized by intensely basophilic cytoplasm, regular cellular features, and cytoplasmic vacuolation (Wright-Giemsa, ×1000).
Analysis of only a Romanowsky-stained smear is not sufficient for a certain distinction between ALL and AML. The cytochemical stains needed to discriminate between the two leukemias are myeloperoxidase, Sudan black, and nonspecific esterases, including alpha naphthyl butyrate and alpha naphthyl acetate esterase. These stains do not react with leukemic lymphoblasts. By contrast, staining with periodic acid–Schiff reagent is positive in over 70 percent of ALL cases, while acid phosphatase reactivity can be demonstrated in about 70 percent of cases with a T-cell immunophenotype. However, neither stain reacts exclusively with leukemic lymphoid cells.
Because leukemic lymphoblasts lack specific morphologic and cytochemical features, immunophenotyping is an essential part of the diagnostic evaluation. The antibodies that distinguished clusters of differentiation (CD) groups recognize the same cellular antigen but not necessarily the same epitope. Most leukocyte antigens lack specificity; hence, a panel of antibodies is needed to establish the diagnosis and to distinguish among the different immunologic subclasses of leukemic cells. The panel used at St. Jude Children’s Research Hospital includes at least one highly sensitive marker (CD19 for B-lineage cells, CD7 for T-lineage cells, and CD13 or CD33 for myeloid cells) and one marker that is highly specific (cytoplasmic CD79a for B-lineage cells, cytoplasmic CD3 for T-lineage cells, and cytoplasmic myeloperoxidase for myeloid cells).21 By using this method of analysis, one can make a firm diagnosis in 99 percent of cases.
Although cases can be further subclassified according to the recognized steps of normal maturation within the B-lineage (early pre-B, pre-B, transitional pre-B, and mature B) and T-lineage (early, mid-, and late thymocyte) pathways,78,79 the only distinctions of therapeutic importance are those between T-cell, mature B, and other B-lineage (B-cell precursor) immunophenotypes.21 Pre-B ALL (with the presence of cytoplasmic immunoglobulin), which occurs in 20 percent of childhood and 10 percent of adult cases, was once considered to be a specific phenotypic subgroup. However, the high-risk features formerly ascribed to this subgroup were found to be more closely associated with the presence of the t(1;19) and the E2A-PBX1 fusion gene (discussed later).80 Transitional pre-B ALL is characterized by the expression of cytoplasmic and surface immunoglobulin mu heavy chains without kappa or lambda light chains. Transitional pre-B ALL is found in approximately 3 percent of childhood ALL cases and is associated with a low presenting leukocyte count, hyperdiploidy, and a favorable prognosis,78 but this ALL phenotype has not been studied in the adult population. In some studies, cases of B-cell-precursor ALL are subdivided into CD10-postive (so-called common ALL) and CD10-negative (pre-pre-B or CD10-negative B-cell-precursor) leukemias, while cases of T-lineage ALL are further classified as pre-T (or pro-T) and mature T-cell leukemias.79,80,81 and 82 Despite their prognostic implications, these refined categories of ALL have not been used in treatment assignments. Table 97-4 summarizes the salient presenting features of six recognized immunologic subtypes of ALL.
TABLE 97-4 PRESENTING FEATURES ACCORDING TO IMMUNOLOGIC SUBTYPE
Expression of myeloid-associated antigens may occur on otherwise typical lymphoblasts. Because of differences in the monoclonal antibodies and immunophenotyping techniques, the frequencies of myeloid-associated antigen expression have ranged from 5 percent to 30 percent in childhood cases and 10 percent to 50 percent in adult cases.54,83,84 The pattern of myeloid-associated antigen expression correlates with certain blast cell genetic features—CD15, CD33, and CD65 in cases with a rearranged MLL gene, and CD13 and CD33 in those with ETV6-CBFA2 (TEL-AML1) fusion.83,84 The presence of myeloid antigens lacks significance in contemporary treatment programs,54,83,84 but it can be useful in immunologic monitoring of patients for minimal residual leukemia (as discussed later).85
Acute lymphoblastic leukemia arises from a lymphopoietic progenitor cell that has sustained specific genetic damage leading to malignant transformation and proliferation. Thus, genetic classification of blast cells could be expected to yield more relevant biologic information than could be obtained by other means. Approximately 60 percent of adult cases and 70 percent of childhood cases can be readily classified into therapeutically relevant subgroups based on the modal chromosome number (or DNA content estimated by flow cytometry), specific chromosomal rearrangements, and molecular genetic changes.21,86,87,88 and 89 Table 97-5 summarizes the prominent clinical and biologic features of cases with the most common genetic abnormalities.
