**Alterations of Nutritional Status in Childhood Acute Leukemia**

Alejandra Maldonado-Alcázar, Juan Carlos Núñez-Enríquez, Carlos Alberto García-Ruiz, Arturo Fajardo-Gutierrez and Juan Manuel Mejía-Aranguré

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52715

**1. Introduction**

Nutritional status is the result of the interaction between environmental and genetic conditions in which a child lives, when these environmental conditions are favorable for life (physical, biological, nutritional and psychosocial), the genetic potential is ex‐ pressed as an ideal state of nutrition, but when conditions are unfavorable such expres‐ sion will be diminished, resulting in altered nutritional status, such as malnutrition, overweight and obesity, which among other things would cause the child did not re‐ spond to a disease or its treatment suitably at a given time. [1]

In different studies conducted in children with cancer, the authors have evaluated the impact of nutritional status, assuming that if a cancer patient is well nourished, have less toxicity caused by antineoplastic drugs, will have a greater immune resistance to processes serious infectious, and therefore have a better survival and quality of life than the patient who is not well nourished, so in this chapter we will mention the most im‐ portant conclusions that have been made with respect to this issue. [2]

Malnutrition is the main nutritional disorder that occurs in children with cancer, and has been defined as a state in which a deficiency of energy, protein, and other nutrients, causes measurable adverse effects on the structure and functioning of organs and body

tissues as well as the clinical course of a disease. In order to explain the mechanisms by which it causes malnutrition in children with cancer, three factors have been proposed: a) factors specific to the tumor (tumor growth factors released by the tumor cells as bombesin and adrenocorticotropic hormone) b) factors related to the patient (pediatric age, low socioeconomic status, poor nutrient intake, increased secretion of growth hor‐ mone and cytokines that are released by the body in response to tumor growth, among the most important are the tumor necrosis factor, interleukins 1 and 6), and last but not least, c) factors related to the treatment (type / dose of chemotherapy, site / dose of radi‐ otherapy and surgery). It is also suggested that all these factors would cause an altera‐ tion in intermediary metabolism, with resultant decrease in appetite, which eventually lead to the patient to lose weight, creating a vicious cycle. [2-6]

**Percentile Diagnosis** <5 Malnourished 5-85 Normal > 85 a < 95 Overweight ≥ 95 Obesity

**Table 1.** Diagnosis by percentile for the indexes weight-for-height, weight-for-age based on the World Health

**Denomination Index Classification**

**Table 2.** Denomination of wasting and stunting with Waterlow´s classification. [12, 13]

Wasting, no stunting Weight-for-height <5 ,

Wasting and stunting Weight-for-height <5 ,

Stunting, no wasting Weight-for-height Normal,

**Table 3.** Combinations of nutritional diagnosis with Waterlow's classification. [12,13]

Wasting Weight-for-height <5 Acute Malnutrition

**Denomination Index Classification**

height-for-age Normal

height-for-age <5

height-for-age <5

**Percentil Diagnosis**

≥5 y <85 Normal ≥85- <94 Overweight ≥95 Obesity

<5 Underweight - Malnourished

**Table 4.** Diagnosis by percentile for the Body Mass Index (BMI) based on the World Health Organization (WHO) tables [10]

Stunting Height-for-age <5 delay in growth or chronic malnutrition

Acute malnutrition

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Exacerbated-chronic malnutrition

Chronic malnutrition

Organization (WHO) tables.

Waterlow´s Classification:

Waterlow´s classifications:

#### **1.1. Prevalence of malnutrition in children with cancer**

It has been reported that children with cancer will develop signs and symptoms of malnutri‐ tion at some point in the disease by up to 50-60% of cases, however, this frequency may vary according to the type of neoplasm, and according to if the study was conducted in devel‐ oped countries or in developing countries, where there has been an increased frequency of nutritional alterations. It should be mentioned, that the study of the prevalence of malnutri‐ tion in children with cancer is mainly determined by whether it is present at diagnosis, this is important because it also could establish their potential impact on the evolution of these patients before treatment started. [7,8]

In this regard, Brinksma A, et al., (2012) reported the prevalence of malnutrition at diag‐ nosis for developed countries, through a systematic review which included patients with different types of childhood cancer, aged from 0-18 years of age for acute leukemias, the prevalence was 10%, 20-50% for neuroblastoma, and those classified as "other malignan‐ cies" was 0-30%, these prevalences are low when compared with those that have been es‐ timated for developing countries where they are as high as 50% for all types of childhood cancers. [2,8,9]

