James W. Fraser, Janet E. Murphy, Eyal C. Attar
INTRODUCTION
Acute lymphoblastic leukemia (ALL) is a highly aggressive neoplasm of hematopoietic cells of lymphoid lineage. Collections of abnormal T- or B lymphoblasts may be found in the bone marrow, peripheral blood, and other extramedullary sites. ALL is predominantly a childhood cancer, with two-thirds of new cases diagnosed in children younger than 15 years of age. ALL was uniformly fatal until the 1960 but, due to advances in chemotherapy and supportive care, is now cured in over 80% of children. Adults diagnosed with ALL, in contrast, have a poor overall prognosis. Important factors in assessing prognosis are the age of the patient, type of lymphoid cell involved (T cell vs B cell), and the presence of high-risk cytogenetic markers, such as the t(9;22) (BCR–ABL) translocation. Burkitt’s lymphoma, a malignancy of mature B cells, has been historically classified as a B-ALL due to its high-grade leukemia-like features but is both diagnostically and prognostically a separate entity from precursor B-ALL. Burkitt’s lymphoma is addressed in the chapter on non-Hodgkin lymphomas.
• ALL is the most common malignancy of childhood.
• Childhood ALL has a much better prognosis than adult ALL.
• Highly aggressive lymphoid malignancy with B-cell (80%) and T-cell (20%) immunophenotypes.
• Certain cytogenetic alterations, such as t(9;22), are associated with inferior prognosis while others, such as t(12;21), are associated with favorable outcomes.
EPIDEMIOLOGY AND ETIOLOGY
Leukemia comprises 32% of malignancies in children younger than 15 years. Of these, the majority are ALL. Each year approximately 2400 children in the United States are diagnosed with ALL. The peak incidence in children is between ages 2 and 5. Leukemia rates are significantly higher in Caucasian children, with a nearly threefold higher incidence over African-American children. ALL is almost 30% more common in males than females. Overall, the incidence of childhood ALL has increased in the past 20 years at a rate of 0.9% per year. Adult ALL is less common, with approximately 1000 new cases diagnosed per year. The incidence of ALL decreases from age 15 until 50; then a second, minor increase in new cases appears. A third peak appears at age 80. The lifetime risk of developing ALL is 0.13%, or approximately 1 in 789 men and women (1).
Several reports have suggested that inadvertent exposure to radiation in utero and postnatal radiation treatment for such conditions as tinea capitis and thymic enlargement increase the risk of ALL (2). A common cytogenetic translocation involving ETV-6 was retrospectively detected in neonatal blood spots of children who were diagnosed with ALL between ages 2 and 5, suggesting that ALL can be initiated by somatic translocation in utero but requires additional molecular events to fully develop (3). Limited and/or inconsistent evidence links ALL to parental smoking, infection, diet, electromagnetic fields, hydrocarbons and, possibly, radiation delivered during the course of diagnostic studies such as CT scans (4).
The following characteristics are associated with ALL:
• Male sex
• Age 2–5
• Caucasian race
• Higher socioeconomic status (SES)
• Hereditary factors (Down syndrome, Bloom syndrome, ataxia telangectasia, neurofibromatosis, Klinefelter syndrome, Shwachman syndrome, and Langerhans cell histiocytosis)
• Radiation and chemical exposure is controversial but may increase overall risk of ALL both in utero and during childhood
• Overall likelihood of developing ALL in one’s lifetime is 0.13%, or 1 in 789
ALL CLASSIFICATION
Proper characterization of the specific hematopoietic lineage involved in ALL is crucial for assessing risk and for treatment. ALL may be classified according to the presence or absence of various cell surface and intracellular markers.
Both immunohistochemistry and flow cytometry may be used to identify expression of cell surface and cytoplasmic proteins. These techniques use panels of lineage-specific antibodies directed against B-lymphoid and T-lymphoid antigens to stain patient bone marrow and lymph node samples. Common immunophenotypes are presented in Table 28-1.
