**2. Diagnosis by flow cytometry**

There are a group of important cellular markers to make the diagnosis of B cell lineage, those are: CD19, CD20, CD22, CD24, and CD79a. The principal and earlier markers for lineage B cells are CD19, CD22 (membrane and cytoplasm respective) and CD79a [1, 2]. The presence of either of these two markers, without further differentiation markers, identifies the neoplastic cell as pro-B ALL (EGIL BI subtype). Positivity of the CD10 antigen (CALLA) defines the neoplastic cell as "common ALL" (EGIL B-II subtype). Cases with additional identification of the cytoplasmic heavy Mu chain are classified as the pre-B group (EGIL B-III subtype), while the presence of surface immunoglobulin light chains as mature B-ALL (EGIL B-IV subtype) [3].

The ontogenetic and immunocytogenetic correlation have particular importance due to prognostic relevance in both B-cell and T-cell lymphoid leukemia. **Table 2**

TCRαβ(+) o TCRγδ(+)

The karyotype alterations that could be found in ALL are numerical and structural changes as well, that have profound prognostic significance. Cytogenetics analysis represents an important step in ALL classification. The conventional karyotype can be useful in identifying recurring translocations, as well as in the identification of gain or loss of chromosomal material; However, the biggest limitation of this technique is the requirement of the cell to enter in metaphase, what is necessary for the obtaining of the material for the analysis of chromosomes. In such cases the technique of fluorescence in situ hybridization (FISH) can allow direct detection and visualization of virtually all investigated chromosomal abnormalities in ALL, with a sensitivity near of 99%, finally, comparative genomic hybridization of matrices (matrix-CGH, a-CGH) and matrices of single nucleotide polymorphisms(SNPs) can allow the identification of cryptic and/or submicroscopic

The aberrations with a good prognosis are: del(12p), t(12p) / t(12; 21) (p13; q22) t(10; 14) (q24; q11) in ALL of lineage B. These abnormalities are relatively rare in

Aberrations associated with intermediate risk include the normal diploid subset plus cases of hyperdiploidy and various other recurrent or random chromosomal

Other aberrations such as isolated trisomy 21, trisomy 8, and perhaps del(6q) and t(1; 19) (q23;p13) / E2A-PBX1 may constitute an intermediate-high risk group; Recent evidence suggests that the previously poor prognosis reported for t (1, 19)

(q23; p13) / E2A-PBX1 could be outweighed by some current therapeutic approaches [10, 11]. Other newly identified aberrations in the intermediate-high risk group are iAMP21 12 and IGH rearrangements, including CRLF2 [12, 13]. Finally, patients with t(9; 22) (q34; q11) or BCR-ABL1 rearrangement with positive FISH test (Philadelphia + ALL), t (4; 11) (q21; q23) or MLL rearrangements

shows the correlation between the different T cell-type leukemia.

Mature T CD3m(+), CD1a(-),

Intermedia or cortical T (T III)

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

**PRECURSOR ONTOGENICS INMUNOPHENOTYPE MOLECULAR/**

Pro T (T I) CD2(-), CD5(-), CD8(-), CD4

Early T CD5(+) d,CD8(-), CD1a(-), CD2(-), TdT(+) Pre T (T II) CD2(+) y/o CD5(+) y/o CD8

(-), TdT(++), CD34(+/-)

(+), CD1a(-), mCD3(-)

CD1a(+),CD34(-), CD4(+), CD8(+), CD3m(+)

**CYTOGENETIC**

*11-TCR*

NUP213 ABL1 HOX11

*NOTCH 1 t (10;14) HIX*

————————————

t (11;14) LMO/TCR

**3. Cytogenetic diagnosis**

*Immunogenetic classification of T cell.*

CD7(++), (CD3c(+), CD3m(-/+) débil

CD7(++), CD3c(+), CD3m(+)

**Table 2.**

changes in the genome [8, 9].

abnormalities.

