Nirali N. Shah and Alan S. Wayne
Approximately 5,000 new cases of acute lymphoblastic leukemia (ALL) are diagnosed each year in the United States, more than half of them in children. There has been significant progress in the development of curative therapy, such that currently children and adults with ALL have expected disease-free survival (DFS) rates of about 80% and 50%, respectively.1,2
EPIDEMIOLOGY
ALL represents the most common pediatric malignancy, accounting for approximately 25% of childhood cancer. The peaks in prevalence of ALL occur between the ages of 2 and 5 years and after age 50. There is a slight male predominance, and Caucasians have a twofold increased risk compared with African-Americans, while the highest incidence is seen in Hispanic children.3
ETIOLOGY AND RISK FACTORS
Certain conditions predispose to ALL, most notably trisomy 21 (Down syndrome) in which the relative risk is increased 15-fold. Other predisposing conditions include immunodeficiency and chromosomal breakage syndromes, but most often no such underlying disorder is found. Epstein-Barr virus (EBV) infection is implicated in a minority of cases of mature B-cell ALL. Environmental exposure risks have been suggested, but with the exception of ionizing radiation, few have been shown to be causal. Acquired chromosomal abnormalities confined to lymphoblasts are found in more than 90% of cases, including aneuploidy (most commonly hyperdiploidy) and/or translocations that in some cases are prenatal in origin. The genes involved in leukemogenesis are frequently transcription factors expressed in hematopoietic tissues.4
CLINICAL FEATURES
Presenting signs and symptoms are almost always caused by lymphoblast infiltration of the bone marrow with resultant blood count abnormalities (Table 12.1). Other organs may also be involved, most commonly the central nervous system (CNS) and the testes. T-cell ALL frequently presents with bulky adenopathy, mediastinal mass, pleural effusion, and/or hyperleukocytosis. Gastrointestinal presentation due to Peyer’s patch involvement, usually ileocecal intussusception, is almost always confined to mature B-cell ALL. There are a number of life- or organ-threatening presentations that require emergent intervention (Table 12.2).
LABORATORY FEATURES
The diagnosis is readily confirmed by the demonstration of lymphoblasts in the blood and/or bone marrow. Blast morphology can be classified into three categories (L1, L2, L3) according to the French-American-British (FAB) system (Table 12.3). Only the latter is of clinical and prognostic significance, because L3 morphology is indicative of mature B-cell or Burkitt-type ALL. Routine hematopathologic analysis, immunohistochemistry, flow cytometry, and cytogenetics are used to define the subtype and further identify prognostic factors. The majority of ALL is of precursor B-cell (pre-B) phenotype (CD10, CD19, CD22, HLA-DR, TDT+), 10% to 20% is T-cell (CD2, CD7+), and less than 5% is mature B-cell or Burkitt-type (CD20, surface-IgM κ or λ+). Certain cytogenetic abnormalities are not apparent on routine karyotyping, and thus molecular testing may be required, most notably for t(12;21) seen in about 25% of cases in children (Table 12.4). Lumbar puncture is required to evaluate the possibility of meningeal leukemia.
Table 12.3 Classification
FAB Morphology
L1: homogeneous blasts, minimal cytoplasm
L2: increased nuclear heterogeneity, prominent nucleoli
L3: basophilic cytoplasm with prominent vacuolization
Bone Marrow
M1: <5% blasts
M2: 5%-25% blasts
M3: >25% blasts
Cerebrospinal Fluid Cytology
CNS-1: no blasts
CNS-2: WBC < 5/μL with blasts
CNS-3: WBC ≥ 5/μL with blasts
or symptomatic CNS involvement (e.g., cranial nerve palsy)
CNS, central nervous system; FAB, French-American-British; WBC, white blood cell.