TABLE 97-5 CLINICAL AND BIOLOGIC FEATURES ASSOCIATED WITH THE MORE COMMON GENETIC SUBTYPES
Two ploidy groups (hyperdiploidy >50 chromosomes and hypodiploidy <45 chromosomes) have clinical relevance. Hyperdiploidy, which occurs in approximately 25 percent of childhood cases and 6 to 7 percent of adult cases, confers a favorable prognosis that may reflect an increased cellular accumulation of methotrexate and its polyglutamates, an increased sensitivity to therapeutic antimetabolites, and a marked propensity of these cells to undergo apoptosis.90,91 and 92 By contrast, hypodiploidy is associated with an exceptionally poor prognosis.86,88,93 Flow cytometric determination of cellular DNA content is a useful adjunct to cytogenetic analysis because it is automated, rapid, and inexpensive, and its measurements are not affected by the mitotic index of the cell population; results can be obtained in virtually all cases. Flow cytometric studies can sometimes identify a small but drug-resistant subpopulation of near-haploid or tetraploid cells that may have been missed by standard cytogenetic analysis.93,94
Phenotype-specific reciprocal translocations are the most biologically and clinically significant karyotypic changes in ALL. Many translocations identified in cases of B-cell and T-cell ALL arise from mistakes in the normal recombination mechanisms that generate antigen receptor genes (Table 97-1). Such rearrangements can mobilize the promotor/enhancer element of the immunoglobulin heavy- or light-chain gene or the T-cell antigen receptor (TCR) beta or alpha/delta gene to sites adjacent to a variety of transcription factors. More often, in cases of B-cell precursor ALL, the rearrangements create fusion genes with transforming properties. The major translocations in ALL affect proteins that have critical functions in cell proliferation, differentiation, or survival.39
The correlations of specific cytogenetic findings with presenting clinical features and blast cell phenotypes (Table 97-5) indicate the prognostic significance of chromosomal abnormalities in patients with ALL. There, also, are compelling reasons to focus on molecular genetic lesions. First, rearrangements affecting the same chromosomal region may involve different genes and represent clinically and biologically diverse entities. For example, among cases with a t(1;19) (q23;p13.3), those without E2A-PBX1 fusion respond well to antimetabolite-based therapy, whereas cases with the fusion product require more intensive therapy.80 Second, molecular analyses can identify several critical submicroscopic genetic alterations not visible by standard karyotyping procedures. ETV6-CBFA2 and TAL1 rearrangements—the most common abnormalities in B-lineage and T-lineage ALL respectively—as well as deletions of tumor suppressor genes such as p53 and p16 are generally detectable only at the molecular level.40,43,95,96 Third, cases with clinically important genetic rearrangements may be missed because of technical errors (e.g., karyotyping of residual normal metaphases and not leukemic metaphases). Hence, assays relying on the multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), in which primers for major risk-defining translocations are included in a single PCR reaction tube, have been developed to facilitate molecular diagnosis.97 By combining such assays with rapid, semiautomated, and nonradioactive detection systems, one can identify translocations in a single PCR reaction mixture within 24 to 36 h.
The initial manifestations of ALL may mimic a variety of disorders. The acute onset of petechiae, ecchymoses, and bleeding may suggest idiopathic thrombocytopenic purpura. The latter disorder is often associated with a recent viral infection, large platelets in blood smears, and normal hemoglobin concentration and no leukocyte abnormalities in blood or marrow. Both ALL and aplastic anemia may present with pancytopenia and complications associated with marrow failure, but in aplastic anemia, hepatosplenomegaly and lymphadenopathy are rare, and the skeletal changes associated with leukemia are absent. The results of bone marrow aspiration or biopsy usually distinguish these two diseases, although the diagnosis may be difficult in a patient presenting with a hypocellular marrow later replaced by lymphoblasts. In one study, transient pancytopenia preceded ALL in 2 percent of all cases of childhood ALL.98 PCR analysis disclosed monoclonality during the preleukemic phase in these patients, suggesting that hypoplasia was due to the inhibition of normal hematopoiesis by leukemic cells.99 ALL should be considered in the differential diagnosis of patients with hypereosinophilia, which may be a presenting feature of leukemia or precede its diagnosis by several months.60
Infectious mononucleosis and other viral infections, especially those associated with thrombocytopenia or hemolytic anemia, can be confused with leukemia. Detection of atypical lymphocytes or serologic evidence of Epstein-Barr virus infection helps to establish the diagnosis. Patients with pertussis or parapertussis may have marked lymphocytosis; however, even in cases with leukocyte counts as high as 50 × 109/liter, the affected cells are mature lymphocytes rather than lymphoblasts. Bone pain, arthralgia, and occasionally arthritis may mimic juvenile rheumatoid arthritis, rheumatic fever, other collagen diseases, or osteomyelitis. Hence, the marrow should be examined if one plans to initiate glucocorticoid treatment for presumed rheumatic diseases.
Childhood ALL should also be distinguished from pediatric small round cell tumors that involve the bone marrow, including neuroblastoma, rhabdomyosarcoma, and retinoblastoma. Generally, in patients with solid tumors, a primary lesion may be found by standard diagnostic studies; disseminated tumor cells often present in characteristic aggregate, and immunophenotypic characteristics of lymphocytes are absent.
Optimal management of patients with ALL requires careful attention to several facets of supportive care, including the immediate treatment or prevention of metabolic and infectious complications, as well as the rational use of blood products. Other important supportive care measures, such as the use of indwelling catheters (see Chap. 19), amelioration of nausea and vomiting, pain control (see Chap. 20), and continuous psychosocial support for the patient and family are essential.
