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A. Characteristics navigator

  1. Also called acute lymphocytic leukemia (but leukemic cells are arrested at blast stage)
  2. Overall nearly 4000 new cases per year in USA
  3. Most common form of leukemia in children
    1. About 300 cases of childhood ALL annually in USA
    2. Majority are "common" type: pre-B cell ALL
    3. About 4% of ALL involves chromosome (chrom) translocation t(9;22)
    4. Translocation t(9;22) is the Philadelphia chrom and is found in 95% of CML
    5. Nearly 80% of children with typical ALL are cured with current therapy
    6. Only ~15-20% of children with ALL with t(9;22) are cured with current therapy [30]
  4. Adult ALL
    1. Account for ~30% of cases of ALL (~1000 new cases per year)
    2. ~20% of cases with Philadelphia chromosome t(9;22) bcr-abl fusion
    3. Prognosis generally poorer than in children
    4. Complete response to first line therapy in ~80%, but overall 5 year survival ~35%
  5. High propensity for central nervous system (CNS) involvement
  6. Standard treatment involves 2 years intensive chemotherapy including intrathecal agents

B. Pathogenesisnavigator

  1. No clear etiologic agent in 95% of cases
  2. Chronic exposure to high doses of electrical currents may increase risk of childhood leukemia [37]
  3. Can develop from any lymphoid precursor cell
    1. No standard cytoplasmic markers or specific morphologic features
    2. Immunophenotyping is required
    3. Molecular studies are often carried out to characterize ALL
    4. Screening of neonatal cord blood shows preleukemic clones with TEL-AML1 fusion genes in >1% of cases; this frequency is >100X higher than ALL incidence (see below0 [2]
  4. Ph+ ALL [2]
    1. ~20% of patients with ALL will have the Philadelphia Chromosome t(9;22)
    2. Typically FAB L2 morphology with CALLA+, CD34+ in adults (see below)
    3. Diagnosis may require PCR in up to 30% of these cases
    4. Ph+ patients produce an altered bcr-abl fusion protein (constitutive tyrosine kinase)
    5. Ph+ patients have worse remission duration and overall survival than negative patients
    6. However, appears to be sensitive to high dose Ara-C (HiDaC)
    7. More sensitive to imitinab (Gleevec®) and dasatinib (Sprycel®) therapies [48]
  5. Immunologic Subtypes: Null cell, T cell, B cell
  6. Null (Pre-B) Cell (70% of cases) [34]
    1. Most are Pre-B Cell (cytoplasmic Ig+), CD10+ (CALLA), CD19+, CD20-, CD45+
    2. About 25% of these ALL cases in children carry the TEL-AML1 fusion gene
    3. This fusion is due to chromosomal translocation t(12;21)(p13;q22)
    4. Carries a good prognosis
  7. T Cell Type (20-25%) [35]
    1. Previously considered poor prognosis but now >75% cures in children
    2. Multiple chromosomal abnormalities (see below)
    3. Typically CD7 and CD3 surface positive
    4. Smad-3 involved in TGFß signalling is lost in acute T-ALL [9]
    5. TGFß normally suppresses proliferation of T lymphocytes
    6. Smad-3 loss is synergistic with loss of p27kip1 (often alerted in ALL)
    7. >50% of cases of T cell ALL have activating mutations in NOTCH1
  8. B Cell ALL
    1. Uncommon, 5% of ALL cases
    2. Intermediate prognosis
    3. B Cell ALL are typically CD19 and CD79a surface positive
    4. Ph+ t(9;22) chrom variant poor prognosis (~20% 5 year survival, see below) [30]
    5. In Ph+ ALL, chromosome 9 c-abl translocates to minor breakpoint cluster region on 22
    6. The t(9;22) translocation in ALL usually produces a 190K fusion protein, whereas the protein is 210K in CML
    7. The t(9;22) translocation in the most common translocation in adult ALL
    8. Pre-B cell ALL with t(5;14) translocation often presents with eosinophilia [16]
  9. Some of the ALL will carry myeloid lineage specific markers such as CD13 or CD33
  10. Chromosome 11q23 Rearrangements [5,7]
    1. Site of mixed-lineage leukemia (MLL) gene
    2. Found in ~8% of children with ALL
    3. Part of t(4p21;11q23), t(11q23;19p13.3), t(9p21-22;11q23) rearrangements
    4. Leukemias with abnormal MLL also tend to express high levels of Flt-3
    5. Very poor outcome associated with these abnormalities
    6. Allogeneic stem cell transplantation does not appear to improve outcome
  11. About 5% of ALL associated with Genetic Syndromes
    1. Down's Syndrome
    2. Bloom's Syndrome
    3. Ataxia-telangiectasia
    4. Nijmegen breakage syndrome
  12. Small minority of ALL associated with exposure to chemotherapeutic drugs, ionizing radiation
  13. Most ALL cases do NOT arise from patients with chronic lymphocytic leukemia (CLL)

