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Definition, Etiology, Pathogenesis Top
Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) are malignancies originating from B-lymphocyte or T-lymphocyte precursor cells (lymphoblasts). The lymphoblasts are present mainly in bone marrow and peripheral blood (B-cell ALL, T-cell ALL) or less frequently in lymph nodes and extranodal sites (B-cell LBL, T-cell LBL). In children <15 years ALL/LBL constitute ~25% of all malignancies and ~75% of all leukemias. In adults they usually develop before 30 years of age and account for ~20% of acute leukemias.
The 2016 World Health Organization (WHO) classification is based on cell origin and biology. In B-cell and T-cell subtypes genetically and molecularly distinct clinical entities are defined, while other types are jointly classified as “ALL/LBL, not otherwise specified.” Burkitt-type ALL is a leukemic manifestation of Burkitt lymphoma, which is currently classified as a mature B-cell malignancy.
The immunophenotypic classification is of key importance for clinical practice. It includes:
1) B-cell ALL: Pro-B (pre-pre-B) ALL, common ALL (CD10+, the most frequent type), pre-B ALL.
2) T-cell ALL: Pro-T and pre-T ALL (CD1a–, cyCD3+), cortical ALL (CD1a+, relatively good prognosis), medullary T-cell ALL (CD1a–, sCD3+).
Clinical Features And Natural History Top
1. Signs and symptoms are similar to acute myeloid leukemia but lymphadenopathy, splenomegaly, or both are observed in as many as 50% of patients, and manifestations of the involvement of erythropoietic and megakaryopoietic lineages are less severe. Twenty five percent of patients develop bone and joint pain. ALL can present as an oncologic emergency, such as febrile neutropenia, tumor lysis syndrome, or leukostasis. Central nervous system (CNS) involvement is relatively more common than in AML and ranges from 3% in B-cell ALL to 8% in T-cell ALL. In patients with T-cell ALL mediastinal lymph node enlargement as well as high white blood cell (WBC) counts are frequent.
2. Natural history: In patients with early disease the abnormalities may be limited to the complete blood count (CBC). Patients with advanced disease present with bleeding, infection, or with signs of CNS, mediastinal, and other organ involvement, which untreated lead to death within a few weeks.
1. CBC: Leukopenia may be observed in patients with certain subtypes of ALL (particularly in early disease); leukocytosis (very high and rapidly increasing in patients with T-cell ALL subtypes). In ~25% of patients with pro-B ALL, WBC counts are >100,000 cells/microL. Anemia, neutropenia, and thrombocytopenia are usually seen. Lymphoblasts may be seen in peripheral blood. Eosinophilia may be also present (in T-cell ALL).
2. Biochemical tests to assess renal function or evidence of tumor lysis (uric acid, phosphate, potassium) in addition to coagulation tests.
3. Bone marrow examination: Bone marrow aspiration with microscopic examination and immunophenotyping.
4. Immunophenotyping using flow cytometry (peripheral blood or bone marrow) is the basis for confirming the diagnosis and the immunophenotypic classification, which facilitates the assessment of prognosis as well as identification of the abnormalities that are used in monitoring minimal residual disease (MRD) during treatment.
5. Cytogenetic and molecular studies: In the majority of patients with ALL, lymphoblasts have an abnormal karyotype, including abnormalities in the chromosome numbers and structure. Translocation t(9;22), also termed the Philadelphia (Ph) chromosome, is found in 20% to 30% of all ALL cases, more frequently in patients with common ALL and in elderly patients (up to 50%), and is associated with the highest risk. Quantitative molecular studies (real-time quantitative polymerase chain reaction) are also used for MRD monitoring (eg, identification of the BCR-ABL1 fusion gene in patients with Ph+ ALL). A number of other genetic abnormalities, beyond the scope of this text, are recognized and tested for in specialized settings to determine prognosis and optimal treatment.
6. Imaging studies: In ~50% of patients with T-cell ALL subtypes, upper mediastinal mass caused by involvement of the thymus and mediastinal lymph nodes is seen. Imaging is useful in assessing the size of the lymph nodes and spleen. A biopsy from extramedullary disease can be obtained for diagnostic purposes.
7. Lumbar puncture: In the case of CNS involvement lumbar puncture may reveal increased cerebrospinal fluid (CSF) cell counts with blasts detected by cytologic examination.
