B-precursor acute lymphoblastic leukemia is often preceded by a period of low- or middle-grade febrility, which can evince a duration of even months. The symptoms caused by the early stages of the disease are not pathognomonic and include anorexia, fatigue, weight loss or a developmental arrest in younger children.

When the malignancy is diagnosed, the abnormal proliferation of lymphoblasts in the bone marrow has already induced an arrest in the production of the other cell lines, namely erythrocytes, platelets and other white blood cells. This state of pancytopenia leads to a multitude of symptoms and signs that are also nonspecific and may include any of the following:

• Pallor, fatigue and weakness, caused by anemia
• Recurring infections due to leukocytopenia
• Petechiae, epistaxis, hematuria or ecchymoses due to thrombocytopenia.
• Skeletal pain
• Neurological symptoms, such as headaches, seizures or vomiting; these may indicate the involvement of the central nervous system.
• Hepatosplenomegaly
• Enlarged lymph nodes

A specific sign that constitutes a warning of a potentially aggressive and refractory disease is telangiectasias on the bulbar conjunctiva in a child with B-ALL; those patients respond poorly to chemo- and radiotherapy.

B-precursor acute lymphoblastic leukemia is diagnosed via a complete blood count, that reveals pancytopenia, a bone marrow biopsy and a smear of the peripheral blood.

More specifically, peripheral blood is found to contain cells with a hypoplastic cytoplasm and comparatively oversized nuclei. The nuclei themselves typically encompass chromatin arranged in large bundles and their shape ranges from round to oval. Vacuoles or granules may also be observed in a microscopic analysis and the cytoplasm is basophilic. On the other hand, a histologic examination of the bone marrow sample is expected to reveal hypercellular characteristics, even though it may by hypocellular or normocellular under some circumstances. Alterations are diffuse and consist of lymphoblasts with hypoplastic cytoplasm and restricted size. As far as normal cells are concerned, a small number of erythroblasts can be detected; normal cells are largely eliminated. Chromatin is characterized by excessive condensation and wide dispersion.

Diagnosis is completed with a cytogenetic analysis, in order to pinpoint the DNA structure, chromosome number, rearrangements and mutations that are associated with B-ALL [20].

All types of acute lymphoblastic leukemia are treated according to a specific protocol and B-precursor acute lymphoblastic leukemia constitutes no exception. The particular details of the treatment may be decided based on the type of genetic mutation and other individualized characteristics of the malignancy. Treatment is initiated with an induction phase, which includes various chemotherapeutic and other agents, such as doxorubicin, vincristine, cyclophosphamide, and prednisone. The induction phase is followed by a consolidation phase after remission has been confirmed, whose purpose is to intensify therapy with drugs such as cytarabine and methotrexate. Finally, a long maintenance phase is required, which may contain cycles of intensified induction therapy, since it can greatly contribute to the ultimate therapeutic goal.

Prophylaxis of the central nervous system is mandatory and is achieved with triple intrathecal therapy; the previous option which involved cranial radiation is gradually being rejected due to the negative effect it can have on the CNS [21] [22] [23]. Antimicrobial and antifungal medications are also administered to patients with profound leukocytopenia, as prophylaxis [24]. The ultimate therapeutic option is stem cell transplantation, which is employed in a relative minority of the cases, approximately in 6% of all patients.

B-precursor acute lymphoblastic leukemia is widely viewed in a more positive prognostic light when compared to T-precursor acute lymphoblastic leukemia [18]. One of the factors that greatly influence the outcome are the exact genetic modifications that are held accountable for the malignancy. More specifically, subtypes with a better-expected outcome are associated with:

• Translocation t(12;21) (TEL-AML1(ETV6-RUNX1))
• Translocation t(1;19) (TCF3-PBX1)
• Hyperdiploidy with over 51 chromosomes

On the other hand, genetic alterations that negatively affect prognosis include:

• Hypodiploidy with less than 44 chromosomes
• Translocation t(9;22) (BCR-ABL1)
• Translocation t(4;11) (MLL-AF4) during infancy

A second factor that can determine the outcome is the extent of minimal residual disease (MRD) on the 15th to 19th day of the initial, induction therapy: 1% of MRD during these days and less than 0.01% MRD at the end of the therapy is associated with a better long-term survival and the patients are considered to be low-risk [19]. Other factors that are linked with a better prognosis include the age of onset between 1 and 9 years old and leukocyte count below 50,000.

The majority of acute lymphoblastic leukemia cases that occur in childhood are induced by genetic defects that can be detected by fluorescence in situ hybridization and karyotyping [6]. In B-precursor acute lymphoblastic leukemia open link the genetic background that leads to the onset of the disease includes the following:

• Translocation t(12;21)(p13;q22) (ETV6-RUNX1 (TEL-AML1))
• Translocation t(9;22)(q34;q11) (BCR-ABL1)
• Translocation t(4;11)(q21;q23) (MLL-AFF1(AF4))
• Hyperdiploidy

B-ALL is categorized under the broader group of acute lymphoblastic leukemia, which is the type of cancer most frequently diagnosed in children in an international scale. ALL has been evincing a gradually increasing incidence during the past decades, with individuals of Hispanic ethnicity being more susceptible to developing the disease, followed by Caucasian patients [7] [8].

Similarly to ALL in general, B-ALL is more commonly diagnosed during the ages of 1 to 4 and constitutes the most frequent cause of death amongst children affected by malignancy. The disease exhibits a clear predilection for male patients. From a prognostic aspect, the dimmest prognosis accompanies occurrences in infancy, with the rest of the pediatric cases followed by a high event-free survival (EFS) rate [9] [10] [11] [12].