C. Diagnosis and Classification navigator

  1. Clinical Disease and Progression
    1. Disease typically manifests when 100 billion to 1 trillion leukemic cells are present [24]
    2. If untreated, death occurs with about 10 trillion leukemic cells
  2. Critical to assess the relapse risk (prognosis) in order to target intensive therapy appropriately
  3. Presentation
    1. Neutropenia - recurrent infections, particularly respiratory
    2. Anemia - malaise, fatigue, lethargy
    3. Thrombocytopenia - bleeding, purpura / petechiae
    4. Pathologic Fractures (such as vertebral compression fractures) [34]
    5. Age and lymphocyte count at presentation are most important prognostic indicators
  4. Hematologic Analysis
    1. Peripheral blood count and smear - blasts
    2. Bone Marrow and special stains
  5. French-American-British (FAB) Classifications
    1. L1 - 65%. Small Regular Blasts
    2. L2 - 30%. Slightly Larger Blasts
    3. L3 - 5%. Burkitt Type. Large Blasts, cytoplasm with vacuolization
  6. High Risk (Poor Prognosis) Patients [1]
    1. Age >10 years and espeically <12 months
    2. Leukocyte count >50K/µL higher risk; >100K/µL very high CNS relapse risk
    3. Patients >60 years old at diagnosis are at highest risk overall
    4. Hypodiploidy (<45 chromosomes)
    5. Translocation t(4;11) with MLL rearrangements (MLL-AF4)
    6. Ph+ ALL (more common in adults with ALL)
    7. T cell worse prognosis than B cell
    8. Evaluation of ALL for chemotherapy resistance genes is currently under investigation
    9. Gene expression (molecular) profiling of B-ALL can identify high relapse risk [3]
    10. In general, black children have higher risk prognostic factors than white children [4]
    11. However, when adjusted for equal care, black and white children have similar outcomes [1]
  7. Low Risk Patients
    1. Age 1 through 9 years
    2. Leukocyte (WBC) count <50K/µL
    3. Hyperdiploidy (>50 chromosomes)
    4. TEL-AML1 (ETV6-CBFA2) or E2A-PBX1 gene fusions
  8. Large Granular Lymphocytic Leukemia [31]
    1. Distinct types of T-cell related leukemia
    2. Derived from circulating large granular lymphocytes (LGL)
    3. LGL are either CD3+,TCR+,CD8+,CD57+ (T cell) or CD3-,TCR-,CD56+,CD57- (natural killer cell)
    4. CD3+ large granular leukemias have much better prognosis than CD3- forms
    5. Increased incidence in rheumatoid arthritis
  9. Patients with no detectable residual disease (detection by polymerase chain reaction) after initial [27] or relapse therapy [38] have best prognosis [1]
  10. Increasing use of gene arrays and gene testing for both prognosis and toxicity predictions