Hyperuricemia and hyperphosphatemia with secondary hypocalcemia are frequently encountered at diagnosis, even before chemotherapy is initiated, especially in patients with B-cell or T-cell ALL or B-cell-precursor leukemia with high leukemic cell burden. These patients should be given intravenous hydration, sodium bicarbonate to alkalinize the urine, allopurinol to treat hyperuricemia, and a phosphate binder to treat hyperphosphatemia, such as aluminum hydroxide, calcium carbonate or acetate (if the serum calcium concentration is low), or sevelamer. Allopurinol, by inhibiting de novo purine synthesis in leukemic blast cells, may reduce the peripheral blast cell count before chemotherapy.100 Allopurinol may decrease both the anabolism and catabolism of 6-mercaptopurine by depleting intracellular phosphoribosyl pyrophosphate and inhibiting xanthine oxidase.101 If oral 6-mercaptopurine and allopurinol are given together, the dosage of 6-mercaptopurine generally needs to be reduced. Allopurinol can cause skin rashes but seldom produces severe allergic reactions.
Nonrecombinant urate oxidase, available in France and Italy, converts uric acid to allantoin, a readily excreted metabolite that is 5 to 10 times more soluble than uric acid and decreases the serum uric acid concentration more rapidly than does allopurinol.102 However, this agent can cause acute hypersensitivity reactions and, in patients with glucose-6-dehydrogenase deficiency, can cause methemoglobulinemia or hemolytic anemia. A recombinant form of urate oxidase has proved to be a safe, highly effective, and rapidly acting uricolytic agent.103
For patients with extreme leukocytosis (leukocyte count >200 × 109/liter), either leukapheresis or exchange transfusion (in small children) can be used to reduce the burden of leukemic cells.104,105 In theory, either treatment should reduce the metabolic complications associated with leukostasis; however, the short- and long-term benefits of these procedures remain in question.106,107 Emergency cranial irradiation, once advocated by some leukemia therapists, probably has no role in these patients.104,105 and 106 Preinduction therapy with low-dose glucocorticoids, adding vincristine and cyclophosphamide in cases of B-cell ALL, is a favored means of ameliorating hyperleukocytosis. Pioneered by French investigators, this method when used in conjunction with urate oxidase has largely eliminated the tumor lysis syndrome and the need for hemodialysis in patients with B-cell ALL.108
Infections are common in febrile patients with newly diagnosed ALL. Thus, any patient presenting with fever, especially those with neutropenia, should be given broad-spectrum antibiotics until infection is excluded. Remission induction therapy can increase susceptibility to infection by exacerbating myelosuppression and mucosal breakdown. Indeed, at least 50 percent of patients undergoing induction therapy will experience infections. Special precautions should be taken to reduce the risk of infection during this critical phase of treatment, including reverse protective isolation and air filtration; elimination of contact with people with infectious or potentially contaminated food products, such as raw cheese, uncooked vegetables, or unpeeled fruits; and antiseptic mouthwash or sitz baths, especially in patients with mucositis. Administration of granulocyte colony-stimulating factor may hasten the recovery from neutropenia and reduce the complications of intensive chemotherapy, but it does not improve the event-free survival rate in either children or adults.109,110 and 111 The diagnosis and treatment of fungal or viral infections are addressed in Chap. 16.
At most medical centers, all patients with ALL are given trimethoprim-sulfamethoxazole, 3 days per week, as prophylactic therapy for Pneumocystis carinii pneumonia.112 Alternative treatments for patients who cannot tolerate trimethoprim-sulfamethoxazole include aerosolized pentamidine, dapsone, and atovaquone.113,114 and 115 Live virus vaccine should not be administered during immunosuppressive therapy. Siblings and other children who have frequent contact with patients should be given inactivated poliomyelitis vaccine but can be immunized against measles, mumps, and rubella. Susceptible patients exposed to varicella should receive zoster immunoglobulin within 96 h of exposure, which usually prevents or modifies the clinical manifestations of varicella. Patients exposed to active cases of influenza A virus infection should be given rimantadine or amantadine prophylactically.
ALL or its treatment can lead to thrombocytopenia. Hemorrhagic manifestations are common but are usually limited to the skin and mucous membranes. Although rare, bleeding in the CNS, lungs, or gastrointestinal tract can be life-threatening. Patients with extremely high leukocyte counts at diagnosis are more likely to develop such complications. Coagulopathy attributable to disseminated intravascular coagulation, hepatic dysfunction, or chemotherapy is usually mild.53,66 Patients receiving induction treatment, including L-asparaginase and a glucocorticoid, are generally in a hypercoagulable state.116,117 Platelet transfusions should be given therapeutically for overt bleeding and may be indicated when platelet counts are less than 10 × 109/liter.118 Children generally do not have active bleeding during remission induction therapy with prednisone, vincristine, and L-asparaginase even when platelet counts are less than 10 × 109/liter. A higher threshold for prophylactic platelet transfusions should be considered for active toddlers and patients with fever or infection. Recombinant thrombopoietin accelerates platelet recovery in solid tumor patients undergoing chemotherapy or marrow transplantation, and it improves the yield of platelet apheresis in normal donors, resulting in higher increments of platelet recovery in the recipients. Additional clinical trials are needed to establish the role of this procedure in patients with ALL.119 Transfusion of packed red cells is indicated in patients with anemia and marrow suppression. Granulocyte transfusions are needed only rarely in patients with absolute neutropenia and documented gram-negative septicemia or disseminated fungal infection who have responded poorly to antimicrobial treatment. All blood products should be irradiated to prevent graft-versus-host disease.