**127**

**3.1 Cytogenetic/genetic risk groups**

adults compared to childhood with ALL.

In recent years, the direct correlation between ontogenetic classification with immunophenotypic expression by flow cytometry and cytogenetic or molecular alterations in type B acute lymphoblastic leukemia has been described (**Table 1**) [3–6].

T-cell ALL constitutes 25% of adult ALL cases. Characteristic T cell markers are CD1a, CD2, CD3 (membrane and cytoplasm), CD4, CD5, CD7, and CD8. CD2, CD5 and CD7 antigens are markers of immature T cells, but none of them is absolutely lineage-specific, so the unequivocal diagnosis of T-ALL is based on the demonstration of superficial / cytoplasmic CD3. In T-ALL CD10 expression is quite common (25%) but non-specific, CD34 andCD13 and / or CD33 myeloid antigens can also be expressed by these cells. The recognized T-ALL subgroups: pro-T EGIL TI (cCD3 +, CD7 +), pre-T EGIL T-II (cCD3 +, CD7 + and CD5 / CD2 +), cortical T EGIL T-III (cCD3 +, Cd1a +, sCD3 + / -) and mature-T EGIL T-IV (cCD3 +, sCD3 +, CD1a) [3–7].


#### **Table 1.**

*Immunogenetic classification of B ALL.*


*Acute Lymphoblastic Leukemia in Adolescents and Young Adults DOI: http://dx.doi.org/10.5772/intechopen.94886*

#### **Table 2.**

normal cellular production of leukocytes, platelets and red blood cells. As a result, when a patient is diagnosed with acute lymphoblastic leukemia, the number of healthy blood cells (red blood cells, white blood cells, and platelets) could be less than normal, although it is not uncommon to see an exaggerated elevation of white

It is more frequent in childhood than in adulthood, being the most common type of leukemia in children, with a peak of incidence between the 2 and 4 years old.

There are a group of important cellular markers to make the diagnosis of B cell lineage, those are: CD19, CD20, CD22, CD24, and CD79a. The principal and earlier markers for lineage B cells are CD19, CD22 (membrane and cytoplasm respective) and CD79a [1, 2]. The presence of either of these two markers, without further differentiation markers, identifies the neoplastic cell as pro-B ALL (EGIL BI subtype). Positivity of the CD10 antigen (CALLA) defines the neoplastic cell as "common ALL" (EGIL B-II subtype). Cases with additional identification of the cytoplasmic heavy Mu chain are classified as the pre-B group (EGIL B-III subtype), while the presence of surface immunoglobulin light chains as mature B-ALL (EGIL

In recent years, the direct correlation between ontogenetic classification with immunophenotypic expression by flow cytometry and cytogenetic or molecular alterations in type B acute lymphoblastic leukemia has been described (**Table 1**) [3–6]. T-cell ALL constitutes 25% of adult ALL cases. Characteristic T cell markers are CD1a, CD2, CD3 (membrane and cytoplasm), CD4, CD5, CD7, and CD8. CD2, CD5 and CD7 antigens are markers of immature T cells, but none of them is absolutely lineage-specific, so the unequivocal diagnosis of T-ALL is based on the demonstration of superficial / cytoplasmic CD3. In T-ALL CD10 expression is quite common (25%) but non-specific, CD34 andCD13 and / or CD33 myeloid antigens can also be expressed by these cells. The recognized T-ALL subgroups: pro-T EGIL TI (cCD3 +, CD7 +), pre-T EGIL T-II (cCD3 +, CD7 + and CD5 / CD2 +), cortical T EGIL T-III (cCD3 +, Cd1a +,

sCD3 + / -) and mature-T EGIL T-IV (cCD3 +, sCD3 +, CD1a) [3–7].