### **2. Nutritional status assessment in children with acute leukemia**

There are several clinical, biochemical and physiological indicators to diagnose malnutri‐ tion in children with cancer; such as the patient's age, the deficit of specific micronu‐ trients and the presence or absence of infection. The severity of their malnutrition is determined mainly by anthropometric indicators, that are the indexes of weight-forheight (w/h) and weight-for-age (w/a), which indicates acute malnutrition (table 1), height-for-age (h/a) which indicate a delay in growth or chronic malnutrition; and the Body Mass Index (BMI), which is a figure that can diagnose a patient for being under‐ weight, overweight or obesity. [10,11] (table 4)


**Table 1.** Diagnosis by percentile for the indexes weight-for-height, weight-for-age based on the World Health Organization (WHO) tables.

#### Waterlow´s Classification:

tissues as well as the clinical course of a disease. In order to explain the mechanisms by which it causes malnutrition in children with cancer, three factors have been proposed: a) factors specific to the tumor (tumor growth factors released by the tumor cells as bombesin and adrenocorticotropic hormone) b) factors related to the patient (pediatric age, low socioeconomic status, poor nutrient intake, increased secretion of growth hor‐ mone and cytokines that are released by the body in response to tumor growth, among the most important are the tumor necrosis factor, interleukins 1 and 6), and last but not least, c) factors related to the treatment (type / dose of chemotherapy, site / dose of radi‐ otherapy and surgery). It is also suggested that all these factors would cause an altera‐ tion in intermediary metabolism, with resultant decrease in appetite, which eventually

It has been reported that children with cancer will develop signs and symptoms of malnutri‐ tion at some point in the disease by up to 50-60% of cases, however, this frequency may vary according to the type of neoplasm, and according to if the study was conducted in devel‐ oped countries or in developing countries, where there has been an increased frequency of nutritional alterations. It should be mentioned, that the study of the prevalence of malnutri‐ tion in children with cancer is mainly determined by whether it is present at diagnosis, this is important because it also could establish their potential impact on the evolution of these

In this regard, Brinksma A, et al., (2012) reported the prevalence of malnutrition at diag‐ nosis for developed countries, through a systematic review which included patients with different types of childhood cancer, aged from 0-18 years of age for acute leukemias, the prevalence was 10%, 20-50% for neuroblastoma, and those classified as "other malignan‐ cies" was 0-30%, these prevalences are low when compared with those that have been es‐ timated for developing countries where they are as high as 50% for all types of

**2. Nutritional status assessment in children with acute leukemia**

There are several clinical, biochemical and physiological indicators to diagnose malnutri‐ tion in children with cancer; such as the patient's age, the deficit of specific micronu‐ trients and the presence or absence of infection. The severity of their malnutrition is determined mainly by anthropometric indicators, that are the indexes of weight-forheight (w/h) and weight-for-age (w/a), which indicates acute malnutrition (table 1), height-for-age (h/a) which indicate a delay in growth or chronic malnutrition; and the Body Mass Index (BMI), which is a figure that can diagnose a patient for being under‐

lead to the patient to lose weight, creating a vicious cycle. [2-6]

278 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**1.1. Prevalence of malnutrition in children with cancer**

patients before treatment started. [7,8]

weight, overweight or obesity. [10,11] (table 4)

childhood cancers. [2,8,9]


**Table 2.** Denomination of wasting and stunting with Waterlow´s classification. [12, 13]

#### Waterlow´s classifications:


**Table 3.** Combinations of nutritional diagnosis with Waterlow's classification. [12,13]


**Table 4.** Diagnosis by percentile for the Body Mass Index (BMI) based on the World Health Organization (WHO) tables [10]

It's important to consider the body composition in children with cancer, with which we are able to determine the quantity of lean mass and body fat in their bodies, in order to see if there is muscular depletion. The anthropometric measures used to get body composition can be the Mid Upper Arm Circumference (MUAC), triceps (TSF), biceps, subscapularis and suprailiac skinfolds; [14] and in case of having the necessary equipment, the use of electric bioimpedance or D-XA (Dual X-Ray Absorptiometry) is recommendable.