Hematopoiesis is the process through which every blood cell is produced by the hematopoietic stem cells (hemocytoblasts), in the bone marrow. It is a complicated procedure that is completed in a staged fashion and is strictly regulated by various transcription factors and signal transduction [13]. B-precursor acute lymphoblastic leukemia is a subtype of acute lymphoblastic leukemia and specifically targets the B precursor cells; the latter are derived from the common lymphoid progenitor cells and subsequently give rise to B cells after the maturation process has been completed.

In B-ALL specifically, a developmental arrest is observed in the stage of B-precursor differentiation, which is attributed to various genetic mutations and leads to a considerable heterogeneity on a clinical scale. The mutations known to underlie the clonal disease include hyperdiploidy with over 40 or 50 chromosomes, translocations such as t(12;21), t(1;19) and t(4;11) and other genetic mutations [14] [15]. It is, however, known that the genetic defects alone are not able to initiate the malignant proliferation of cells: it has been hypothesized that defects in the modification of chromatin, tumor suppression and the regulation of the cellular cycle are mandatory in order for the malignancy to fully develop into B-precursor acute lymphoblastic leukemia [16] [17].

The genetic mutations that underlie B-precursor acute lymphoblastic leukemia cannot be prevented. However, any individual can minimize their chances of suffering from B-ALL, if they avoid certain risk factors that have been associated with the malignancy. Those risk factors include exposure to benzene, high dose ionizing radiation and smoking.

B-precursor acute lymphoblastic leukemia (B-ALL) is classified under the category of acute lymphoblastic leukemia (ALL). ALL generally encompasses the wider cancer group of B-cell malignancies, one of which is B-ALL. B-cell leukemia is more commonly diagnosed during childhood and 75% of the cases affect children that are below the age of 6 years old.

Depending on cellular morphology, the FAB classification divides acute lymphoblastic leukemias into 3 categories, namely L1, L2 and L3. L1 comprises round-shaped blasts with clumped chromatin. L2 is the type of leukemia characterized by larger cells with a more delicate arrangement of chromatin and L3 cells contain vacuoles and are generally larger. B-precursor leukemia is an L1 or L2 type malignancy, with cells that express the B-cell antigens and/or surface light chains [1] [2].

The malignancy is characterized by an abnormal genetic background which includes various diverse translocations, hypo- or hyperdiploidy. The Philadelphia chromosome might also be present, and so can the MYC rearrangement [3] [4] [5].

B-precursor acute lymphoblastic leukemia is diagnosed with a standard complete blood count (CBC), which will reveal pancytopenia. The symptoms related to this type of cancer are non-pathognomonic and include manifestations of the existent pancytopenia, such as pallor, fatigue, bleeding tendencies and recurrent infections. Treatment is standardized and aggressive, as it consists of an induction, consolidation and long maintenance phase, which are all met with success in the majority of the cases. Cases of non-responsive B-ALL are treated with a stem cell transplantation, although a relative minority of the patients are required to undergo such a procedure.

Production of cellular components: red blood cells, platelets, and white blood cells takes place in the bone marrow. The process through which every single cell is produced is called hematopoiesis. It is a complex procedure that involves a single type of original bone marrow cell, the hematopoietic stem cell, which undergoes differentiation and produces the final, mature lines of blood cells. Acute lymphoblastic leukemia (ALL) is a type of cancer which causes an increased production of lymphoblasts, which fail to differentiate into mature T or B lymphocytes. B-precursor acute lymphoblastic leukemia (B-ALL) is a subtype of ALL, which leads to an abnormally overproduced line of those cells that differentiate into B lymphocytes. The malignant cells display developmental arrest, in the sense that their maturation process is halted at a prime period. This phenomenon causes a failure of the bone marrow to produce normal lymphocytes and at the same time prevents the other cellular components from developing too.

B-ALL is a result of various genetic mutations and other abnormalities. Additional defects in physiological procedures that have not yet been completely defined also play a role in the onset of the disease. Risk factors that have been associated with B-LL include high dose ionizing radiation, benzene exposure, and smoking.

As mentioned before, B-LL leads to the inability of the bone marrow to produce all three lines of cells: platelets, red blood cells and white blood cells. Consequently, patients affected by the malignancy present with a multitude of non-specific symptoms related to these deficiencies. The most common symptoms associated with B-LL are:

• Weight loss
• Anorexia
• Fatigue, weakness
• Nosebleeds
• Bruises on the body or gums that cannot be otherwise explained
• Swollen lymph nodes in the armpits, neck, groin, that appear as palpable lumps
• Frequent infections
• Pallor
• Headaches
• Vomiting

B-precursor acute lymphoblastic leukemia is diagnosed with blood tests that reveal decreased levels of blood cellular components. It is also required to perform a bone marrow biopsy, as well as a blood smear; the latter is used to observe the shape and structure of the blood cells under a microscope. Finally, genetic testing in order to identify the exact genetic mutation is also mandatory for a definitive diagnosis to be made. B-ALL is treated like all types of ALL, with chemotherapy. Treatment consists of an induction stage, which comprises various medications and, after the disease has subsided, a second round of therapy is administered, which is called the consolidation stage. This is an intensified cycle of chemotherapeutic agents. Treatment is completed with the administration of the final round of therapy, called maintenance therapy; it can last for quite a long time. Due to the aggressive type of treatment that has been designated for B-ALL, the results are usually positive, with patients achieving high survival rates and complete remission. In cases where chemotherapeutic aggressive treatment fails to cure the disease, a stem cell transplantation can be attempted, although it is a last resort therapy reserved for refractory and unresponsive cases.

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