PROGNOSTIC FACTORS
Clinical and biologic features, as well as initial response to therapy, are used to determine risk-directed treatment for individuals with pre-B ALL (Table 12.5).5 Age is a strong prognostic determinant, and outcome is inferior in infants and adults in comparison to children. T-cell and mature B-cell disease have historically had lower DFS rates than pre-B ALL; however, stratified treatment has minimized this difference. Recently, genomic analysis has revealed molecular alterations and profiles associated with poor outcome, thus allowing further discrimination of diagnostic subtype, risk classification, and treatment-response prediction.4
TREATMENT
Many chemotherapeutic regimens are effective for children and adults with ALL. Therapy is stratified based on clinicopathologic features, and treatment should be directed by physicians familiar with subtype-specific regimens. The following core recommendations are based on results of large cooperative group clinical trials.1,2,6-9
Therapy should be instituted as soon as possible after diagnosis.
Treatment is based on phenotype and prognostic factors and includes the following phases: induction, consolidation, CNS sterilization, and maintenance for a total of 2 to 3 years (Table 12.6). Initial induction therapy often consists of 3 to 5 drugs given as a 28-day cycle, although there are alternative approaches.8 A variety of consolidation and intensification regimens are commonly employed, some of which are detailed below. Multiple consolidation/intensification blocks are often advised for high-risk patients. A late reinduction phase, also known as delayed intensification, improves DFS for children who are slow early responders (SER).10 Randomized trials of various intensification blocks for adults have shown mixed results.11,12 The application of pediatric regimens to adult ALL has improved the DFS rates especially for adolescents and young adults, but at the expense of toxicity in older individuals.2,9,13-15 Prolonged maintenance with a total treatment duration of 24 to 36 months improves DFS for both adults and children.
Table 12.4 Common Chromosomal Translocations
t(12;21): TEL/AML1 (25% childhood ALL)
t(1;19): E2A/PBX1
t(9;22): BCR/ABL p190 fusion (25% adult ALL)
11q23: MLL, multiple fusion partners (70% infant ALL)
14q11 or 7q35: TCR,T-cell phenotype
t(8;14), t(8;22), t(2;8): c-myc/Ig, mature B-cell (Burkitt) phenotype
ALL, acute lymphoblastic leukemia.
Table 12.6 Common Treatment Regimens for Pre-B-cell Acute Lymphoblastic Leukemia and T-cell Acute Lymphoblastic Leukemia*
Induction Regimen (Weeks 1–4)
3-Drug
4-Drug: Add the following to above
5-Drug: Add the following to above
Response evaluation
Day 14 bone marrow
Day 28 bone marrow
Post-induction Regimens
Pretreatment criteria
Consolidation (Week 5)
Standard Berlin-Frankfurt-Munster Study Group (BFM)
Augmented BFM
High-dose methotrexate with leucovorin rescue
Capizzi
Ifosfamide/etoposide
Interim Maintenance
Delayed Intensification/Reinduction
With or without:
Maintenance/Continuation Regimen
Repeat cycles to complete 24–36 mo of total treatment.
*A BCR/ABL kinase inhibitor should be incorporated into the treatment regimen for individuals with Philadelphia chromosome–positive ALL.
†6-MP and methotrexate doses should be adjusted to maintain the ANC between 750–1,500/μL and the platelet count >75,000/μL. IM, intramuscular; IT, intrathecal; IV, intravenous; PO, oral; SQ, subcutaneous; MRD, minimal residual disease.