**Reference value Diagnosis**

**Table 7.** Prealbumin reference values and diagnosis [17]

influence the patient's response to the treatment.

leukemia in children at different stages of treatment. [22-25]

quate and aggressive to those classified as high risk. [26,27]

**3.1. Prognosis**

17 - 42 g/dl Well-nourished

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<17 g/dl Malnourished

**3. Impact of malnutrition in Acute Lymphoblastic Leukemia (ALL)**

It is important to make a full assessment of nutritional status in these children as this can

The study of the impact of malnutrition in children with cancer has been conducted pri‐ marily in patients with acute leukemia, specifically in (ALL) perhaps because it is the most common type of cancer in children worldwide. [18-21] In two papers published one by Underzo et al., and in another by Reilly J, et al., reported that the prevalence of mal‐ nutrition at diagnosis in patients with ALL was 7% for developed countries, and on the contrary, in different studies conducted in developing countries have reported higher prevalence of up to 21-23%, which confirms the statement that in countries with low eco‐ nomic development, malnutrition occurs more frequently, This could be a result of pov‐ erty. It is for this reason that for several years, these countries have made efforts to determine the true impact of malnutrition as a prognostic factor in patients with acute

As is known chemotherapy used in the treatment of patients with ALL has some serious ef‐ fects that may endanger the life of patients at a given time. Among the most common side effects of QT are toxicity to various organs, infection, hemorrhage, tumor lysis syndrome (TLS), among others., which would be the cause of high morbidity and mortality. It is for this reason that the current chemotherapy protocols in children with ALL are based on a risk classification to reduce toxicity in low-risk patients as well as ensure that therapy is ade‐

In the group of patients with ALL who are malnourished at diagnosis, it was found that che‐ motherapy is more toxic and less effective compared to those found with adequate nutri‐ tional status, specifically haematological toxicity is the cause of most complications, such as an increased risk to present infections, bleeding and an increased risk of relapse, the above due to neutropenia, thrombocytopenia, and discontinuation of treatment, respectively.

The main effect of malnutrition on treatment, is due to an alteration of the biodisponibility of antineoplastic drugs, which is achieved through the following mechanisms: a) changes in absorption, eg for drugs like methotrexate and 6 mercaptopurine, b) the decreased drug

With the mid upper arm circumference and the triceps skinfold, you can calculate the mus‐ cle and fat area by using the following formula:


Then comparing the score with the Frisancho tables where:

**Table 5.** Diagnosis by percentile for upper arm muscle area based on Frisancho tables. [14]

Aside from those anthropometric indicators, there are biochemical indicators that are used to diagnose protein malnutrition, like albumin and pre-albumin which are the most impor‐ tant due to their hepatic synthesis, and total protein. [15,16]

The half- life of albumin is 20 days, therefore it can assess acute malnutrition and can be used as a morbidity and mortality prognosis factor.


**Table 6.** Albumin reference values and diagnosis [15]

Prealbumin has a 2 days half life wich means it is a very sensible marker for acute malnutrition, but the result may be affected by inflammatory reaction, therefore is not useful to track changes on the nutritional status unlike albumin that can be a better marker for protein malnutrition. [16]


**Table 7.** Prealbumin reference values and diagnosis [17]

It is important to make a full assessment of nutritional status in these children as this can influence the patient's response to the treatment.

## **3. Impact of malnutrition in Acute Lymphoblastic Leukemia (ALL)**

The study of the impact of malnutrition in children with cancer has been conducted pri‐ marily in patients with acute leukemia, specifically in (ALL) perhaps because it is the most common type of cancer in children worldwide. [18-21] In two papers published one by Underzo et al., and in another by Reilly J, et al., reported that the prevalence of mal‐ nutrition at diagnosis in patients with ALL was 7% for developed countries, and on the contrary, in different studies conducted in developing countries have reported higher prevalence of up to 21-23%, which confirms the statement that in countries with low eco‐ nomic development, malnutrition occurs more frequently, This could be a result of pov‐ erty. It is for this reason that for several years, these countries have made efforts to determine the true impact of malnutrition as a prognostic factor in patients with acute leukemia in children at different stages of treatment. [22-25]

#### **3.1. Prognosis**

It's important to consider the body composition in children with cancer, with which we are able to determine the quantity of lean mass and body fat in their bodies, in order to see if there is muscular depletion. The anthropometric measures used to get body composition can be the Mid Upper Arm Circumference (MUAC), triceps (TSF), biceps, subscapularis and suprailiac skinfolds; [14] and in case of having the necessary equipment, the use of electric

With the mid upper arm circumference and the triceps skinfold, you can calculate the mus‐