ALL is a heterogeneous disease with many distinct subtypes; a uniform approach to therapy is no longer appropriate. A stringent assessment of the relapse hazard is necessary in order to avert undertreatment or overtreatment. There is disagreement over the risk criteria and the terminology for defining prognostic subgroups. Usually, childhood ALL cases are divided into low-, standard- (intermediate- or average-), and high-risk groups, while adult cases are considered to have either standard- or high-risk features. The only exception is B-cell ALL, which requires a unique treatment approach. At many medical centers, infants with ALL are considered to be a special subgroup and are treated differently from other children.
The most effective contemporary treatment regimens for B-cell ALL are drug combinations that include cyclophosphamide given over a relatively short time (3 to 6 months). The first major breakthrough in this disease was reported by French investigators, who achieved a 68 percent event-free survival rate in their LMB 84 study that featured high-dose cyclophosphamide, high-dose methotrexate, vincristine, doxorubicin, and conventional doses of cytarabine.108 More recently, in the LMB 89 study, the same group reported a cure rate of 80 percent, obtained with increased doses of both methotrexate (to 8 g/m2 per dose) and cytarabine (2 g/m2 per dose) and the addition of etoposide (for patients with a large leukemic cell burden).120 This achievement established a standard against which other trials are now measured. Successful treatments have also been developed by the Berlin-Frankfurt-Münster (BFM) consortium, using a multiagent regimen that incorporated fractionated cyclophosphamide, high-dose methotrexate (5 g/m2), etoposide, ifosfamide, and cytarabine (2 g/m2 per dose);121 and by the Pediatric Oncology Group study, using fractionated cyclophosphamide, vincristine, and doxorubicin, alternating with high-dose methotrexate and cytarabine.122 Whether etoposide or ifosfamide contributed to the improved results will require further study.
Effective CNS therapy is an essential component of successful high-dose regimens for B-cell ALL, and generally consists of methotrexate and cytarabine administered both systemically and intrathecally. Whether or not cranial irradiation should be used in therapy for CNS leukemia is controversial. Although it was a component of a very successful French regimen,120 cranial irradiation was not included in other successful protocols, and the French group has excluded it from their current trial. B-cell ALL rarely, if ever, recurs after the first year, so that prolonged continuation therapy is not a requirement in this disease.
The same treatment approach has also been taken in adults with B-cell ALL, yielding promising results in several trials.123,124 A cure rate of approximately 50 percent can now be achieved in adult patients, including those with initial CNS leukemia. Some investigators recommend reduced doses of methotrexate and cytarabine for adults over 60 years of age in order to reduce toxicity.124
B-CELL-PRECURSOR AND T-CELL ALL
Treatment for leukemias affecting the B-cell-precursor and T-cell lineages consists of three standard phases: remission induction, intensification (consolidation), and prolonged continuation therapy. CNS-directed therapy, which overlaps with other treatments, is begun early and is given for different lengths of time, depending on the patient’s risk of relapse and the intensity of the primary systemic regimen.
Remission Induction The first goal of therapy for patients with leukemia is to induce a complete remission with restoration of normal hematopoiesis. The induction regimen invariably includes a glucocorticoid (prednisone, prednisolone, or dexamethasone) and vincristine, as well as L-asparaginase for children or an anthracycline for adults.21,125,126 and 127 With improvements in chemotherapy and supportive care, the rate of complete remission now ranges from 97 to 99 percent in children and from 70 to 90 percent in adults. At the time a complete clinical remission is induced, patients have various degrees of residual leukemia, and some may still have as many as 10 billion leukemic cells.128 Since the extent of residual disease correlates well with long-term outcome,85,129,130 and 131 the concept of a “molecular” or “immunologic” remission, defined as leukemic involvement of less than 0.01 percent of nucleated marrow cells,21 is beginning to supplant the traditional perception of remission, which is based solely on blast cell morphologic criteria.
Intensive induction therapy with four or more drugs has been credited with improving long-term clinical outcomes in several pediatric trials.51,132,133 and 134 This approach is driven by the premise that more rapid and complete reduction of the leukemic cell burden will forestall the development of drug resistance. Similar approaches in adults have been limited by a low tolerance to drug toxicities.125,126 and 127 However, use of a five-drug induction regimen (cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase) in two consecutive CALGB studies produced a complete remission rate of 85 percent,54,111 while 2 weeks of L-asparaginase added to standard induction therapy with prednisone, vincristine, and daunorubicin yielded a remission rate of 88 percent in 109 adults with ALL.135 Similarly, a combination of prednisone, vincristine, L-asparaginase, and high-dose daunorubicin (270 mg/m2) resulted in a remission rate of 93 percent in 60 adults.136 Fifty-eight of 66 adults (88%) attained remission when given a “preinduction” course of etoposide and cytarabine, followed by prednisone, vincristine, and doxorubicin.137
Perhaps because of its increased penetration into cerebrospinal fluid and its longer half-life,138 dexamethasone, when used in induction and continuation therapy, provides better control of systemic and CNS disease than does prednisone in children with ALL.139,140 Three forms of L-asparaginase, each with a different pharmacokinetic profile, are available—one derived from Erwinia carotovora, another prepared from Escherichia coli, and a third made of a polyethylene glycol (PEG) form of the E. coli product.141 The dosages of these three products are based on their half-lives. PEG L-asparaginase, which has the longest half-life, is usually administered at 2500 IU/m2 every other week for two doses in cases of newly diagnosed ALL. By contrast, the Erwinia product, with the shortest half-life, is generally given at 10,000 IU/m2 three times per week for 6 to 12 doses. The dosages of E. coli L-asparaginase range from 6000 to 10,000 IU/m2, administered two to three times per week for 6 to 12 doses. In one randomized trial, the clinical outcome in patients treated with L-asparaginase derived from E. coli was better than that in patients treated with Erwinia carotovora, given at the same dosage.142 Different E. coli preparations have different pharmacologic and pharmacokinetic properties,143 mandating dosage adjustment to avoid excessive toxicities.144,145 Among the various anthracyclines (daunorubicin, doxorubicin, and mitoxantrone) given to adults wit h ALL, one has not proved superior to another146,147; however, daunorubicin is used most commonly.