Allogeneic stem cell transplantation (SCT): Although relapse rates are lower after allogeneic SCT compared with chemotherapy, treatment-related mortality rates are higher after transplantation.16 Thus, SCT is rarely used for children in first remission (CR1) except within the context of clinical trials for individuals with extremely poor prognostic features such as induction failure.17,18 Given the relatively poor results of chemotherapy in older individuals, some groups recommend allogeneic SCT in CR1 for adults with human leukocyte antigen (HLA)-matched sibling donors.2 When SCT is employed in the treatment of ALL, the conditioning regimen typically utilizes total body irradiation (TBI), which has been shown to decrease the relapse risk. 18
Risk-group assignment for B-precursor ALL: Although there is protocol-specific variability in the approach to risk-adapted therapy, in general, age, white blood cell (WBC) count, CNS involvement, DNA index, and phenotype are used for the initial risk-group assignment (Table 12.5).1,2,5,9 Subsequently, the risk group may be elevated based on cytogenetics and response to therapy, the latter of which is defined by morphologic blast reduction (in peripheral blood on day 7 or bone marrow on day 7 or 14) and further quantified by minimal residual disease determination (MRD) by flow cytometry or polymerase chain reaction amplification.1,2,9 Recent studies have demonstrated the prognostic value of MRD determination at various treatment phases for adults and children with ALL. 19,20
Infant ALL: Children younger than 1 year at diagnosis should be treated on age-specific protocols with certain agents dosed by weight to decrease the risk of severe toxicity.
T-ALL: Patients with T-cell phenotype are treated similarly to higher risk group pre-B ALL. Improved outcome has been associated with the use of intensified therapy that commonly includes high-dose methotrexate and intensified l-asparaginase. 21,22
Mature B-ALL: Patients with mature B-cell phenotype ALL should be treated with Burkitt lymphoma regimens and should include the anti-CD20 monoclonal antibody rituximab.23
CNS-directed therapy: All patients require CNS sterilization. Intensive intrathecal chemotherapy in combination with systemic agents that have good CNS penetration, most notably dexamethasone and high-dose methotrexate, are highly effective (Table 12.7). To minimize neurotoxicity, radiation is usually reserved for those with active meningeal leukemia or at very high risk of CNS relapse (Table 12.8). 24
Testicular leukemia: Males with testicular involvement have historically received radiation to both testes, although recent studies suggest that radiation might be spared when testicular involvement resolves completely during initial induction.25
DOSE MODIFICATION
Improved outcome is associated with greater drug exposure, and every attempt should be made to administer protocol-specified doses unless toxicity precludes their delivery. Importantly, 6-mercaptopurine (6-MP) and methotrexate dosing should be increased during maintenance to achieve a targeted degree of myelosuppression (Table 12.6). In the event of significant chemotherapy-related toxicity, individual agents should be dose-reduced or discontinued as clinically indicated. Specific agents may require dose adjustment for renal or hepatic dysfunction. Patients with thiopurine S-methyltransferase deficiency (approximately 1:300 incidence) require significant dose reductions of 6-MP to avoid severe toxicity. Individuals with Down syndrome tolerate methotrexate poorly and require elimination or dose reduction of that agent.
EXTRAMEDULLARY LEUKEMIA
Current chemotherapy regimens are associated with low rates of extramedullary relapse in both the CNS and testes. Importantly, patients with isolated extramedullary relapse also require systemic therapy. Radiation is currently reserved primarily to treat overt CNS leukemia (Table 12.8).
NEW TREATMENT APPROACHES
Molecularly targeted agents have been applied to the treatment of ALL with improved outcomes. For example, the BCR/ABL tyrosine kinase inhibitors, imatinib mesylate (Gleevec), dasatinib, and nilotinib have been successfully utilized in combination with chemotherapy to improve results in Philadelphia chromosome-positive ALL.26,27 Monoclonal antibody-based therapies that target differentiation antigens expressed on the surface of lymphoblasts (e.g., CD19, CD20, CD22, CD52) have also shown promise in the setting of ALL.8,23,28,29
MANAGEMENT OF RELAPSE
The chance of cure decreases substantially after relapse. Attaining a second remission is critical and often times can be achieved with standard four- or five-drug reinduction regimens (Table 12.6).30 The likelihood of prolonged DFS with standard regimens varies based in large part on the duration of the initial complete remission and the site of relapse. For those with bone marrow relapse and CR1 durations of more than 18–36 months, approximately 35% will achieve prolonged DFS with intensive re-treatment. Outcome is guarded with shorter CR1 durations, multiple relapses, or induction failure.30 Curative salvage using standard chemotherapy and radiation is more likely in the setting of isolated extramedullary relapse.31,32
Allogeneic Stem Cell Transplantation
For patients with HLA-matched sibling donors, allogeneic SCT in second CR is standard care.16-18 The risks of transplant-related morbidity and mortality are increased with alternative donors (unrelated and HLA-mismatched related), with such transplants being consequently commonly reserved for short CR1 durations or subsequent relapses.