**Percentile Diagnosis**

0 – 5 Wasted

5.1 – 15 Below average

85.1 - 95 Above Average

>95 High muscle

Aside from those anthropometric indicators, there are biochemical indicators that are used to diagnose protein malnutrition, like albumin and pre-albumin which are the most impor‐

The half- life of albumin is 20 days, therefore it can assess acute malnutrition and can be

Prealbumin has a 2 days half life wich means it is a very sensible marker for acute malnutrition, but the result may be affected by inflammatory reaction, therefore is not useful to track changes on the nutritional status unlike albumin that can be a better marker for protein malnutrition. [16]

**Reference value Diagnosis** 3.5 - 5.5 g/dl Well-nourished 2.8 - 3.5 g/dl Malnourished Grade 1 2.1 - 2.7 g/dl Malnourished Grade2 < 2.1 g/dl Malnourished Grade 3

15.1 – 85 Average

bioimpedance or D-XA (Dual X-Ray Absorptiometry) is recommendable.

280 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**Table 5.** Diagnosis by percentile for upper arm muscle area based on Frisancho tables. [14]

tant due to their hepatic synthesis, and total protein. [15,16]

used as a morbidity and mortality prognosis factor.

**Table 6.** Albumin reference values and diagnosis [15]

cle and fat area by using the following formula:

Then comparing the score with the Frisancho tables where:

As is known chemotherapy used in the treatment of patients with ALL has some serious ef‐ fects that may endanger the life of patients at a given time. Among the most common side effects of QT are toxicity to various organs, infection, hemorrhage, tumor lysis syndrome (TLS), among others., which would be the cause of high morbidity and mortality. It is for this reason that the current chemotherapy protocols in children with ALL are based on a risk classification to reduce toxicity in low-risk patients as well as ensure that therapy is ade‐ quate and aggressive to those classified as high risk. [26,27]

In the group of patients with ALL who are malnourished at diagnosis, it was found that che‐ motherapy is more toxic and less effective compared to those found with adequate nutri‐ tional status, specifically haematological toxicity is the cause of most complications, such as an increased risk to present infections, bleeding and an increased risk of relapse, the above due to neutropenia, thrombocytopenia, and discontinuation of treatment, respectively.

The main effect of malnutrition on treatment, is due to an alteration of the biodisponibility of antineoplastic drugs, which is achieved through the following mechanisms: a) changes in absorption, eg for drugs like methotrexate and 6 mercaptopurine, b) the decreased drug transport by the reduction or lack of plasmatic proteins, and c) by decrease in hepatic metab‐ olism of the antineoplastic mainly caused by a lack of enzymatic activity by cytochrome P450. [28-37]

**3.3. Malnutrition and early mortality**

drome (TSL) were also detected. [47]

Early mortality can be defined as death during the first year of treatment, and it includes treat‐ ments as chemotherapy of induction to remission, central nervous system prophylaxis and con‐ solidation. In several cases around the globe, the early mortality rate for developed countries is significantly lower than the one presented in developing countries. Main causes for early mor‐ tality include complications during chemotherapy treatment, such as infections, hemorrhages

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A 1999 study conducted by Silverman and collaborators in the Dana-Farber Cancer Institute, United States; a mortality rate of 2% in the first stage of treatment was reported, mainly caused by infections. [46] Another study conducted in the UK in 1997 also measured the rate of early mortality in these patients, reporting a mortality rate of barely 1.2%, with infections still being the main cause of death; however, cases of brain hemorrhage and tumor lysis syn‐

The country that reports the lowest percentage of mortality in early stages of treatment is Germany, which reported only a 1% death rate in their patients between 1984 and 1996; with

While that's the case in developed countries, where very low mortality rates are reported; a study conducted by Rivera Luna and collaborators in Mexico's Instituto Nacional de Pedia‐ tría (INP) threw results of a 15% mortality rate during the phases of induction to remission. [37] In other developing countries like Honduras, El Salvador, Brazil, and India mortality al‐ so shows a spike in rates compared to developed countries, with an early mortality rate of

> Germany U.K. U.S.A El Salvador Brazil Mexico India Honduras 1% 1.20% 2% 12.50% 15% 15% 17% 21%

**Graphic 1.** Incidence of early mortality in patients with ALL around the world.

and toxicity, since their presence often represent an interruption in the treatment.

most of the deceases caused by hemorrhages and tumor lysis. [41]

