**3.4 Prognostic factors**

*Advances in Hematologic Malignancies*

central nervous system at diagnosis [81] (**Table 1**).

ALL is a hematologic malignancy with uncontrolled proliferation of lymphoblasts of B- or T-cell origin. ALL cases are clinically classified as B-cell precursor (BCP), mature B-cell, or T-cell types. BCP-ALL arises in B lymphocytes in the early stages of development in the bone marrow and affects 75–80% of adult patients. Mature B-cell ALL arises in more mature developing lymphocytes. This type of ALL is less common and accounts for around 3–5% of all adult cases. In around 20–25% of cases, ALL arises in developing T cells. This type of ALL can be further classified as early, mid, or late, depending on the maturity of the affected cell. T-cell ALL is commonly presented with a high white blood cell count and involvement of the

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

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

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"

**ALL classification Subtypes Ref** B-ALL B-cell precursor ALL (75–80%) [81]

T-ALL Early T-cell precursor ALL (20%)

Mature B-cell ALL (3–5%)

Mid or late subtypes of T-ALL (5%)

**3.1 Classification**

**3.2 Incidence and risk**

long-term remission [86].

**3.3 Symptoms and diagnosis**

white and male.

**80**

**Table 1.**

*Classification of ALL subtypes.*

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 leukocyte count exceeding 50,000/mm3 are classified as high risk according 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

phase of treatment and the achievement of remission at the end of induction are predictors of relapse risk and have prognostic importance. Gender has also been recognized as a prognostic factor, with females having a better outcome than males overall.

#### *3.4.1 Cytogenetic/genetic risk*

Cytogenetic analyses have demonstrated that chromosomal aberrations (insertions, deletions, translocations, and inversions) and numerical alterations (hyperdiploid, pseudodiploid, and hypodiploid) are hallmarks of ALL [106]. The prevalence of genetic subtypes differs with age and is of prognostic relevance. Approximately half of pediatric leukemia cases involve aneuploidy (with changes in chromosome number), including high hyperdiploidy (50–67 chromosomes) or hypodiploidy (44 chromosomes or fewer) [107]. The chromosome most frequently gained in patients with high hyperdiploidy is 21 (>90% cases with trisomy or tetrasomy of chromosome 21) [108]. It is thought that the duplication of specific chromosomes contributes to leukemogenesis, making high hyperdiploidy a stronger prognostic factor than hypodiploidy. Hypodiploidy has been associated with dismal prognosis in all observed cases of ALL. Near-haploid (24–31 chromosomes) and low-hypodiploid (32–39 chromosomes) ALLs exhibit activation of Ras- and PI3Ksignaling pathways, suggesting that these pathways may be a target for therapy in aggressive hypodiploid ALLs [109]. Studies in the pediatric population have identified genetic syndromes that are connected to the predisposition in a minority of cases of ALL, such as Down syndrome, Fanconi anemia, Bloom syndrome, ataxia telangiectasia, and Nijmegen breakdown syndrome [89, 110, 111].

Characteristic translocations include erythroblast transformation-specific (ETS) variant 6–Runt-related transcription factor 1 (ETV6-RUNX1), the most common translocation (15–25% of pediatric ALL patients) caused by t(12;21)(p13;q22). The prognosis of ALL with ETV6-RUNX1 is excellent [112]. A second common translocation in pediatric ALL is transcription factor 3-PBX homeobox 1 (TCF3- PBX1), which is caused by t(1;19)(q23;p13) and is observed in 5–10% of ALL cases. Previously, patients with this translocation were considered to have poor prognosis, but a recently improved treatment has resulted in better outcomes [113]. A small percentage of ALL patients (3–5%) exhibit the reciprocal translocation t(9;22) (q34;q11), also referred to as the "Philadelphia (Ph) chromosome." The Ph chromosome is largely prominent in patients suffering from chronic myeloid leukemia (CML) and is molecularly characterized by the creation of a non-receptor tyrosine kinase gene (BCR-ABL1) via the fusion of RhoGEF and GTPase-activating protein (BCR) and ABL proto-oncogene 1 (ABL1) [114].

The prevalence of t(9;22) in adult ALL can range from 15 to 50% and increases with age [115]. Ph chromosome positivity has been widely considered to be a factor for poor prognosis. The development of tyrosine kinase inhibitors (TKI), which directly target BCR-ABL1, has shown to significantly improve the treatment strategy for Ph-ALL. Rearrangement of the mixed-lineage leukemia 1 gene (MML1), also known as KMT2A (lysine [K]-specific methyltransferase 2A), on chromosome 11q23 is found in a unique group of acute leukemias and predicts a very poor outcome [116].

More recently, a variant with a similar gene expression profile to Ph-positive ALL, but without the BCR-ABL1 rearrangement, has been identified. This so-called Ph-like ALL, or BCR-ABL1-like ALL, has been associated with poor response to induction chemotherapy, elevated minimal residual disease, and poor survival [117]. The prevalence of Ph-like ALL is common among all ages, ranging from 10 to 15% in children to over 25% in young adults [118]. Patients with Ph-like ALL

**83**

**Table 2.**

*Prognosis in B-ALL.*

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

associated with refractoriness to chemotherapy in adults [121].

The prognosis of the B-ALL subtypes is shown in **Table 2**.