Intensification (Consolidation) Therapy With restoration of normal hematopoiesis, patients in remission become candidates for intensification therapy. Such treatment, administered shortly after remission induction, refers to high doses of multiple agents not used during the induction phase or to readministration of the induction regimen. More commonly used regimens in childhood cases include high-dose methotrexate with or without 6-mercaptopurine51,132,148,149; high-dose L-asparaginase given for an extended period133,150; an epipodophyllotoxin plus cytarabine132,151; or a combination of dexamethasone, vincristine, L-asparaginase, doxorubicin, and thioguanine, with or without cyclophosphamide.51,134 This phase of therapy has improved outcome, even in patients with low-risk ALL.151 A very high dose of methotrexate (5 g/m2) appears to improve the outcome of treatment in patients with T-cell ALL.51 This finding is consistent with data indicating that T-lineage blast cells accumulate methotrexate polyglutamates (active metabolites of the parent compound) less avidly than do B-cell precursors,152 so that higher serum levels of the drug are needed for an adequate therapeutic effect.153 In fact, the conventional dose of methotrexate (1 g/m2) may be too low for many patients with B-cell-precursor ALL.154,155
The value of intensification treatment is less certain in adults with ALL. In two randomized trials, high doses of cytarabine and daunorubicin, which had been effective against acute myelogenous leukemia, failed to improve the clinical outcome over results achieved without these agents.156,157 In another randomized trial, prolonged (4-month) consolidation therapy with methotrexate, cytarabine, thioguanine, cyclophosphamide, and L-asparaginase yielded essentially the same leukemia-free survival rate as did short (1-month) consolidation therapy with cyclophosphamide and L-asparaginase.158 These results notwithstanding, the outcomes of several nonrandomized studies strongly suggest a benefit from intensive consolidation therapy, especially in young adults. In cases of T-cell ALL, the benefit derives from both cyclophosphamide and cytarabine; while in other standard-risk and high-risk ALL, it derives from high-dose cytarabine.54,125,159,160 More striking perhaps is the markedly improved results in two German multicenter trials with high-dose cytarabine and mitoxantrone in cases bearing the t(4;11), which generally confers a dismal outcome.161
Continuation Therapy Excluding cases of mature B-cell leukemia, children with ALL require prolonged continuation therapy for reasons that are still poorly understood. Perhaps, long-term drug exposure or the host immune system is needed to kill residual, slowly dividing leukemic cells or to suppress their growth, allowing programmed cell death to occur. In one study, attempts to shorten the duration of moderately intensive chemotherapy to 18 months or less resulted in a high rate of relapse after cessation of therapy.162 In a meta-analysis of 42 trials, a third year of continuation therapy reduced the likelihood of relapse during the third year, but there was no advantage to prolonging treatment beyond 3 years.163 Several studies have demonstrated that the third year of continuation therapy benefits boys but not girls.164,165 and 166 Hence, the general rule is to discontinue all therapy in girls who remain in remission for 2 to 2 1/2 years and in boys whose remissions have continued for 3 years. It remains unclear whether the duration of therapy can be shortened for patients who have received contemporary forms of intensive therapy. It is also uncertain whether adults with ALL require prolonged continuation therapy. In two trials of postremission treatment given for 5 to 10 months, the median durations of remission ranged from 9 to 12 months.146,157 These poor results may reflect inadequate treatment for remission induction or inadequate consolidation therapy. In most adult trials, continuation therapy is given for 2 years.
A combination of methotrexate administered weekly and mercaptopurine administered daily constitutes the usual continuation regimen for children with ALL. Accumulation of higher intracellular concentrations of the active metabolites of methotrexate and administration of this combination to the limits of tolerance (as indicated by low leukocyte counts) have been associated with an improved clinical outcome.167,168,169 and 170 One recent study showed that the dose intensity of 6-mercaptopurine was the most important pharmacologic factor influencing treatment outcome.171 The effect of 6-mercaptopurine is better when the drug is given to patients in the evening.172 It should not be given with milk or milk products, as both decrease its bioavailability.173 Although the merits of oral versus parenteral administration of methotrexate continue to be debated, the latter route affords a way to circumvent problems of decreased bioavailability and poor compliance, especially in adolescents.174 Prolonged oral administration of methotrexate in divided doses has proved inferior to intermittent intravenous infusions of the drug at higher doses.175 By contrast, 6-mercaptopurine is best given orally on a daily basis. Its intravenous administration does not improve outcome and may produce an inferior result.175 Antimetabolite treatment should not be withheld because of isolated elevations of liver enzymes, since such abnormalities in liver function are tolerable and reversible.176
A few patients (1 in 300) have an inherited deficiency of thiopurine S-methyltransferase, the enzyme that catalyzes the S-methylation (inactivation) of 6-mercaptopurine. In these patients standard doses of 6-mercaptopurine have potentially fatal hematologic side effects. The drug should be given in much smaller doses (e.g., 10-fold reduction).177 Further, about 10 percent of the affected patients are heterozygous for this enzyme deficiency and thus have intermediate levels of the methyltransferase.178 This subgroup can be treated safely with only moderate reductions in 6-mercaptopurine dosage and appears to have better clinical outcome than patients with homozygous wild-type phenotype. The genetic basis of this autosomal codominant trait was recently identified, opening the way for molecular diagnosis of these cases.179 To this end, emphasis has been placed on the study of inherited differences in the metabolism and disposition of various chemotherapeutic drugs, due to genetic polymorphisms in drug-metabolizing enzymes, drug transporters, receptors, and targets.29 Ultimately, therapy can be designed according to the hosts’ and leukemic cells’ genetic constitution.