Pro B CD 10(-), CD 34 (++),

Common CD10 (+++), CD 34(+),

Pre B CD 10(+), CD34(-),

TdT ++

Mature CD20(+), TdT(-), CD10

λ(+)

**PRECURSORS ONTOGENICS INMUNOPHENOTYPE MOLECULAR CYTOGENETIC**

t(v;11q23.3), rearrangement MLL

t(9;22) (q34.1;q11.2)(BCR-ABL1), t(12;21)( p13.2;q22.1) (TEL-AML1/ ETV6-RUNX1); t(5;14)(q31.1;q32.3) (IL3-IGH); hiperdyploid, hipodyploid

t(5;14)(q31.1;q32.3) (IL3-IGH); hiperdyploid, hipodyploid

rearregment of MYC, t(8;14), t(2;8),

(KMT2A), t(4;11)

t(8;22)

CD 20(-), TdT(++)

CD20 (-/+), Cadena μ (-), TdT (++)

CD20(+), Cadena μ (+),

(+), CD34(-), k(+) o

blood cells but all of them lymphoblasts.

**2. Diagnosis by flow cytometry**

B-IV subtype) [3].

*Acute Leukemias*

CD 19 (+), CD 22 (+), CD79a(+), HLA-DR(+)

**Table 1.**

**126**

*Immunogenetic classification of B ALL.*

When it appears in adulthood, it implies a worse prognosis.

*Immunogenetic classification of T cell.*

The ontogenetic and immunocytogenetic correlation have particular importance due to prognostic relevance in both B-cell and T-cell lymphoid leukemia. **Table 2** shows the correlation between the different T cell-type leukemia.

#### **3. Cytogenetic diagnosis**

The karyotype alterations that could be found in ALL are numerical and structural changes as well, that have profound prognostic significance. Cytogenetics analysis represents an important step in ALL classification. The conventional karyotype can be useful in identifying recurring translocations, as well as in the identification of gain or loss of chromosomal material; However, the biggest limitation of this technique is the requirement of the cell to enter in metaphase, what is necessary for the obtaining of the material for the analysis of chromosomes. In such cases the technique of fluorescence in situ hybridization (FISH) can allow direct detection and visualization of virtually all investigated chromosomal abnormalities in ALL, with a sensitivity near of 99%, finally, comparative genomic hybridization of matrices (matrix-CGH, a-CGH) and matrices of single nucleotide polymorphisms(SNPs) can allow the identification of cryptic and/or submicroscopic changes in the genome [8, 9].

#### **3.1 Cytogenetic/genetic risk groups**

The aberrations with a good prognosis are: del(12p), t(12p) / t(12; 21) (p13; q22) t(10; 14) (q24; q11) in ALL of lineage B. These abnormalities are relatively rare in adults compared to childhood with ALL.

Aberrations associated with intermediate risk include the normal diploid subset plus cases of hyperdiploidy and various other recurrent or random chromosomal abnormalities.

Other aberrations such as isolated trisomy 21, trisomy 8, and perhaps del(6q) and t(1; 19) (q23;p13) / E2A-PBX1 may constitute an intermediate-high risk group; Recent evidence suggests that the previously poor prognosis reported for t (1, 19) (q23; p13) / E2A-PBX1 could be outweighed by some current therapeutic approaches [10, 11]. Other newly identified aberrations in the intermediate-high risk group are iAMP21 12 and IGH rearrangements, including CRLF2 [12, 13].

Finally, patients with t(9; 22) (q34; q11) or BCR-ABL1 rearrangement with positive FISH test (Philadelphia + ALL), t (4; 11) (q21; q23) or MLL rearrangements at 11q23, monosomy 7, hypodiploidy (and the closely related near triploid group) fell into the high-risk cytogenetic category, with a disease-free survival (DFS) rate of approximately 25%, or 10% in the specific case of Phi + ALL prior to introduction of tyrosine kinase inhibitors (TKI) [14, 15]. The presence of the Phi + chromosome in ALL can constitute 25–50% of CD10 + or pre-B cases and represent the most frequent alteration in adult and elderly patients, found in more than 50% of cases in the 6th decade of life [16]. Secondary chromosomal abnormalities in addition to t(9; 22) (q34; q11) may worsen the prognosis [17] however this has not yet been proven in the TKI era [18]. Currently the most group with the most unfavorable prognosis among cases with known genetic / molecular aberration is represented by t(4; 11) (q21; q23) with MLL1 rearrangement unless an allogeneic hematopoietic stem cell transplantation is performed [19].