*with 5-year overall survival of >90%, 70–90%, and <70%, respectively.*

harbor a diverse range of genetic alterations which activate cytokine receptor and kinase signaling pathways. Common genomic features of Ph-like ALL include alterations of B-lymphoid transcription factor genes (particularly IKZF1 deletions) as well as rearrangements and mutations of CRLF2, ABL-class tyrosine kinase genes, EPOR, JAK-STAT signaling, and RAS signaling (NRAS, KRAS, PTPN11, NF1) and other less common kinase alterations (FLT3, NTRK3, BLNK, TYK2, PTK2B) [119]. These mutated genes can be successfully targeted with tyrosine kinase inhibitors [117]. Another new high-risk subtype identified in diagnosis of ALL is B-ALL, which is characterized by intrachromosomal amplification of

Genome-wide profiling studies have revealed components of multiple cellular and signaling pathways that are frequently mutated in ALL (referred to as cooperative mutations). Deletions in key transcription factors involved in B-cell development include IKAROS family zinc finger 1 (IKZF1), transcription factor 3 (E2A), early B-cell factor 1 (EBF1), and paired box 5 (PAX5). Kinase-activating mutations include rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, as well as mutations involved in tumor suppression (CDKN2A/CDKN2B, PTEN, and RB1), RAS signaling (NRAS, KRAS, and PTPN11), transcriptional regulation (ETV6, ERG, TBL1XR1, and CREBBP), and epigenetic modification (CREBBP, EP300, SETD2, and NSD2) [117]. In all ALL subtypes, multiple cooperating mutations are acquired or enriched for during leukemia development and progression [120]. TP53 disruption has also been detected in relapsed B-ALL and T-ALL, as well as in newly diagnosed children and adult ALL cases. Correlation with poorer outcome has been illustrated and is

Next-generation sequencing (NGS), most notably transcriptome sequencing, has led to the identification of several novel rearrangements that are not made evident by conventional genetic analysis, including DUX4-rearranged [122], MEF2Drearranged [103], and ZNF384-rearranged B-ALL and ETV6-RUNX1-like B-ALL [123]. These new ALL subtypes have distinct clinical and biological characteristics.

**Molecular subtype Prognosis Frequency (%) References** Hyperdiploid Favorable 20–30 [107, 108] ETV6-RUNX1 Favorable 15–25 [112] TCF3-PBX1 Intermediate 5–10 [113] KMT2A rearranged Unfavorable 5 [116] BCR-ABL1 Unfavorable 5–50 [114, 115] BCR-ABL1 like Unfavorable 10–25 [118] Hypodiploid Unfavorable 3 [109] iAMP21 unfavorable 2 [102] DUX4 rearranged Favorable 4–5 [122] MEF2D rearranged Unfavorable 2–3 [103] ZNF384 rearranged Intermediate 2–3 [123] ETV6-RUNX1 like Intermediate 2–3 [123] *Favorable, intermediate, and unfavorable prognoses of acute lymphoblastic leukemia (ALL) subtypes are associated* 

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

chromosome 21 (iAMP21) [102].

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

harbor a diverse range of genetic alterations which activate cytokine receptor and kinase signaling pathways. Common genomic features of Ph-like ALL include alterations of B-lymphoid transcription factor genes (particularly IKZF1 deletions) as well as rearrangements and mutations of CRLF2, ABL-class tyrosine kinase genes, EPOR, JAK-STAT signaling, and RAS signaling (NRAS, KRAS, PTPN11, NF1) and other less common kinase alterations (FLT3, NTRK3, BLNK, TYK2, PTK2B) [119]. These mutated genes can be successfully targeted with tyrosine kinase inhibitors [117]. Another new high-risk subtype identified in diagnosis of ALL is B-ALL, which is characterized by intrachromosomal amplification of chromosome 21 (iAMP21) [102].

Genome-wide profiling studies have revealed components of multiple cellular and signaling pathways that are frequently mutated in ALL (referred to as cooperative mutations). Deletions in key transcription factors involved in B-cell development include IKAROS family zinc finger 1 (IKZF1), transcription factor 3 (E2A), early B-cell factor 1 (EBF1), and paired box 5 (PAX5). Kinase-activating mutations include rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, as well as mutations involved in tumor suppression (CDKN2A/CDKN2B, PTEN, and RB1), RAS signaling (NRAS, KRAS, and PTPN11), transcriptional regulation (ETV6, ERG, TBL1XR1, and CREBBP), and epigenetic modification (CREBBP, EP300, SETD2, and NSD2) [117]. In all ALL subtypes, multiple cooperating mutations are acquired or enriched for during leukemia development and progression [120]. TP53 disruption has also been detected in relapsed B-ALL and T-ALL, as well as in newly diagnosed children and adult ALL cases. Correlation with poorer outcome has been illustrated and is associated with refractoriness to chemotherapy in adults [121].

Next-generation sequencing (NGS), most notably transcriptome sequencing, has led to the identification of several novel rearrangements that are not made evident by conventional genetic analysis, including DUX4-rearranged [122], MEF2Drearranged [103], and ZNF384-rearranged B-ALL and ETV6-RUNX1-like B-ALL [123]. These new ALL subtypes have distinct clinical and biological characteristics. The prognosis of the B-ALL subtypes is shown in **Table 2**.


*Favorable, intermediate, and unfavorable prognoses of acute lymphoblastic leukemia (ALL) subtypes are associated with 5-year overall survival of >90%, 70–90%, and <70%, respectively.*