Intermittent pulses of vincristine and a glucocorticoid improve the efficacy of antimetabolite-based continuation regimens163 and therefore have been widely adopted in the treatment of childhood ALL. Another integral component of many protocols is reinduction therapy introduced relatively soon after patients have attained their first remission. This treatment, which relies on the same drugs that were used during the initial phase of induction therapy, has improved outcomes in both children and adults with ALL.51,159,163 Prolonged intensification including a second reinduction phase or rotational administration of non-cross-resistant drug pairs during continuation treatment may further improve outcome in patients with standard- or high-risk ALL.180,181 and 182
Therapy of the Central Nervous System The CNS is a frequent sanctuary site for leukemic cells requiring presymptomatic therapy for CNS involvement in patients with ALL. Cranial irradiation (2400 cGy) plus intrathecal methotrexate, administered after the induction of complete remission, became the cornerstone of ALL therapy in the 1970s.183 Concern that cranial irradiation may cause late neurologic sequelae and occasional brain tumors stimulated efforts to replace this modality with intensive intrathecal and systemic chemotherapy administered early in the clinical course to patients with a low risk of CNS relapse. This approach has lowered rates of CNS relapse to 2 percent or less in several studies.72,149,180,184,185 and 186
Whether certain groups of patients at high risk of relapse should be treated with cranial irradiation is unclear. In one retrospective study, children with T-cell ALL and leukocyte counts less than 100 × 109/liter had similar outcomes whether or not they received cranial irradiation. However, among those with higher leukocyte counts, the irradiated group had significantly better long-term responses than did patients given intrathecal therapy exclusively.186 These results are not conclusive because systemic chemotherapy differed between the two groups and may have been more effective in the irradiated patients. Nonetheless, in the context of effective systemic chemotherapy, a radiation dose as low as 1200 cGy appears to provide adequate protection against CNS relapse, even in high-risk patients (e.g., those with T-cell ALL and leukocyte counts > 100 × 109/liter).186
Allogeneic Stem Cell Transplantation Hematopoietic stem cell transplantation during first remission remains controversial. In adult ALL, long-term event-free survival rates range from 30 to 40 percent with chemotherapy alone and from 40 to 60 percent with allogeneic transplantation.187,188 and 189 However, it is difficult to interpret these results because the proportions of patients in similar risk groups differed from study to study, as did the criteria for patient selection. Even so, the results of both the adult and pediatric studies suggested that allogeneic transplantation may be of benefit in some high-risk cases.189,190 Thus, because of their unfavorable prognosis, patients with the Ph chromosome, the t(4;11), or poor initial response to induction therapy commonly receive allogeneic stem cell transplantation during the first remission.126,189,190,191 and 192 Exceptions to this general rule include children with Ph-chromosome-positive ALL and low presenting leukocyte counts (<25 × 109/liter) or good initial responses to prednisone, as well as children 1 to 9 years of age with the t(4;11) translocation—all of whom are potentially curable with intensive chemotherapy.193,194,195 and 196 Even adults with the t(4;11) can expect a 50 percent prospect of long-term event-free survival when treated with high-dose cytarabine and mitoxantrone.161 Hence, the indications for transplantation in first remission are variable and should be reevaluated as chemotherapy continues to improve. Currently, allogeneic s tem cell transplantation is the treatment of choice for adults and most children with Ph-chromosome-positive ALL and those who require extended induction therapy to attain complete remission.