Bone marrow microscopy and immunophenotyping are essential for diagnosis. The presence of lymphoblasts must be documented and ≥2 B-cell or T-cell markers must be found to confirm the diagnosis. In ~20% of patients, features of LBL are predominant, with infiltrates affecting mainly lymph nodes and <20% to 25% blasts in bone marrow; in such cases examination of a lymph node may be necessary.
Poorly differentiated AML; infectious mononucleosis; other viral infections, particularly causing lymphocytosis, thrombocytopenia, or hemolytic anemia; other conditions causing pancytopenia; non-Hodgkin lymphomas.
Choice of therapy based on patient-related and disease-related factors helps in management decisions. Older patients with comorbidities do not receive the same chemotherapy medications as younger patients with good performance status. In patients with Philadelphia chromosome the use of tyrosine kinase inhibitors (TKIs) is indicated.
1. Initial treatment is aimed at decreasing leukemic cell burden to reduce the risk of tumor lysis syndrome; this may involve the use of prednisone or dexamethasone. Prophylaxis of tumor lysis syndrome should be provided to all patients initiating therapy (see Tumor Lysis Syndrome). This includes IV fluids and allopurinol, a xanthine oxidase enzyme inhibitor that is considered to be one of the most effective drugs used to decrease urate levels. In patients with high disease burden and increased urate levels, rasburicase, a recombinant urate oxidase enzyme that catalyzes uric acid and helps its elimination, may be used.
2. Remission induction is aimed at removing tumor burden; this includes 3-drug to 4-drug combination chemotherapy regimens (eg, vincristine, an anthracycline, glucocorticoids [prednisone or dexamethasone], and pegylated asparaginase; usually for 4 weeks). Assessment for response to therapy at the end of induction determines if further combination chemotherapy is required for refractory or measurable disease.
3. Remission consolidation is aimed at removing MRD; this includes sequential cycles of high-dose or intermediate-dose antineoplastic agents. These usually include vinca alkaloids, glucocorticoids, thiopurines, and asparaginase.
4. Postconsolidation treatment:
1) In standard-risk patients and in patients who are not eligible for hematopoietic stem cell transplantation (HSCT), maintenance treatment is continued for 2 years, provided the MRD-negative status is maintained.
2) In high-risk patients (>80% of adult patients; see Prognosis, below), allogeneic HSCT from a human leukocyte antigen (HLA)-compatible sibling or an unrelated donor should be considered.
5. Treatment of Ph+ ALL: Chemotherapy combined with TKIs (imatinib, dasatinib) with the goal of allogeneic HSCT in patients who qualify for this therapy. Because genetic mutations such as T135I may infer resistance to TKI therapy, ponatinib would be the TKI of choice.
6. Prevention and treatment of CNS involvement: All patients receive intrathecal chemotherapy during induction for prophylaxis. Those with CNS disease receive therapeutic intrathecal chemotherapy doses as well as—depending on the risk profile, age, and comorbidities—CNS radiation.
7. Management of patients with no response to the first-line treatment or with relapses: New agents, drugs with no cross-resistance with the first-line agents, other drug combinations, HSCT (all decided in specialized settings only).
8. Supportive treatment as in acute myeloid leukemia.
2) Late complications: Obesity and metabolic syndrome, peripheral neuropathy, cardiotoxicity, neurocognitive deficits, and secondary malignant neoplasms.
1) Standard-risk group:
a) Age <35 years.
b) WBC <30,000 cells/microL in B-cell ALL or <100,000 cells/microL in T-cell ALL.
c) Immunophenotype: Common/pre-B ALL or cortical (CD1a+) T-cell ALL.
d) Complete remission (CR) achieved within <4 weeks.
2) High-risk group: All patients not included in points 1 and 3.
3) Very high-risk group: Karyotype t(9;22) (Ph+, BCR-ABL1+).
The importance of risk groups may change in the course of treatment. Apart from the above cytogenetic abnormalities, the most important adverse prognostic factor that is the basis for the classification of patients into standard-risk and high-risk groups is the MRD status monitored using cytogenetic or molecular studies at subsequent stages of treatment. CR is achieved in >90% of adult patients with ALL. Overall 5-year survival rates in adults: 54% in patients <30 years of age; 35% in patients 30 to 44 years of age; 24% in patients 45 to 60 years of age; and 13% in patients >60 years of age.
Patients with the Ph chromosome historically had a poor prognosis but the use of TKI (imatinib) has improved the rates of event-free survival in this group.