Acute Lymphoblastic Leukemia
KeywordsAcute Lymphoblastic Leukemia Hematopoietic Stem Cell Transplantation Minimal Residual Disease Remission Induction Prophylactic Cranial Irradiation
Acute lymphoblastic leukemia (ALL) is a malignant disease that arises from several cooperative genetic mutations in a single B- or T-lymphoid progenitor, leading to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Although cases can be subclassified further according to the multiple stages of T- or B-cell maturation, these distinctions are not therapeutically useful.
ALL accounts for about 12 % of all childhood and adult leukemias diagnosed in developed countries and for 60 % of those diagnosed in persons younger than 20 years. It is the most common cancer in children (25 % of all cases) and has a peak incidence in patients between the ages of 2 and 5 years, with a second, smaller peak in the elderly.
The factors predisposing children and adults to ALL remain largely unknown. Children with certain constitutional genetic abnormalities (e.g., trisomy 21) are at increased risk of developing ALL and inherited mutations in TP53, PAX5 and ETV6 have also been described recently in familial (as well as sporadic) ALL. However, disease susceptibility for most patients is mainly influenced by common genetic variants (with eight risk loci discovered thus far) identified by genome-wide association studies (GWAS). A recent study identified germline mutations in 4.4 % of children and adolescents with ALL, a finding not only improve our understanding of leukemogenesis but also has major implications in direct patient care and genetic counseling of patients and families. Ionizing radiation and mutagenic chemicals have been implicated in some cases of ALL, but their contributions appear negligible.
ALL is essentially a disease of acquired genetic abnormalities which can be found in leukemic cells in all cases of ALL, including chromosomal translocations, DNA copy number gains or losses, and epigenetic changes. On average, each case has 10–20 nonsilent coding mutations. Chromosomal translocations often activate transcription factor genes, which in many cases control cell differentiation, are developmentally regulated, and frequently encode proteins at the tops of critical transcriptional cascades. These “master” oncogenic transcription factors, which can exert either positive or negative control over downstream responder genes, are aberrantly expressed in leukemic cells as a single gene product or as a unique fusion protein combining elements from two different transcription factors. Activating mutations of NOTCH1, a gene encoding a transmembrane receptor that regulates normal T-cell development, and mutations of PAX5, a gene essential for B-lineage commitment and maintenance, have been identified to be the most frequent cooperative mutations in T-cell and B-cell ALL, respectively. Genome-wide studies including second-generation sequencing (exome, transcriptome, and whole-genome sequencing) have resulted in the revision of genetic classification of ALL by identifying new subtypes, defined the constellations of structural genetic alterations and sequencing mutations that characterize each subtype, and identified genetic targets for therapy.
Fatigue and lethargy
Dyspnea, angina, and dizziness (older patients mainly)
Limp, bone pain, or refusal to walk (young children)
Pallor and bleeding in the skin or mouth cavity
Enlarged liver, spleen, and lymph nodes (more pronounced in children)
Anemia, low neutrophil count, and low platelet count
Metabolic abnormalities (e.g., high serum uric acid and phosphorus levels)
BCR-ABL1 fusion gene due to the t(9;22), or Philadelphia chromosome – 25 % of adult cases and 3–4 % of childhood cases (improved outcome with tyrosine kinase inhibitor treatment)
ETV6-RUNX1 (also known as TEL-AML1) fusion gene due to a cryptic t(12;21) – 22 % of childhood cases (favorable prognosis)
Hyperdiploidy (more than 50 chromosomes per cell) – 25 % of childhood cases (favorable prognosis)
Hypodiploidy (fewer than 45 chromosomes per cell) – 2 % of childhood cases and 2 % of adult cases (unfavorable prognosis)
Contemporary risk-directed treatment can cure up to 90 % of children and up to 50 % of adults with ALL. Cases are generally classified as standard or high risk in adults and as low, standard, and high risk in children. Factors used to determine the relapse hazard include the presenting leukocyte count, age at diagnosis, gender, immunophenotype, karyotype, molecular genetic abnormalities, initial response to therapy, and the amount of “minimal residual leukemia” upon achieving a complete remission. The level of minimal residual during remission induction and consolidation therapy is the most important prognostic indicator because it accounts for the collective effect of leukemic cell genetics, micro-environment, host factors, and chemotherapy potency.
Multidrug remission induction regimens almost always include a glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and at least a third agent (l-asparaginase or anthracycline), administered for 4–6 weeks. Some treatments rely on additional agents to increase the level of cell kill, thereby reducing the likelihood of the development of drug resistance and subsequent relapse. However, several studies suggest that intensive remission induction therapy may not be necessary for low or standard-risk patients, provided that they receive postinduction intensification therapy. Remission induction rates now range from 98 % to 99 % in children and from 80 % to 95 % in adults. Complete clinical remission is traditionally defined as restoration of normal blood cell formation with a blast cell fraction of less than 5 % by light microscopic examination of the bone marrow. With this definition, some patients in complete remission may harbor as many as 1 × 1010 leukemic cells in their body. With sensitive and specific methods developed to measure minimal residual disease, it is now recognized that most patients actually have less than 0.01 % of residual leukemia after 4–6 weeks of remission induction therapy, and they have excellent treatment outcome. By contrast, patients with 1 % or more leukemic cells after remission induction treatment have a poor prognosis and may be candidates for hematopoietic stem cell transplantation. To improve treatment outcome, most protocols specify an intensification (or consolidation) phase in which several effective antileukemic drugs are administered in high doses soon after the patients attain a complete remission. Reinduction treatment, essentially a repetition of the initial induction therapy administered during the first few months of remission, has become an integral component of successful ALL treatment protocol.
Regardless of the intensity of induction, consolidation, or reinduction therapy, all children require 2–2½ years of continuation treatment, usually methotrexate and mercaptopurine, with pulses of vincristine and dexamethasone for low-risk cases, and multiagent intensive chemotherapy for standard- and high-risk cases. The need for continuation therapy in adults is less clear, although in most cases it is discontinued after 2–2½ years of complete remission. The central nervous system can be a sanctuary site for leukemic cells, requiring intensive, intrathecally administered chemotherapy that begins early during the remission induction phase, extending through the consolidation phase and into the continuation phase. Once considered standard treatment, prophylactic cranial irradiation can be safely omitted in contemporary protocols featuring effective systemic and intrathecal chemotherapy. However, some protocols still use this treatment modality in up to 10 % of patients who are at very high risk of relapse in the central nervous system.
For selected high-risk cases, such as patients who require extended therapy to attain initial complete remission or those with high level or persistence of minimal residual disease after remission induction, hematopoietic stem cell transplantation is currently the treatment of choice. In light of the development of new therapeutics, the indications for transplantation should be continuously evaluated. For example, therapy with ABL1 tyrosine kinase inhibitors (imatinib mesylate, dasatinib, nilotinib or ponatinib) has improved the duration of remission of patients with Philadelphia chromosome-positive ALL, and those with Philadelphia chromosome-like ALL and “ABL-class” kinase alterations, and reduced the need of transplantation for a substantial proportion of these patients. The recent development of chimeric antigen receptor-modified autologous or allogeneic T cells promises to provide a new treatment option. Finally, the optimal clinical management of patients with ALL requires careful attention to methods for the prevention or treatment of metabolic and infectious complications, which may otherwise be fatal.
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