COURSE AND PROGNOSIS
Relapse is defined as the reappearance of leukemic cells at any site in the body. Most relapses occur during treatment or within the first 2 years after its completion, although in some instances initial relapses have been observed 10 years or more after diagnosis.197 The marrow remains the most common site of relapse in ALL. Anemia, leukocytosis, leukopenia, thrombocytopenia, enlargement of the liver or spleen, bone pain, fever, or a sudden decrease in tolerance to chemotherapy may signal the onset of marrow relapse. In other sites, such as the CNS and testes, the frequency of relapse has decreased, and in contemporary programs of childhood ALL treatment, the rates of CNS and testicular relapse are generally less than 2 percent.198 Leukemic relapse occasionally occurs at other extramedullary sites, including the eye, ear, ovary, uterus, bone, muscle, tonsil, kidney, mediastinum, pleura, and paranasal sinus.199
Marrow relapse, with or without extramedullary involvement, portends a poor outcome for most patients. Factors indicating an especially poor prognosis in previously treated patients include relapse on therapy or after a short initial remission, after intensive primary therapy, a T-cell immunophenotype, the Ph chromosome, the presence of circulating blasts, or a high leukocyte count at relapse.200,201,202,203,204,205 and 206 Prolonged second remissions (>3 years) may be obtained with chemotherapy in as many as one-half of patients with late relapses (i.e., >6 months after cessation of therapy) but in only approximately 10 percent of those with early relapse.200,201,205 In patients who develop hematologic relapse on therapy or shortly thereafter, allogeneic hematopoietic stem cell transplantation is the treatment of choice.207,208,209,210,211,212 and 213 Autologous transplantation offers no substantial advantage over chemotherapy as postinduction treatment.214,215 and 216 For patients without histocompatible related donors, transplantation of stem cells from matched unrelated donors has yielded encouraging results.217,218 Umbilical cord blood offers a second transplant option that does not require the same degree of histocompatibility as procedures relying on marrow stem cells from children or adults.219,220 and 221 Whether the lower ri sk of graft-versus-host disease associated with cord blood transplants will lead to an increased risk of relapse due to a reduced graft-versus-leukemia effect is uncertain. Transplantation with large doses of T-cell-depleted hematopoietic stem cells from haploid-identical donors, following enhanced myeloablation and immunosuppression, has produced a disease-free survival rate that compares favorably with results in patients receiving transplants from matched unrelated donors.222 For patients who relapse after allogeneic transplantation, a second transplant or donor T-lymphocyte infusion may occasionally result in sustained remission.223,224 For patients who receive only chemotherapy therapy, a second course of CNS-directed treatment is needed to prevent subsequent CNS relapse.225
Although extramedullary relapse frequently presents as an isolated finding, most, if not all, occurrences are associated with minimal residual disease in the marrow.226,227 Hence, these patients require intensive systemic treatment to prevent subsequent hematologic relapse. The efficacy of retrieval therapy for patients with an isolated CNS relapse depends largely on whether they have received prior CNS irradiation. Intensive chemotherapy and craniospinal irradiation can be expected to secure long-term second remissions in at least half of the previously unirradiated group.205,228,229 For patients with earlier prophylactic irradiation, this rate generally does not exceed 30 percent; hence, some investigators have selected hematopoietic stem cell transplantation as a treatment option for this small subgroup.216,230 There is no firm evidence indicating an advantage of either autologous or allogeneic transplantation over intensive chemotherapy.
One-third of patients with early testicular relapse and two-thirds with late recurrences in this site became long-term survivors after salvage chemotherapy and bilateral testicular irradiation.231,232,233,234 and 235 Whether this experience can be extrapolated to patients who have received contemporary intensive treatment is uncertain. One study showed that some patients with late isolated testicular relapses can be successfully treated with chemotherapy, including very high dose methotrexate, without the addition of radiotherapy.236 The optimal treatment and prognosis for patients who relapse at unusual extramedullary sites are also unclear. However, the same principles that apply to the clinical management of CNS or testicular relapse would likely hold for this subgroup.
Despite the increasing intensity of curative treatment for childhood ALL, judicious use of supportive care has reduced the rate of early death from 8 percent in the early 1970s to less than 2 percent in the 1990s.21 However, the death rate among older patients receiving remission induction therapy can be as high as 30 percent, owing to increased hematologic and nonhematologic toxicities (e.g., hepatotoxicity and cardiotoxicity).53 This poor tolerance of chemotherapy and consequent reduction of dose intensity largely account for the generally poor clinical outcome in elderly patients.
Table 97-6 summarizes the more common side effects associated with antileukemic therapy. Hyperglycemia develops in 10 percent of children during induction therapy with prednisone, vincristine, and L-asparaginase and may require short-term insulin treatment. An adolescent age, obesity, a positive family history for diabetes mellitus, and Down syndrome are associated with an increased susceptibility to this complication.237 This induction regimen can also cause a hypercoagulable state,238 leading to cerebral thromboses, peripheral vein thromboses, or both in up to 2 percent of patients. Cerebral thrombosis should be distinguished from transient ischemic lesions, which are associated with acute hypertension and severe constipation. These lesions are located at the watershed areas between the major cerebral arteries and are generally reversible.239 Sagittal sinus thrombosis, on the other hand, can be diagnosed by magnetic resonance imaging or computed tomography (Fig. 97-8).
TABLE 97-6 SIDE EFFECTS ASSOCIATED WITH ANTILEUKEMIC THERAPY
FIGURE 97-8 This T1-weighted magnetic resonance image without contrast demonstrates a clot in the superior sagittal sinus (arrow) and several frontal lobe hematomas.
Emphasis on intensive use of methotrexate and glucocorticoids has led to an increased frequency of neurotoxicity240,241 and 242 and aseptic necrosis of bone,243,244,245 and 246 respectively, underscoring the need for judicious use of even seemingly benign agents. For example, methotrexate given in divided doses of 25 mg/m2 every 6 h four times daily in four weekly courses can result in acute neurologic toxicity if subsequent leucovorin treatment is inadequate.240 Many of the long-term survivors of childhood ALL have developed severe osteoporosis,247,248 focusing attention on the need for early identification of bone lesions and the introduction of therapy to prevent fractures.