Some other karyotypes alterations are exclusive to specific ALL syndromes. Translocations involving chromosome 8 (MYC gene), as well as t (8; 14) (q24; q32) (90% of cases), t (8; 22) (q24; q11) (10% of cases) and t (2;8) (rarely observed) are practically present in 100% of cases of mature B-ALL with L3 / Burkitt morphology and immunoglobulins in the clonal surface. Typical cytogenetic aberrations are also found in the T lineage, the most frequent involve resection points of 14q11, for example, t (10; 14) (q24; q11), t (11; 14) (p13; q11) and others, the presence of t (8; 14) with resection points at q24; q11 (q24; q32 in line B ALL) in T cell ALL is associated with aggressive lymphomatous presentation [20–22].

An interruption in IKZF1 encoding the Ikaros transcription factor has been frequently observed in ALL with BCR / ABL rearrangement (80% of cases). The IKZF1 mutation predicts poor outcome in the treatment of ALL, Phi+ or not [13, 23–25].

By integrating genome-wide technologies the "BCR / ABL-like" subgroup has been suggested and identified in adult and child populations [26, 27] and represents approximately 15% of ALL ontogeny B cases. This subgroup It is characterized by a gene expression that is similar to that of BCR/ABL + patients, with frequent detection of the IKZF1 mutation and CRLF2 rearrangements but with where abysmal differences in the outcomes. Other mutations and / or rearrangements that activate tyrosine kinases has also been revealed as poor prognosis factor such as rearrangement of IGH-CRLF2, NUP214-ABL1, EBD1-PDGRB, BCR-JAK2 fusions and STRN3 JAK2, which have been associated with a very poor prognosis [28].

A large set of mutations in T cell-line ALL has been identified by sequencing techniques including NOTCH1, FBW7, BCL11B, JAK1, PTPN2, IL7R and PHF6, some of them have recognized prognostic importance, while others require further investigation. In fact, NOTCH1 and / or FBW7 mutations that occur in more than 60% and around 20% of cases, respectively, are generally associated with a favorable outcome. A new prognostic model has been recently proposed defining as low risk those with NOTCH1 and FBW7 mutations and those with lesions involving RAS/PTEN as high-risk. JAK1 mutations, which increase JAK activity and impair

• Cases with trisomy 4,10 y 17 more favorable results

• Complex karyotype (5 o more abnormalities)

• Ph-like ALL intrachromosomal amplification 21(iAMP21)

• t(12;21) (p13;q22):ETV6-EUNX1<sup>a</sup>

• t(8;22)(q34;q11.2):BCR-ABL1

• KMT2A, t(4;11) • t(v;14q32)/IgH

**Cytogenetic alterations Gene Frequency in**

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

t(12,21) (p13;q22) ETV6-RUNX1

t(1;19) (q23;p13) TCF3-PBX1

t(10;14) (q24;q11) HOX11

t(11;14) (q11)(p13;q11) (p15;q11) TCR y

*Frequency of Chromosomic and molecular alterations by age group.*

**Risk Cytogenetic alterations**

Poor • Hypodiploidy

Good • Hypodiploidy (51-65 chromosomes)

t(9;22) (q34;q11):Philadelphia

chromosome(Ph+)