TABLE 28-1 COMMON IMMUNOPHENOTYPE PROFILES OF LYMPHOID AND MYELOID MALIGNANCIES
Both B and T lymphoblasts typically express terminal deoxytransferase (TdT) and/or the primitive hematopoietic cell surface marker CD34. Approximately 80% of adult ALL patients have B-ALL, while 5% have Burkitt’s (an aggressive tumor of peripheral follicular B cells) and the remainder are precursor T-cell ALL.
Precursor B-ALL cells express CD19 and at least one other B-lineage marker such as CD20, CD24, CD22, CD21, or CD79. More than 90% also express CD10, a marker known as CALLA, or common ALL antigen. In addition, 25% of patients have cytoplasmic Ig staining.
Precursor T-cell leukemias express CD7, TdT, and cytoplasmic CD3 antigen. Expression of CD1a is highly characteristic of T-ALL. More highly differentiated thymocytes acquire CD2 and CD5 and, later, CD4 and CD8. Mature thymocytes express functional T-cell receptor (TCR) and surface CD3. TCR rearrangement studies may be conducted to establish clonality.
As in adults, approximately 80% of children with ALL too have B-ALL, whereas 2% have mature B-cell (Burkitt’s) leukemia/lymphoma and 15% T-ALL.
• ALL may be classified as B- or T-cell origin using intracellular and cell surface markers.
• B-ALL markers most commonly include: CD10, CD19, CD20, CD21, CD22, CD24, and CD34 and TdT. Twenty-five percent of B-ALL will have cytoplasmic Ig staining.
• T-ALL markers include CD7, TdT, CD1a, and cytoplasmic CD3. More differentiated leukemia markers of T-cell origin include CD2, CD5, and CD4 or CD8.
DIAGNOSIS OF ALL
CLINICAL PRESENTATION
Children with ALL may have an insidious or explosive course before diagnosis, whereas adults present more uniformly with rapid-onset disease. Physical signs and symptoms are the result of marrow failure from leukemia cell proliferation.
Patients commonly present with signs and symptoms of anemia, such as pallor, fatigue, lethargy, and, in adults, cardiac angina. Thrombocytopenia, another common sign, manifests as easy bruising, bleeding, and petechiae. Underproduction of normal neutrophils predisposes patients to infections, such as pneumonias, tooth infections, and sinusitis.
Leukemia cell expansion within the marrow may lead to bone pain and, in young children, resistance to walking. Extramedullary deposition leads to lymphadenopathy, hepatosplenomegaly with abdominal tenderness to palpation, and testicular enlargement, while involvement of the CNS leads to headaches, nausea, vomiting, and cranial nerve palsies. A mediastinal mass, which may be seen in T-cell ALL, may result in chest discomfort, shortness of breath, dyspnea on exertion, and superior vena cava syndrome.
Rapidly proliferating disease may result in spontaneous tumor lysis with renal failure and electrolyte imbalances. Many patients present with fevers without infectious etiologies.
A summary of clinical features is presented in Table 28-2.
TABLE 28-2 CLINICAL MANIFESTATIONS OF ALL
Marrow failure
• Anemia: pallor, fatigue, lethargy, angina
• Thrombocytopenia: bruising, petechiae
• Neutropenia: infection
Clonal expansion
• Bone pain, resistance to walking in children
• Tender lymphadenopathy
• Hepatosplenomegaly
• Fever
• Mediastinal mass
• Testicular mass
CNS infiltration
• Headache
• Nausea, vomiting
• Cranial nerve palsies
DIAGNOSTIC STUDIES
The WHO classification describes three distinct entities of ALL: B-ALL with recurrent genetic abnormalities, B-ALL not otherwise specified (cytogenetically normal), and T-ALL. To classify a hematologic malignancy as ALL, there must be at least 25% involvement of precursor lymphoblasts committed to the B-cell or T-cell lineage present in the bone marrow and blood. This diagnostic criterion contrasts with AML, which requires ≥20% myeloblasts in the bone marrow or blood for diagnosis. Burkitt’s lymphoma is classified as a “mature” B-ALL and is the exception to this rule. Burkitt’s cells are negative for both myeloperoxidase (MPO) and TdT but stain positively for B-cell markers and, often, have light chain restriction.
The diagnostic workup consists of blood tests, imaging, bone marrow aspiration and biopsy, and lumbar puncture (LP) (Table 28-3). The CBC and peripheral blood smear may show leukocytosis with lymphoblasts (Figure 28-1) with decreases in normal blood counts. Serum chemistries reflect the degree of tumor burden and cell lysis; patients with tumor lysis exhibit hyperuricemia, hypocalcemia, hyperphosphatemia, hyperkalemia, and elevated LDH. Bone marrow aspiration reveals hypercellularity with increased lymphoblasts. CNS involvement is present in 5%–15% of adults and children alike, and is more frequently associated with the precursor T-cell immunophenotype. LP and subsequent CNS analysis will show blasts by cell count and cytology and may demonstrate an elevated opening pressure and protein and glucose derangements. Evidence exists that a traumatic LP may seed the CNS in unaffected children. Consequently, a traumatic tap as suggested by the presence of red blood cells in the cell analysis represents an indication for intensification of CNS therapy (5). An anterior mediastinal mass may be detected in 5%–10% of children and 15% of adults by chest X-ray, a finding more commonly associated with T-ALL.
TABLE 28-3 WORKUP AND FINDINGS SEEN IN ALL
CBC and peripheral smear
• Leukocytosis or leukopenia
• Lymphoblasts
• Anemia
• Thrombocytopenia
Serum chemistries
• Hyperuricemia
• Hyperkalemia
• Hypocalcemia
• Hyperphosphatemia
• Elevated LDH reflective of high-tumor burden and cell lysis
Bone marrow
• Homogeneous lymphoblast field with hypercellular marrow (>25% blasts)
• Residual myeloid and erythroid precursors are morphologically normal
• A few/absent megakaryocytes
LP
• CNS blasts
• Elevated opening pressure
• Elevated protein
• Decreased glucose
Radiology
• Anterior mediastinal mass (more often associated with T-cell ALL)
• PET/CT scanning of the neck, chest, abdomen, and pelvis may reveal lymphadenopathy
• Testicular ultrasound for patients with a scrotal mass
FIGURE 28-1 Morphology of ALL cells. Slides showing: (A) peripheral smear with lymphoblasts, and (B) bone marrow aspirate. Leukemic lymphoblasts are large cells with a high nuclear-to-cytoplasmic ratio and prominent nucleoli. Cells with “hand mirror” contours may be seen in the peripheral blood in ALL. (Courtesy Rob Hasserjian, MGH Cancer Center.)
RISK STRATIFICATION
CLINICAL FACTORS
Treatment of ALL is based on assignment of risk derived from immunophenotype, cytogenetics, and clinical prognostic factors. In children, the Rome/NCI (National Cancer Institute) criteria have traditionally assigned children to standard versus high-risk categories for treatment based on age and WBC count at diagnosis. Children ages 1–9 with B-cell ALL who present with WBC count <50,000/µl at diagnosis are considered standard risk, while all others are high risk. Recent trials have employed Children’s Oncology Group (COG) criteria for risk assessment, in which age and WBC count determine initial risk; cytogenetics and subsequent response to therapy substratify patients during treatment into a four-category algorithm that maximizes cure rate and minimizes exposure to toxic chemotherapies in low-risk patients.
Factors that influence prognosis in children are summarized in Table 28-4. Overall, mature B cell and precursor T-cell ALL immunopheno-types have poorer prognosis, and children with leukemias of this origin are assigned to the high-risk treatment group regardless of blast count at presentation. Age at presentation is crucial, with the age group 1–9 being most favorable. Children younger than 1 year have an exceptionally poor prognosis, with aggressive disease (higher WBC at presentation, often accompanied by massive hepatosplenomegaly) attributed to a high frequency of the t(4;11) MLL-AF4 translocation, which occurs in 50% of infants. Adolescents (10–20 years) have a poorer prognosis than younger children, presenting more frequently with T-cell disease and Philadelphia-positive B-cell disease. Interestingly, young adults in their late teens have improved outcomes when treated on pediatric protocols compared to adult protocols. This may relate to increased use of non-myelotoxic drugs and stricter compliance with pediatric treatments—possibly aided by increased parental participation (“the mommy factor”) (6).
TABLE 28-4 PROGNOSTIC FACTORS IN CHILDHOOD ALL
Patient ethnicity has historically been a factor: African-Americans and Native Americans have generally experienced poorer outcomes, with higher WBC counts, increased prevalence of lymphadenopathy, and mediastinal mass on presentation. However, this difference is reduced when patients are provided equal access to care (7).
Important clinical factors include organ involvement (lymph nodes, spleen, liver, testes), which portends poor prognosis, as does the absence of anemia and thrombocytopenia, which correlates with explosive disease. Likewise, CNS involvement is associated with a lower rate of remission and higher rate of relapse. Finally, clearance of blasts is routinely measured at days 7 and 14 of induction chemotherapy; nonclearance of blasts at these time points is associated with a 2.7-fold relative risk of relapse in children and half to two-thirds less chance of 5-year overall survival in adults (8, 9).
Risk assignment in adults is less succinctly defined. In the absence of consensus guidelines, individual consortia have developed parameters to govern their trials. The Cancer and Leukemia Group B (CALGB) criteria for high-risk patients include:
1. age greater than 30, which is inversely correlated with achievement of complete remission (CR), duration of CR, and overall survival. The linear worsening of prognosis with age in adult ALL makes it difficult to define a threshold of low versus high risk.
2. WBC at presentation >30,000/µl
3. Presence of a mediastinal mass
CYTOGENETICS
Genetic lesions in ALL are common and correlated with immunophenotype, response to treatment, and disease recurrence (Figure 28-2). The WHO identifies six cytogenetic subcategories associated with prognosis in precursor B-cell ALL, summarized in Table 28-5. In children, classical cytogenetic lesions associated with favorable prognosis in precursor B-cell disease are the t(12;21) (TEL/AML) translocation, found in 15%–25% of children with ALL, and hyperdiploidy, with chromosome counts >50 per cell, found in 30% of children (vs 2% of adults). Trisomies of chromosomes 4, 10, 17, while not a WHO subcategory, also correlate with favorable prognosis in children (10).
FIGURE 28-2 Estimated frequencies of specific genotypes among children and adults with ALL. (From Pui E. Drug therapy: acute lymphoblastic leukemia. N Engl J Med. 1998; 339: 605–615. Copyright © 1998 Massachusetts Medical Society. All rights reserved.)
TABLE 28-5 WORLD HEALTH ORGANIZATION (WHO) PROGNOSTIC IMPLICATIONS OF GENETIC ALTERATIONS IN PRECURSOR B-LYMPHOBLASTIC LEUKEMIA
Treatment failure in B-ALL is associated with the t(4;11) (MLL-AF4) translocation, commonly found in infantile ALL with high blast counts (11). In both adults and children, the Philadelphia chromosome t(9;22) (BCR–ABL) portends negative prognosis. Prevalence of t(9;22) is striking in older adults, with 50% of patients over 50 exhibiting this mutation. Both the 210-kD gene product, identical to the one found in CML, and a smaller, 190-kD protein are found in Ph+ ALL, with equal prognostic implications (12). Finally, the t(1;19) (E2A-PBX1) translocation is associated with early treatment failure in B-ALL (13).
Prognosis in T-ALL is not as well correlated with specific cytogenetic mutations. The T-cell immunophenotype more often presents with aggressive features, including mediastinal mass and CNS infiltration, but no single karyotype confers this risk. Approximately 50% of precursor T-cell clones have activating mutations of the NOTCH1 gene, but the prognostic significance of this mutation is not yet defined (14). Preclinical studies are currently underway assessing the efficacy of notch inhibitors, such as γ-secretase inhibitors, in both B- and T-ALL (15, 16). Translocations involving the TCR genes on chromosomes 7 and 14 are common.
Additional genetic techniques, such as microarray gene expression profiling and comparative genomic hybridization (CGH), are being used to explore novel molecular lesions operative in ALL. These techniques may be used to further substratify patients within cytogenetic groups but are most useful in patients who have normal cytogenetics.