Treatment with anthracyclines can produce severe cardiomyopathy, especially when these agents are given to young girls in high cumulative and peak doses.249,250 Whether there is a safe cumulative dose of anthracycline is controversial.251,252 Several ongoing trials will evaluate whether dexrazoxane can prevent anthracycline-induced cardiotoxicity without interfering with antileukemic activity.253 Cranial irradiation has been implicated as the cause of numerous late sequelae in children, including neuropsychologic deficits and endocrine abnormalities leading to obesity, short stature, precocious puberty, and osteoporosis.21 In general, these complications are seen in girls more often than in boys and in young children more often than in older ones. Many children with profound deficiencies of growth hormone are receiving hormone replacement therapy, which permits acceptable final heights to be attained without an increase in the relapse hazard.21 The current practice of limiting both the use and dose of cranial irradiation promises to lower the frequency of many treatment sequelae.
The most devastating complication is the development of a second cancer, especially brain tumors and acute myelogenous leukemia. Children who received cranial irradiation at 6 years of age or younger and those with ETV6-CBFA2 fusion in their leukemic lymphoblasts are most susceptible to the development of brain tumors.254,255 The intensive use of antimetabolites before and during cranial irradiation also increases the risk for brain tumor development.255 The median latency period for high-grade brain tumor is 9 years but almost 20 years for low-grade tumors (e.g., meningioma).254 Patients with low-grade brain tumors have an excellent prognosis, while the outcome for those with high-grade tumors is very poor. Acute myelogenous leukemia has been linked to intensive treatment with the epipodophyllotoxins (teniposide and etoposide), with the risk of disease development apparently depending on treatment schedule and the concomitant use of other agents (e.g., L-asparaginase, alkylating agents, and perhaps antimetabolites).256,257 The long-term survival rate for patients with this complication is very low, even when they undergo allogeneic stem cell transplantation.257 There has been no indication that the incidence of cancer or birth defects has increased among the offspring of adult survivors of childhood ALL.258,259 and 260
The cornerstone of the modern therapeutic approach to childhood ALL has been careful assessment of the risk of relapse, so that only standard- or high-risk cases are treated with intensive therapy, with less toxic treatments, usually antimetabolites, reserved for low-risk cases. By contrast, virtually all adult patients are candidates for intensive therapy. Of the many variables that influence prognosis, treatment is the most important.261 Some of the factors that have emerged as useful prognostic indicators disappeared as treatment improved; others have shown predictive strength in one or several trials but not in others. For example, T-cell and B-cell ALL, once associated with a very bad prognosis, now have long-term response rates of 70 percent to 80 percent in children51,108,120,121 and 122 and 50 percent to 60 percent in adults53,123,124 as a result of effective intensive chemotherapy.
Age and leukocyte count continue to be used for risk classification in virtually every pediatric clinical trial involving B-cell-precursor ALL. In a workshop sponsored by the U.S. National Cancer Institute, participants agreed on a presenting age between 1 and 9 years and a leukocyte count of less than 50 × 109/liter as the minimal criteria for low-risk ALL.262 This criterion probably applies only to B-cell precursor ALL and not to T-cell ALL. Among adults, the outcome of therapy worsens with increasing age and leukocyte count.52,53 and 54,125,126 and 127,263,264 and 265 However, there are no clear guidelines for assigning prognostic value to particular increments of age or leukocyte numbers. In general, an age of less than 60 years is considered to be a practical guide for selecting candidates who might benefit from intensive therapy, including allogeneic transplantation. Any decision to begin aggressive treatment in patients older than 60 years must be weighed against the risk of increased morbidity and mortality.
Gender has long been recognized as a significant prognostic factor in childhood ALL. Despite the consistency of this finding, gender differences have attracted only scant attention from leukemia therapists, until recently.198,266,267 Although both boys and girls have benefited from recent improvement in therapy, boys continue to fare worse than girls, a result only partially explained by the higher frequency of T-cell ALL in boys.198 Gender has less influence in adult ALL; however, when a sex difference in survival was observed, males had the inferior outcome.53 The historically poor prognosis for children of African ancestry with ALL has largely been abolished by more effective treatment.268
Age and certain genetic subtypes of ALL are strongly correlated with prognosis. For example, 70 percent to 80 percent of infants (<1 year old) have rearrangements of the MLL gene and a very poor survival rate.269 Adolescent and adult patients have relatively high frequencies of MLL rearrangements and the Ph chromosome, together with low rates of long-term survival.52,88,270 By contrast, two favorable genetic abnormalities—hyperdiploidy (>50 chromosomes per cell) and ETV6-CBFA2 fusion—occur mainly in children 1 to 9 years of age.21,95,96 Despite their close relation to the biologic properties of leukemic blast cells, genetic abnormalities do not offer a precise guide to clinical outcome. For example, as many as 20 percent of children with hyperdiploid- or ETV6-CBFA2-positive ALL eventually have a relapse.21 On the other hand, there are subgroups of patients with MLL rearrangements and a favorable age195,196,271,272 or BCR-ABL with low initial leukocyte counts or a good response to early treatment193,194,273 who fare well on contemporary protocols.
A useful adjunct in risk assessment is the response to early treatment, as measured by the rate of clearance of leukemic cells from the blood or marrow274,275 and 276 or by the level of minimal residual disease after the induction of a clinical remission.85,129,130 and 131,277,278 We have now included this factor in our risk classification system (Table 97-7). Whether the alteration of treatment intensity according to the level of minimal residual disease will improve long-term outcome in patients with ALL remains to be determined.
TABLE 97-7 RISK CLASSIFICATION SYSTEM IN ST. JUDE TOTAL THERAPY STUDY XIV
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn