**3.2 Incidence and risk**

The incidence of ALL is estimated at 1.7 per 100,000 population in the United States [82] and 1.28 per 1 000,000 individuals in Europe [83] each year. ALL is the most frequent cancer in children, accounting for 30% of all cancers and 80% of leukemias, with peak incidence occurring at 2–5 years of age. The incidence decreases with age progression and rises back up with a second peak in patients above the age of 50 years, representing about 15% of leukemias [84]. ALL is more common in males than females. Survival rates were poor 50 years ago, when leukemia was considered to be an intractable disease. Currently, pediatric patients with ALL have dramatic cure rates with 80–90% achieving complete remission (CR) [85]. However, prognoses in the elderly remain miserable. Despite a high rate of response to induction chemotherapy, only 30–40% of adult patients with ALL will achieve long-term remission [86].

There are a few risk factors which can increase the possibility for ALL, such as exposure to high levels of radiation, industrial chemicals (such as benzene), pesticides [87], certain types of chemotherapy used to treat other cancers, certain types of viral infections (human T-cell lymphoma/leukemia virus-1 or Epstein-Barr virus) [88], inherited genetic syndromes (such as Down syndrome) [89], and being white and male.

#### **3.3 Symptoms and diagnosis**

Most clinical manifestations of ALL exhibit the accumulation of malignant, poorly differentiated lymphoid cells within the bone marrow, peripheral blood, and other tissues. Symptoms of ALL are generally nonspecific with a combination of constitutional symptoms and signs of bone marrow failure (anemia, thrombocytopenia, leukopenia). Common symptoms include "B symptoms"


**81**

*New Protein Markers of Chronic Lymphocytic and Acute Lymphocytic Leukemia*

(fever, weight loss, night sweats), easy bruising or bleeding, fatigue, dyspnea, and infections. Lymphadenopathy, splenomegaly, or hepatomegaly can be also present [90, 91]. CNS involvement at time of diagnosis occurs in 5–8% of patients and presents most commonly as cranial nerve deficits or meningismus [86]. Current standards for the diagnosis of ALL are based on the classification of lymphoid neoplasms according to the World Health Organization (WHO) 2008 criterion [92]. Diagnosis of ALL is established by the presence of 20% or more lymphoblasts in the bone marrow or peripheral blood [90]. Flow cytometry and cytogenetic testing are needed to confirm the diagnosis and provide risk stratification. Immunophenotyping by flow cytometry has become the standard procedure for ALL diagnosis and subclassification and was also developed as a useful tool for the detection and monitoring of minimal residual disease. In B-lineage ALL, the most important markers for diagnosis, differential diagnosis, and subclassification are CD19, CD10, CD20, CD22, CD24, and CD79a [93, 94]. For T-lineage, they are CD1a, CD2, CD3, CD4, CD5, CD7, and CD8 [95]. Cytogenetics and karyotyping are helpful in the identification of recurrent translocations, chromosomal abnormalities, and numerical alterations. Fluorescence in situ hybridization (FISH) is a useful technique for detecting and localizing the presence or absence of specific DNA sequences on chromosomes, with 99% sensitivity. Finally, array-comparative genomic hybridization (array-CGH, a-CGH) and single-nucleotide polymorphism (SNP) arrays can facilitate the identification of cryptic and/or submicroscopic changes in the genome [96, 97]. Lumbar puncture with CSF analysis is the current standard of care for the diagnosis of CNS involvement. If the CNS is involved, brain MRIs should be performed. Other possible evaluations include a complete blood count alongside cytologic analysis of target cells to evaluate other hematopoietic cell lines, coagulation profiles, and

ALL is a highly heterogeneous disease, and several clinical and biologic characteristics of ALL are used in risk stratification and prognostication. Disease characteristics (e.g., cytogenetics, molecular genetics, immunophenotypes) are substantially different between childhood, young adult, and adult ALL cases. Prognostic factors applied to ALL include age, white blood cell count (WBC), time to achieve a complete hematologic remission, minimal residual disease (MRD) persistence [98], and genetic aberrations. Older age and higher leukocyte count are associated with poor prognosis. Children older than 10 years with a

to the National Cancer Institute criteria (NCI-HR) [99]. ALL in young adults leads to poorer outcomes and exhibits high-risk genomic features (BCR-ABL1, BCR-ABL1-like, ETP-ALL [100], JAK mutation, CRLF2 alteration [101], iAMP21 [102], or DUX4 translocation [103]). The National Cancer Institute defined adolescent and young adults (AYA) to be those aged 15–39 years old. AYAs may benefit from pediatric-inspired regimens and are thus considered separate from adults >40 years [104]. Elderly patients tend to have a form of the disease characterized by intrinsically unfavorable biology (BCR-ABL1, BCR-ABL1-like, hypodiploidy, and complex karyotype), more medical comorbidities, and an inability to tolerate standard chemotherapies. They also experience a higher risk of relapse. As such, patients over the age of 60 have particularly poor outcomes, with only 10–15% surviving long term [105]. Response to chemotherapy is a strong prognostic indicator in ALL. Clearance of leukemic blasts in the early

are classified as high risk according

*DOI: http://dx.doi.org/10.5772/intechopen.85449*

serum chemistries [80].

**3.4 Prognostic factors**

leukocyte count exceeding 50,000/mm3

**Table 1.**

*Classification of ALL subtypes.*

#### *New Protein Markers of Chronic Lymphocytic and Acute Lymphocytic Leukemia DOI: http://dx.doi.org/10.5772/intechopen.85449*

(fever, weight loss, night sweats), easy bruising or bleeding, fatigue, dyspnea, and infections. Lymphadenopathy, splenomegaly, or hepatomegaly can be also present [90, 91]. CNS involvement at time of diagnosis occurs in 5–8% of patients and presents most commonly as cranial nerve deficits or meningismus [86]. Current standards for the diagnosis of ALL are based on the classification of lymphoid neoplasms according to the World Health Organization (WHO) 2008 criterion [92]. Diagnosis of ALL is established by the presence of 20% or more lymphoblasts in the bone marrow or peripheral blood [90]. Flow cytometry and cytogenetic testing are needed to confirm the diagnosis and provide risk stratification. Immunophenotyping by flow cytometry has become the standard procedure for ALL diagnosis and subclassification and was also developed as a useful tool for the detection and monitoring of minimal residual disease. In B-lineage ALL, the most important markers for diagnosis, differential diagnosis, and subclassification are CD19, CD10, CD20, CD22, CD24, and CD79a [93, 94]. For T-lineage, they are CD1a, CD2, CD3, CD4, CD5, CD7, and CD8 [95]. Cytogenetics and karyotyping are helpful in the identification of recurrent translocations, chromosomal abnormalities, and numerical alterations. Fluorescence in situ hybridization (FISH) is a useful technique for detecting and localizing the presence or absence of specific DNA sequences on chromosomes, with 99% sensitivity. Finally, array-comparative genomic hybridization (array-CGH, a-CGH) and single-nucleotide polymorphism (SNP) arrays can facilitate the identification of cryptic and/or submicroscopic changes in the genome [96, 97]. Lumbar puncture with CSF analysis is the current standard of care for the diagnosis of CNS involvement. If the CNS is involved, brain MRIs should be performed. Other possible evaluations include a complete blood count alongside cytologic analysis of target cells to evaluate other hematopoietic cell lines, coagulation profiles, and serum chemistries [80].