TREATMENT
Chemotherapy is the mainstay of treatment for ALL. The treatment regimen depends upon immunophenotype and clinical and molecular risk category. Table 28-6 provides a global approach to the treatment of patients with ALL.
TABLE 28-6
With standard protocols, children with ALL attain remission in 98% of cases, with 80% surviving at least 5 years from diagnosis (17). In contrast, approximately 85% of adults achieve CR, with a median duration of remission of 15 months and ultimate cure rate of only 25%–40%.
Mature B-cell ALL does not respond well to chemotherapy traditionally used for precursor ALL. However, event-free survival (EFS) rates exceeding 90% have been obtained with treatments designed for Burkitt’s lymphoma, which emphasize cyclophosphamide and the rapid rotation of antimetabolites in high dosages (Table 28-7). This strategy differs from therapies for precursor ALL, which involve sequential modules of remission induction, intensification, CNS prophylaxis, and maintenance. Patients with large sites of disease, as in precursor T-cell ALL with a mediastinal mass, often require involved field radiation therapy in addition to systemic chemotherapy. Typical regimens for precursor and mature B-cell ALL are provided in Table 28-7.
TABLE 28-7 COMMON ADULT ALL TREATMENT REGIMENS
Precursor acute B-cell lymphoblastic leukemia/lymphoma
• CALGB 19802 (Stock, et al. Blood. 2003; 102: 1375a)
• CALGB 9111 (Larson, et al. Blood. 1998; 92: 1556)
Precursor acute T-cell lymphoblastic leukemia/lymphoma
• GMALL/MSCMCC (Hoelzer, et al. Blood. 2002; 99: 4379)
Mature B-cell leukemia/Burkitt’s lymphoma
• GMALL (German Multicenter Study Group for Treatment of Adult ALL) (Hoelzer, Ludwig, et al. Blood. 1996; 87: 495.)
• BFM GMALL/NHL 2002(Hoelzer, et al. Blood. 2003; 102: 236a)
• BFM 86 (Reiter, et al. Blood. 1994; 84: 3122-3133)
• Modified Magrath Regimen (Lacasce, et al. Leuk Lymphoma. 2004; 45: 761–767.)
• (R)-HyperCVAD (Thomas et al. J Clin Oncol. 1999; 17: 2461-2470, Thomas et al. Cancer. 2006; 106: 1569–1580.)
Remission induction aims to restore normal blood counts and marrow appearance, reduce the percentage of blasts to <5%, and eliminate extramedullary disease. Standard treatment regimens consist of vincristine, a glucocorticoid (usually prednisone or dexamethasone), L-asparaginase, and, often, an anthracycline such as doxorubicin or daunorubicin. Three to four drugs are used for standard-risk patients, while up to seven drugs may be used in high-risk cases. For adult patients, a five-drug regimen known as “CAVP-L” incorporates the alkylating agent cyclophosphamide with daunorubicin, vincristine, prednisone, and L-asparaginase and is commonly used for induction (18). Another regimen known as “Hyper-CVAD” utilizes hyperfractionated doses of cyclophophamide in induction alternating with cycles of cytarabine and methotrexate. Intensification aims to eliminate residual leukemia, prevent relapse, and reduce the possible emergence of drug-resistant cells. In children, high-dose methotrexate with mercaptopurine is commonly used. Reinduction with the initial drug combination often follows after several months.
Maintenance therapy preserves remission. ALL requires 2–3 years of maintenance, significantly longer than other chemoresponsive cancers. Standard maintenance regimens may incorporate daily mercaptopurine, weekly methotrexate, and monthly pulses of vincristine and prednisone. CNS prophylaxis While the incidence of CNS involvement is relatively rare (5%–15%), the CNS represents a sanctuary site for ALL that may be the source of systemic relapse at a later date or site of disease occurrence despite systemic remission. The CNS is routinely prophylaxed using intrathecal (IT) chemotherapy consisting of methotrexate and/or cytarabine. Cranial irradiation, too, is a standard component of prophylaxis. Supportive care includes administration of white blood cell growth factors, antibiotics for infection prophylaxis and treatment, blood product transfusions, and treatment of electrolyte disturbances.