D. Treatment [33] navigator

  1. Requires Systemic and CNS Chemotherapy
    1. Remission - induction therapy is first given
    2. This is followed by instnsification (consolidation) therapy once normal hematopoiesis occurs
    3. Continuation therapy (long term maintenance) for 2 years is standard of care
    4. Complete remissions (CR) ~98% for children, ~85% for adults
    5. Hematologic remission (<5% lymphoblasts in bone marrow) achieved in >90% of cases
    6. However, ~75% of patients are "cured" of disease
    7. Residual leukemia detection with PCR after induction identifies high risk patients [22]
    8. Gene expression profiling has suggested resistance genes for standard chemotherapy [11]
    9. Patients with <1% residual blasts have very low risk of relapse (see below)
    10. Antiseizure medications that do not alter chemotherapy metabolism should be used [32]
    11. These include gabapentin (Neurontin®) or valproic acid
    12. Consider allogeneic stem cell transplantation in high risk patients such as Ph+ ALL [44]
  2. Standard Therapy [16,44]
    1. Treatment of ALL (except mature B cell type) for 2 years is required to reduce risk of relapse
    2. Induction: vincristine + prednisone + L-asparaginase + cyclophosphamide + daunorubicin
    3. Intrathecal treatment (methotrexate (MTX) ± cytarabine) required to prevent CNS relapse
    4. Intensification (consolidation) is given to eradicate residual ALL once normal hematopoiesis has been achieved (high dose MTX, mercaptopurine (6-MP) or high dose L-asparaginase)
    5. Residual disease is detected by PCR in ~40% of patients after induction therapy [22]
    6. Prophylaxis against CNS disease: systemic and intrathecal MTX along with 6-MP
    7. Cranial irradiation is generally reserved only for high risk disease, due to long term effects
    8. High dose methotrexate (5gm/m2) may improve outcome in T-ALL [1] or early B-ALL [44]
    9. Slow response defined as >25% blasts on bone marrow at day 7 of induction therapy
    10. Augmented therapy for patients with slow responses increases 5 year survival [21]
    11. ALL in <1 year olds has poor prognosis and likely benefits from intense, hybrid protocol [8]
  3. Post-Remission (Maintenance) Therapy
    1. After remission, patients receive maintenance therapy
    2. Usually includes MTX and 6-MP
    3. Adjusting MTX dose for individual clearance rates improves outcome of B-ALL [20]
    4. Children with very-high risk ALL in first CR benefit from allogeneic transplant compared with chemotherapy [45]
    5. Very high risk: failure to achieve CR after first four drug induction, gene t(9;22) or t(4;11), or T cell phenotype, or WBC >100x10e9/L after prednisone [45]
    6. 6-MP is strongly preferred over 6-thioguanine for maintenance therapy, with similar efficacy and much reduced side effects [13]
    7. Adding pulse vincristine + dexamethasone to MTX + 6-MP maintenance therapy does not improve relapse free or overall survival in intermediate risk pediatric ALL [18]
  4. Mature B-cell ALL
    1. Short-term intensive chemotherapy is given
    2. High dose MTX, cytarabine and cyclophosphamide
  5. Major Side Effects
    1. Vincristine - neuropathy
    2. Aspariginase (Elspar®) - anaphylactic reactions, pancreatitis, hypoproteinemia, bleeds
    3. Pegasparginase may be substituted for aspariginase if allergic reactions occur [42]
    4. Methotrexate - bone marrow suppression, mucositis, PML (JC Virus reactivation)
    5. Teniposide - bone marrow suppression
    6. G-CSF (Filgrastim®) in children with ALL reduced hospital stay and infections [17]
    7. G-CSF had no effect on mortality or rate of hospitalization for febrile neutropenia [17]
    8. Increased brain tumor risk in ALL patients treated with intrathecal chemotherapy (methotrexate) who have thiopurine methyltransferase (TPMT) mutations [29]
  6. Reduction of Toxicity
    1. Thiopurine methyltransferase (TPMT) metabolizes thiopurines and is a polymorphic gene
    2. TPMT heterozygotes with reduced enzyme activity have lower rates of minimal residual disease following early intense chemotherapy for ALL [12]
    3. Addition of dexrazoxane, a free-radical scavenger, can reduce anthracycline (daunorubicin or doxorubicin) induced cardiac damage without affecting anti-ALL therapy [10]
    4. Patients should receive prophylaxis for pneumocystis pneumonia (usually TMP/SMX)
    5. Cranial irradiation is only used for (very) high risk patients including T-ALL (especially with leukocyte counts >100K/µL) and leukemia in the CNS at diagnosis [1]
  7. Radiation
    1. Local and/or CNS irradiation in selected cases
    2. CNS radiation given to all patients with documented CNS involvement
    3. CNS radiation also given to high risk patients
    4. CNS radiation should be used sparingly as it increases risk of brain tumors [29]
  8. Monitoring for Recurrence
    1. Overall, disease recurs in ~25% of patients
    2. Polymerase chain reaction (PCR) detection of leukemia specific DNA is used [15,22]
    3. High level residual disease detected by PCR identifies high risk patients [22,24]
    4. Majority of patients, even with clinical complete remission, have residual tumor cells
    5. Remission durations >35 months have been found with residual leukemic cells
    6. Relatively high levels of leukemic cell DNA are found in persons with recurrent diesease
    7. These data show that "cures" do not require complete eradication of leukemic clones
    8. Patients with positive residual disease have a >40% risk of relapse at 3 years [24]
    9. Patients with negative residual disease have 3-15% risk of relapse at 3 years [24]
    10. These techniques are being used to select for earlier therapy of relapses
  9. Treatment of Recurrence
    1. Topoisomerase Inhibitors were original therapy
    2. Etoposide (VP-16, VePesid®) [43]
    3. Teniposide (VM-26, Vumon®) - approved for refractory ALL in children
    4. In children, intensive vincristine and prednisone is often used
    5. Intensive reinduction therapy only improves long term survival ~4% in children [23]
    6. In children with "slow response" to chemotherapy, augmented therapy provided 5 year survival of 78% versus 67% for standard chemotherapy [21]
    7. Clofarabine (Clolar®) is approved in ALL relapsed after at least 2 prior regimens
    8. Nelarabine approved for recurrent T-cell ALL (see below) [47]
  10. Second Remission ALL in Children
    1. Stem Cell Transplantation from HLA-identical siblings
    2. More effective than chemotherapy in inducing long term remissions
  11. Bone Marrow Transplantation (BMT) [25,30]
    1. Especially for adults with ALL, in atypical ALL, very high risk childhood ALL [45]
    2. Allogeneic transplants usually from HLA-identical siblings
    3. In children with acute leukemia, umbilical blood cell transplant with up to 2 HLA mismatches has similar 5 year outcomes to allogeneic transplant with less GVHD [49]
    4. Leukemia free survival rates similar for BMT versus chemotherapy groups
    5. Early death in BMT was higher than chemotherapy, but:
    6. Probability of relapse after BMT in 9 years was 30% versus 66% for chemotherapy
    7. Increasing dose of infused, T-cell depeleted donor cells increases engraftment [25]
    8. T cell depleted stem cells will engraft without GVHD even with HLA mismatch [25]
    9. HLA matched related donor BMT is recommended in patients atypical t(9;22) ALL [30]
    10. Mismatches at HLA-A and HLA-C, but not HLA-D associated with GVHD [26]
    11. Consider BMT with anergic (CD28 blocked) histoincompatible bone marrow [28]
    12. Note that this BMT preparative regimen is under development (not standard of care)
  12. Immunological Detection of Residual Leukemic cells [19]
    1. Rapid immunological assay of bone marrow aspirates in treated children
    2. Detection of residual cells correlated with genetic abnormalities (Ph and MLL genes)
    3. Immunologically detectable disease correlates with relapse
    4. Bone marrow aspiration should be evaluated immunologically at 3 months into therapy

E. Specific Agents for ALL Treatment navigator

  1. Imatinib (Gleevec®) [36,39]
    1. Tyrosine kinase inhibitor (STI571) specific for Bcr-Abl
    2. Active in chronic myeloid leukemia (CML) with Philadelphia (Ph+) chromosome
    3. Response rate in Ph+ ALL is ~60% with duration weeks to months
    4. Primarily resistant Ph+ ALL express high levels of Bruton's tyrosine kinase
    5. Gene expression profiles can be used to predict response to imatinib [39]
    6. Point mutations in the ATP binding domain or activation loop of Bcr-Abl protein lead to resistance [40]; mutated disease may respond to dasatinib [48]
  2. Dasatinib (Sprycel®) [48]
    1. Inhibits multiple tyrosine kinases including mutated bcr-abl resistant to imatinib
    2. Approved for Ph+ ALL resistant to or intolerant of imatinib
    3. Complete hematologic response in 31%, major cytogenetic response in 58% of imatinib resistant Ph+ ALL
    4. Diarrhea, nausea, vomiting and abdominal are most common
    5. Major thrombocytopenia and neutropenia more common than with imatinib
  3. Clofarabine (Clolar®, Evoltra®) [46]
    1. Purine nucleoside analog, antimetabolite
    2. Inhibits ribonucleotide reductase and acts as chain terminator
    3. Approved for acute lymphoblastic leukemia (ALL) relapsed after at least 2 prior therapies
    4. Given intravenously over 2 hours daily for 5 consecutive days
    5. Repeat every 2-6 weeks based on organ function, blood count recovery
    6. Bone marrow suppression is major problem, some liver function abnormalities

F. Prognosis [4,6,23]navigator

  1. Overall 5 year survival rate is 75-85%
  2. 5 year event free survival 70-80%
  3. About 2000 children become >5 year ALL survivors each year in USA
  4. A number of late treatment sequelae can occur even with >10 year survival
  5. Second Neoplasms Related to Radiation
    1. About 90% of second neoplasms are radiation related
    2. Risk of second neoplasm 21% at 20 years with ANY radiation therapy
    3. Risk of second neoplasm <1% with NO radiation therapy
    4. Brain tumors and encephalopathy associated with cranial radiation
    5. Radiation also increased overall risk of late death
  6. Overall Risk of Second Neoplasms [9]
    1. Cumulative overall second neoplasm risk 4% at 15 years and ~11% at 30 years
    2. About 35% of tumors are myeloid malignancies, 11% basal carcinomas, 15% meningiomas
    3. Acute myeloid leukemia (AML) complicates anthracycline and alkylating agent therapy
    4. Lifelong monitoring for recurrent tumors is required
  7. For non-irradiated patients, life expectancy similar to general population
  8. Other Late Effects of Therapy
    1. Cardiomyopathy associated with anthracyclines
    2. Osteonecrosis (bone death) associated with glucocorticoids, local irradiation
    3. Osteoporosis associated with cranial irradiation, glucocorticoids, high dose chemotherapy (HDC)
    4. Thyroid dysfunction common after cranial and neck irradiation, HDC
    5. Short stature associated with cranial irradiation, glucocorticoids, HDC

G. Adult T Cell Leukemia (ATL) [41] navigator

  1. Tumor is an acute leukemia-lymphoma of T lymphocytes
    1. Etiologically linked to human T lymphotropic virus I (HTLV-I)
    2. Occurs in <5% of persons with HTLV-1 infection
    3. HTLV-1 latency typically >30 years
    4. <2000 cases per year in USA
    5. Related to chronic leukemia due to T cells (T-CLL)
  2. Multilobulated malignant T lymphocytes
    1. Dense chromatin with HTLV-1 integrated into the genome
    2. These malignant T cells display 10,000-35,000 IL-2 receptor alpha chains
  3. Types of Disease
    1. Smoldering
    2. Chronic
    3. Acute Leukemia
    4. Lymphomatous
  4. Symptoms
    1. Lymphadenopathy
    2. Organomegaly
    3. Skin lesions - rapidly progressive in some cases
    4. Central Nervous System involvement
    5. Pulmonary disease
    6. Hypercalcemia: common; usually symptomatic
  5. Prognosis
    1. Smoldering and Chronic Forms: ~2 year median survival
    2. Acute and Lymphomatous Forms: ~5 month median survival; none long term
    3. Pre-T phenotype prognosis is worse than more mature phenotype
  6. Treatment
    1. Highly resistant to conventional chemotherapy
    2. Interferon alpha has shown some complete remissions (<10%) with some prolonged life
    3. Interferons beta and gamma have shown some mild benefits
    4. Nelarabine
  7. Nelarabine (Arranon®) [47]
    1. Prodrug of deoxyguanosine analog 9-ß-D-arabinofuranosylguanine (ara-G)
    2. FDA approved for T-ALL third line therapy (also for T cell lymphoblastic lymphoma)
    3. CR in 18% with 20.6 week median survival in adults
    4. CR in 23% with 13 week median survival in children
    5. Cytopenias, headache, somnolence, neurotoxicity can occur
    6. Neurotoxicity can be fatal is dose limited: paresthesia, ataxia, confusion, seizure, coma

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