**Table 3.**

**Table 4.**

**129**

*Cytogenetic risk groups.*

Hypodiploidy (>50 chromosomes) – 7% 25% Hypodiploidy (<44 chromosomes) – 2% 15

t(v;11q23), t(4;11), t(11;19) KMT2A 10% 8%

t(5;14) (q31;q32) IL3-IGH < 15 <1% t(8;14), t(2;8), t(8;22) c-MYC 4% 2% t(1;14) TAL-1 12% 7%

t(5;14) (q35;q32) HOX11L2 1% 35

BCR-abl1-like/Ph-like Multiple 10-30% 15% LLA-B con iAMP21 RUNX11 – 2% ETP Multiple 2% 25% Ikaros IKZF1 25-35% 12-17%

(TEL-AML1)

(E2A-PBX1)

(TLX1)

TCR

**adults**

BCR-ABL1 25% 2-4%

2% 22%

3% 6%

8% 15

20-25% 10-20%

**Frequency in children**

Hypodiploid ALL, considered a high risk factor has been extensively evaluated in pediatric ALL [29] Alterations involving tyrosine kinase receptors and RAS gene signaling (i.e., NRAS, KRAS, FLT3, and NF1) can be detected in up to 70% of haploid cases, while hypodiploid cases are characterized by lesions involving members of the Ikaros family, particularly IKZF2 and by TP53 interruptions which can be identified in 91.2% of these. In adult ALL, these cases are characterized by nonrandom chromosome loss and CDKN2A / B with locus deletion as the only recurrent abnormality; As previously reported, in children these cases often harbor TP53 mutations [30].

The TP53 mutation is detected in 6.4% of all ALL cases and a correlation with a worse result has been demonstrated. In adults, TP53 mutations are identified at diagnosis in 8.2% of cases (11.1% of T-ALL and 6.4% of B-ALL), and are preferably identified without molecular aberrations and are associated with refractoriness to chemotherapy [31, 32].

In T cell-ALL, well-recognized aberrations are: Rearrangement of the T-cell receptor (TCR) gene, chromosomal deletions and focal gene deletions, in addition, chromosomal rearrangements can also lead to fusion genes in the framework of Chimeric proteins with oncogenic properties such as thePICALM-MLLT10, NUP214-ABL1 fusion for medin episomes, EML-ABL1, theSET-NUP214 fusion and MLL-type genetic rearrangements have uncertain significance [33, 34].


#### *Acute Lymphoblastic Leukemia in Adolescents and Young Adults DOI: http://dx.doi.org/10.5772/intechopen.94886*

#### **Table 3.**

at 11q23, monosomy 7, hypodiploidy (and the closely related near triploid group) fell into the high-risk cytogenetic category, with a disease-free survival (DFS) rate of approximately 25%, or 10% in the specific case of Phi + ALL prior to introduction of tyrosine kinase inhibitors (TKI) [14, 15]. The presence of the Phi + chromosome in ALL can constitute 25–50% of CD10 + or pre-B cases and represent the most frequent alteration in adult and elderly patients, found in more than 50% of cases in the 6th decade of life [16]. Secondary chromosomal abnormalities in addition to t(9; 22) (q34; q11) may worsen the prognosis [17] however this has not yet been proven in the TKI era [18]. Currently the most group with the most unfavorable prognosis among cases with known genetic / molecular aberration is represented by t(4; 11) (q21; q23) with MLL1 rearrangement unless an allogeneic hematopoietic stem cell

Some other karyotypes alterations are exclusive to specific ALL syndromes. Translocations involving chromosome 8 (MYC gene), as well as t (8; 14) (q24; q32) (90% of cases), t (8; 22) (q24; q11) (10% of cases) and t (2;8) (rarely observed) are practically present in 100% of cases of mature B-ALL with L3 / Burkitt morphology and immunoglobulins in the clonal surface. Typical cytogenetic aberrations are also found in the T lineage, the most frequent involve resection points of 14q11, for example, t (10; 14) (q24; q11), t (11; 14) (p13; q11) and others, the presence of t (8; 14) with resection points at q24; q11 (q24; q32 in line B ALL) in T cell ALL is

An interruption in IKZF1 encoding the Ikaros transcription factor has been frequently observed in ALL with BCR / ABL rearrangement (80% of cases). The IKZF1 mutation predicts poor outcome in the treatment of ALL, Phi+ or not [13, 23–25]. By integrating genome-wide technologies the "BCR / ABL-like" subgroup has been suggested and identified in adult and child populations [26, 27] and represents approximately 15% of ALL ontogeny B cases. This subgroup It is characterized by a gene expression that is similar to that of BCR/ABL + patients, with frequent detection of the IKZF1 mutation and CRLF2 rearrangements but with where abysmal differences in the outcomes. Other mutations and / or rearrangements that activate

associated with aggressive lymphomatous presentation [20–22].

tyrosine kinases has also been revealed as poor prognosis factor such as

rearrangement of IGH-CRLF2, NUP214-ABL1, EBD1-PDGRB, BCR-JAK2 fusions and STRN3 JAK2, which have been associated with a very poor prognosis [28]. Hypodiploid ALL, considered a high risk factor has been extensively evaluated in pediatric ALL [29] Alterations involving tyrosine kinase receptors and RAS gene signaling (i.e., NRAS, KRAS, FLT3, and NF1) can be detected in up to 70% of haploid cases, while hypodiploid cases are characterized by lesions involving members of the Ikaros family, particularly IKZF2 and by TP53 interruptions which can be identified in 91.2% of these. In adult ALL, these cases are characterized by nonrandom chromosome loss and CDKN2A / B with locus deletion as the only recurrent abnormality; As previously reported, in children these cases often harbor TP53

The TP53 mutation is detected in 6.4% of all ALL cases and a correlation with a worse result has been demonstrated. In adults, TP53 mutations are identified at diagnosis in 8.2% of cases (11.1% of T-ALL and 6.4% of B-ALL), and are preferably identified without molecular aberrations and are associated with refractoriness to

In T cell-ALL, well-recognized aberrations are: Rearrangement of the T-cell receptor (TCR) gene, chromosomal deletions and focal gene deletions, in addition, chromosomal rearrangements can also lead to fusion genes in the framework of Chimeric proteins with oncogenic properties such as thePICALM-MLLT10,

NUP214-ABL1 fusion for medin episomes, EML-ABL1, theSET-NUP214 fusion and

MLL-type genetic rearrangements have uncertain significance [33, 34].

transplantation is performed [19].

*Acute Leukemias*

mutations [30].

**128**

chemotherapy [31, 32].

*Frequency of Chromosomic and molecular alterations by age group.*

A large set of mutations in T cell-line ALL has been identified by sequencing techniques including NOTCH1, FBW7, BCL11B, JAK1, PTPN2, IL7R and PHF6, some of them have recognized prognostic importance, while others require further investigation. In fact, NOTCH1 and / or FBW7 mutations that occur in more than 60% and around 20% of cases, respectively, are generally associated with a favorable outcome. A new prognostic model has been recently proposed defining as low risk those with NOTCH1 and FBW7 mutations and those with lesions involving RAS/PTEN as high-risk. JAK1 mutations, which increase JAK activity and impair


**Table 4.** *Cytogenetic risk groups.*


**5. Treatment of the AYA group**

*DOI: http://dx.doi.org/10.5772/intechopen.94886*

*Acute Lymphoblastic Leukemia in Adolescents and Young Adults*

schemes (**Tables 6** and **7**).

**Studies Number of**

*No comparative studies of pediatric regimens.*

**Table 6.**

**131**

**cases**

This group is considered as a "superimposed" population since pediatric schemes have improved their degrees of response compared to adult designed schemes. Initially, the treatment regimens in this group of patients were based on regimens for adults, showing complete remissions in a low percentage, a couple of examples are the UKALLXII/ECOG [41] case study that reported complete remission (CR) nearly 51% after 1 chemotherapy cycle with increase to 91% after 2 induction cycles and the CALGB8811 [42] study that reported RC of 62–86% after 1 and 2 cycles of induction to remission respectively; On the other hand, the LALA-94 [43] study reported CR rate of 72% after one treatment cycle up to 84% after 2 treatment cycles, thus we have to mention the Hyper-CVAD scheme with a CR rate in the first cycle reported in 81% with increase after 2 cycles to 92% [44]; the DFCI45 pilot study showed an RC of 82% in the first induction cycle. Due to the above, it's clear that treatment schemes based on adults'schemes are ineffective to achieve CR, for these reasons the AYA Group was separated looking for different treatment schemes which includes two large groups, those based on pediatric schemes with expansion in the group of age and modified pediatric inspiration

By reviewing the pediatric regimens with extension to the age group of treatment was possible to increase the degree of response in this group classified as AYA; in adult regimens, complete remissions ranging from 51% to a maximum of 82% were reported after 1 cycle of treatment, however, in **Table 1** we observe that pediatric regimens in general achieved a higher percentage of complete response or remission after applying 1 cycle of induction, showing with the highest degree of complete response in 98% of the cases for the studies: TOTAL TERAPY IV, 46 PETHEMA ALL 96.47 DCOG, 58 ALL97.59, however, it should be noted that the study with greater robustness in this group that showed the highest CR is the

> **Age (rank)**

CCG 1961 262 16-21 95 5/72 5/78 [38] DFCI9101/9501 51 15-18 94 5/78 5/81 [40] UKALL 2003 229 16-24 97 5/72 5/76 [39] TOTAL TERAPY XV 45 15-81 98 5/86 5/88 [45] PETHEMA ALL 96 81 15-30 98 6/61 6/69 [46] HOVON (FRALLE 93) 54 17-40 91 2/66 2/72 [47] NOPHO 2008 221 18-45 NR 5/74 5/78 [48] FRALL 2000 186 15-19 96 5/74 5/80 [49] INTERGROUPC10403 296 17-39 NR 2/66 2/79 [50] FRALLE93 77 15-20 94 5/67 NR [51] DCOG 47 15-18 98 5/69 5/79 [52] ALL97 61 15-17 98 5/65 NR [53] AIEOP 150 14-18 94 5/67 5/67 [54] *CR: Complete Remission, Ref. Reference, DFS: Disease Free Survival, OS: Overall Survival, NR: Not Reported.*

**% CR**

**DFS (years/%)**

**OS (years/%)** **Ref.**

#### **Table 5.**

*WHO classification of lymphoblastic leukemia.*

proliferation and survival, have been associated with refractoriness of chemotherapy and should be considered as poor prognosis markers [35, 36].

Recurrent chromosomal and molecular abnormalities characterize ALL subtypes in adults and children (**Table 3**) and often provide prognostic information that can influence risk stratification and treatment decisions (**Table 4**). The frequency of certain subtypes differs between adult and child ALL, what partially explains the difference in clinical outcomes between patient populations [6, 30, 34, 36].

The most recent classification of the World Health Organization (WHO) for acute lymphoblastic leukemia ins shown in **Table 5**.

#### **4. Treatment**

The evolution in treatment of patients with ALL has progressed over time, this in order to achieve better survival, relapse-free rates and the quest to achieve cure. We will divide this issue into two large groups: AYA group (adolescents and young adults) and the group of people over 40 years old; and subdivided focusing on status of Philadelphia chromosome (positive and negative).

Chemotherapy treatment is divided into treatment phases with different goals: [38, 39].

Induction: it is the phase that seeks to achieve remission normalizing the parameters of the blood count (Hb >10 gr/dl, Neutrophils >1000 /mm3, platelets >100,000/mm3) as well normalization of the organs affected by diagnosis (liver, kidney, lung).

Consolidation: in this phase, the aim is to keep the patient in remission and achieve a negative minimal residual disease (MRD) that will impact the prognosis.

Maintenance: this phase seeks to avoid relapse of the disease and prepare for an elective suspension [38–40].