Response to therapy The efficacy of chemotherapy is evaluated by repeated analysis of peripheral blood and bone marrow samples at regular intervals. Response to therapy is measured in several ways:
1. Time interval to achieve CR with induction chemotherapy. Adults who do not achieve CR by 4 weeks are twice as likely to relapse, and have a negligible 5-year disease-free survival rate.
2. Detection of minimal residual disease. More sensitive techniques such as flow cytometry and PCR can detect one lymphoblast in 104 and 106 normal cells, respectively. Current research has correlated an MRD >10-4 with significantly lower rates of relapse-free survival within the first year, within 5 years (15% vs 71% MRD neg) and higher rates of treatment failure following autologous stem-cell transplant (77% vs 25% MRD neg) in non T-ALL (19). However, an MRD >104 detected before allogeneic stem-cell transplantation does not appear to have a significant effect on outcome.
Allogeneic hematopoietic cell transplantation has been shown to improve outcomes in high-risk groups such as t(9;22)-positive adults. Indeed, prospective outcome data on 267 unselected adult patients with (9;22) positive ALL showed 5-year OS to be 44% and 36% for patients who received sibling matched allo-HSCT (hematopoietic stem-cell transplantation) or matched unrelated HSCT, respectively, versus 19% who underwent chemotherapy alone (20). Following remission induction, patients undergo conditioning with chemotherapy (and sometimes radiation therapy) and transplantation with allogeneic hematopoietic cells. Transplantation not only provides hematopoietic rescue but also donor lymphocytes, which may mediate a graft versus leukemia/lymphoma effect (21). Recent evidence suggests that even adults with standard risk disease benefit from allo-HSCT over standard consolidation and maintenance chemotherapy if a matched related donor is available.
Nonmyeloablative strategies are currently under investigation for older patients and those unable to receive myeloablative conditioning due to other medical conditions. Current research is evaluating the benefit of purged autologous hematopoietic stem cells, reduced-intensity conditioning regimens, and use of alternative stem cells sources such as cord blood.
Salvage chemotherapy Relapsing patients undergo reinduction with repeated use of induction agents or salvage regimens based on high-dose cytarabine in combination with other agents such as mitoxantrone. Allogeneic transplantation, when possible, frequently follows for such high-risk patients if remission is attained. Despite the benefit of these therapies in the short term, only 7% of patients with relapsed ALL achieve an overall survival >5 years (22). Relapsed patients who undergo allo-HCT have improved survival compared to those who do not.
Novel treatments Advances in survival have outpaced significant alterations in chemotherapy for ALL; survival is attributed to improvements in risk stratification such that patients receive sufficient chemotherapy while toxicities are minimized. Current investigation in pharmacogenomics may result in personalized approaches to chemotherapy types and dosages. For example, discovery of an autosomal recessive polymorphism in the thiopurine methyltransferase (TPMT) gene, responsible for inactivation of 6-mercaptopurine, has altered how chemotherapy is dosed. TPMT-deficient patients achieve toxic levels when standard doses of 6-MP are administered, but their event-free survival has been historically better—a finding with implications for optimal dosing in wild-type patients as well (23). In the future, pharmacogenomics may help to identify polymorphisms and permit dosing to maximal effect in patients.
The targeted ABL kinase inhibitor imatinib mesylate (Gleevec) has shown activity in patients with t(9;22)-positive disease, mainly when administered with standard chemotherapies (24). Second generation tyrosine kinase inhibitors that include dasatinib (Sprycel) and nilotinib (Tasigna) also have activity in Ph+ disease. The novel nucleoside analogue clofarabine is approved in pediatric ALL, while nalarabine (ara-G) is approved in relapsed and refractory T-ALL. Current trials are evaluating the benefit of monoclonal antibodies, such as the anti-CD20 agent rituximab (Rituxan), inotuzumab ozogamicin (a conjugate of calicheamicin with an anti-CD22 antibody), bispecific T-cell engager (BiTEs) antibodies such as blinatumomab (one portion binds T cells and the other CD19 on B-cell tumor cells), the proteasome inhibitor bortezomib, and inhibitors of molecular targets perturbed in ALL, such as NOTCH.
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