SUPPORTIVE CARE
Aggressive monitoring and supportive care are essential throughout all phases of treatment.
Antiemetics
Nausea and vomiting, common during induction, consolidation, intensification, and CNS-directed therapy, are managed with routine antiemetic prophylaxis and treatment.
Tumor Lysis Syndrome
Rapid blast lysis can result in life-threatening metabolic complications. Tumor lysis syndrome is usually seen within the first few hours to days of initiation of induction chemotherapy. Patients with WBC higher than 100,000/μL, elevated serum lactate dehydrogenase (LDH), and/or elevated uric acid are at increased risk and those with mature B-cell ALL (L3 or Burkitt-type) are at extreme risk. Tumor lysis precautions should be started as soon as possible after diagnosis and at least 6 to 12 hours prior to the start of induction. Prophylaxis and monitoring should continue until disease burden is reduced, peripheral blasts are clear, and it is apparent that no tumor lysis has developed, usually for 3 to 7 days. The following measures are indicated for all patients around initial induction33:
Allopurinol: 100 mg/m2 per dose orally, three times daily. Urate oxidase (rasburicase) is an alternative for management of extreme hyperuricemia, especially in the setting of renal insufficiency. Rasburicase can cause severe hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and thus should be avoided in such patients.
Hydration: Intravenous fluids at a rate of at least twice the maintenance requirements (120 mL/m2/ hour) should be titrated to maintain a urine specific gravity of 1.010 or less and normal urine output. Because of the risk of hyperkalemia, potassium should be avoided.
Frequent serial laboratory monitoring is required during initiation of induction chemotherapy. Complete blood count (CBC), potassium, phosphorous, calcium, creatinine, blood–urea nitrogen (BUN), and uric acid should be assayed every 4 to 6 hours for the first 24 to 48 hours, then less frequently once stable.
Transfusions
Blood transfusion should be used to prevent complications related to severe cytopenias. To decrease the risk of transfusion-associated complications, specialized products should be used.
Platelets: To prevent bleeding, platelet counts should routinely be maintained above 10,000/μL. Higher levels are recommended for management of bleeding, prior to invasive procedures such as lumbar puncture, and to reduce the risk of CNS hemorrhage related to leukostasis in the setting of hyperleukocytosis. Single donor platelets are recommended whenever possible to decrease donor exposure and the risk of HLA-alloimmunization.
Red blood cells (RBCs): Concomitant anemia partially offsets the hyperviscosity associated with severe hyperleukocytosis. Thus, RBC transfusion should be avoided if possible when the WBC is higher than 100,000/μL. If transfusion is necessary, the hemoglobin and hematocrit should be increased slowly using small aliquots of packed RBCs until the peripheral blast count is reduced.
Irradiation: To reduce the risk of transfusion-associated graft-versus-host disease, all cellular blood products should be irradiated.
Leukodepletion: Platelets and red cells should be leuko-reduced to decrease the risk of febrile reactions, HLA-alloimmunization with subsequent platelet-refractoriness, and transmission of cytomegalovirus (CMV) infection.
Infection Prophylaxis
Aggressive surveillance, prophylaxis, and treatment for bacterial, fungal, viral, and opportunistic infections are essential to prevent morbidity and mortality.
Pneumocystis jiroveci pneumonia (PCP): Patients should receive PCP prophylaxis with trimethoprim/ sulfamethoxazole continuing until 6 months after chemotherapy is completed.
Neutropenic fever: Patients with an absolute neutrophil count (ANC) less than 500/μL and temperature 38.3°C or higher should be evaluated for possible infection and treated empirically with parenterally administered broad-spectrum antibiotics. Antifungal therapy should be initiated for neutropenic fever that persists for 5 to 7 days. Antibiotics should be continued until the ANC rises to above 500/μL, fever resolves, cultures are negative, and any suspected infection is fully treated.
Intravenous immunoglobulin (IVIG): Hypogammaglobulinemia is common during treatment for ALL. Immunoglobulin G (IgG) levels should be assayed for those with recurrent infections, and if low, IVIG supplementation should be considered (approximately 500 mg/kg every 4 weeks as needed to maintain an IgG level of 500 mg/dL).
Myeloid growth factors: Granulocyte colony-stimulating factor (G-CSF) during induction has been shown to improve outcome for adults, but no benefit was demonstrated in a pediatric study. Myeloid growth factor support should be employed during treatment of mature B-cell ALL (Burkitt or L3) in both children and adults.
Chemotherapy Prophylaxis
Agent-specific prophylaxis should be utilized as clinically indicated. For example, gastritis prophylaxis is recommended during corticosteroid administration. Leucovorin rescue is indicated to prevent severe toxicity after high-dose methotrexate. To reduce the risk of conjunctivitis associated with high-dose Ara-C, corticosteroid ophthalmic solution should be administered during and for 24 to 48 hours after treatment. Mesna should be used in an attempt to prevent hemorrhagic cystitis associated with high-dose ifosfamide and cyclophosphamide.
Nutritional Support
Nutritional status should be monitored and supplementation provided as indicated. Routine folic acid use should be avoided with methotrexate administration because it may counteract the therapeutic efficacy of folate antagonism.
Psychosocial Support
Multidisciplinary support for the patient and family is an important part of successful treatment.
EVALUATIONS
Serial evaluations to monitor for response, relapse, complications, and therapy-associated toxicity should be conducted throughout all treatment phases.
Evaluations during Treatment
History, physical examination, and routine laboratory assessments including CBC and chemistry panel should be performed regularly throughout treatment.
Bone marrow aspiration should be obtained at the following times:
Induction day 7 or 14 to assess early response.
Induction day 28 to assess remission status. If indeterminate, repeat every 1 to 2 weeks until recovery in order to confirm remission or induction failure.
End of therapy.
Suspected relapse.
Flow cytometry, cytogenetics, and/or molecular genetic studies can be used to monitor minimal residual disease, which is prognostic.
CSF cell count and cytology should be performed at the time of all intrathecal chemotherapy administrations. Lumbar puncture should also be performed if CNS relapse is suspected.
Evaluations after Treatment
Follow-up evaluations to include history, physical examination, and routine laboratory studies (CBC, chemistry panel) should be conducted to monitor for toxicity and recurrent disease until at least 5 years after completion of treatment on the following schedule (or as clinically indicated):
Every 1 to 2 months during the first year.
Every 2 to 3 months during the second year.
Every 3 to 4 months during the third year.
Every 6 months during the fourth year.
Yearly thereafter.
Late Effects
Life-long follow-up to monitor for a variety of possible late complications of treatment is recommended.34 The following are among the most frequent late effects:
Cardiomyopathy: To decrease the risk of cardiotoxicity, cumulative anthracycline doses are usually limited to less than 400 mg/m2. Echocardiograms for left ventricular function determination should be performed at baseline, at completion of treatment, every 1 to 2 years after treatment until serial studies remain normal, and as clinically indicated.
Neurologic toxicity: Children are at especially high risk of neurotoxicity from chemotherapy and radiation. All patients should be monitored for neurologic toxicity including neurodevelopmental dysfunction.
Endocrinologic dysfunction: Patients should be monitored for endocrinopathies including growth retardation, hypothyroidism, and infertility.
Osteonecrosis: Corticosteroids, especially dexamethasone, are associated with a high incidence of osteonecrosis.
Secondary malignancy: Patients should be monitored for secondary malignancies because these continue to develop even in the second decade after treatment.
References