20.8%, 12.5%, 14.9% and 17% respectively, as you can see in Graph 1. [48-51]

Furthermore. highlight the importance of studying on the subject of how malnutrition af‐ fects the prognosis of patients with ALL, because in some of the studies did not allow con‐ clusions to determine whether the association exists in some of these studies were given the limitations by factors such as inadequate sample size, the inconsistency in how to assess the nutritional status between studies, and also have not been studied other possible complica‐ tions in the evolution of these patients, such as relapse, abandonment in the treatment, among others. [28,38-40]

#### **3.2. Survival**

Moreover, since 1980 the rates of event-free survival has improved in patients with ALL, currently reported survival at 5 years is 80% and 10-year survival is 60% in developed countries, however, in developing countries cure rates are less than 35%, so on a quest to determine the factors related to mortality in developed countries, but mainly in devel‐ oping countries, has been studied by different authors on the role of malnutrition on sur‐ vival of patients with ALL; remain controversial until now because while on the one hand, some authors have reported that survival rates are lower in malnourished patients compared with patients who are well nourished and of the same risk, in other studies, it has not been possible to confirm this association. [8,29,41] According to Reilly J, et al., There are three mechanisms that explain the direct influence of malnutrition on survival of patients with ALL: The first, means that if there is a greater severity of malnutrition, there will be a greater severity of leukemia this because as we know, malnutrition is a surrogate marker of the disease state, the second mechanism is related to immune sys‐ tem dysfunction that occurs in malnourished patients, which would cause increased sus‐ ceptibility to potentially serious infections could lead to the death of the patient, and finally, a mechanism related to adipose tissue, which has as one of its main functions be‐ ing a facilitator to take place the pharmacokinetics of many anticancer drugs, this tissue is functionally and structurally altered in malnutrition, resulting in a lower effective anti‐ neoplastic drugs and greater toxicity and that both could be potential factors sufficient to endanger the patient's life, however this mechanism has been studied by other authors who found no such effect. [23-39]

Therefore, it is believed that malnutrition alone is a major factor in poor prognosis and sur‐ vival of patients with ALL, however, it is noteworthy that most of the studies performed, are from developed countries and / or where it is mainly evaluated the impact of malnutri‐ tion on long-term survival, so it is necessary to know whether the association also exists in developing countries, because these populations have certain characteristics, such as fre‐ quencies malnutrition and deaths occur primarily during the first year of treatment much higher, and it also has been reported as one of the main obstacles to improved survival rates in patients with ALL. [39,42-45]

#### **3.3. Malnutrition and early mortality**

transport by the reduction or lack of plasmatic proteins, and c) by decrease in hepatic metab‐ olism of the antineoplastic mainly caused by a lack of enzymatic activity by cytochrome

282 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

Furthermore. highlight the importance of studying on the subject of how malnutrition af‐ fects the prognosis of patients with ALL, because in some of the studies did not allow con‐ clusions to determine whether the association exists in some of these studies were given the limitations by factors such as inadequate sample size, the inconsistency in how to assess the nutritional status between studies, and also have not been studied other possible complica‐ tions in the evolution of these patients, such as relapse, abandonment in the treatment,

Moreover, since 1980 the rates of event-free survival has improved in patients with ALL, currently reported survival at 5 years is 80% and 10-year survival is 60% in developed countries, however, in developing countries cure rates are less than 35%, so on a quest to determine the factors related to mortality in developed countries, but mainly in devel‐ oping countries, has been studied by different authors on the role of malnutrition on sur‐ vival of patients with ALL; remain controversial until now because while on the one hand, some authors have reported that survival rates are lower in malnourished patients compared with patients who are well nourished and of the same risk, in other studies, it has not been possible to confirm this association. [8,29,41] According to Reilly J, et al., There are three mechanisms that explain the direct influence of malnutrition on survival of patients with ALL: The first, means that if there is a greater severity of malnutrition, there will be a greater severity of leukemia this because as we know, malnutrition is a surrogate marker of the disease state, the second mechanism is related to immune sys‐ tem dysfunction that occurs in malnourished patients, which would cause increased sus‐ ceptibility to potentially serious infections could lead to the death of the patient, and finally, a mechanism related to adipose tissue, which has as one of its main functions be‐ ing a facilitator to take place the pharmacokinetics of many anticancer drugs, this tissue is functionally and structurally altered in malnutrition, resulting in a lower effective anti‐ neoplastic drugs and greater toxicity and that both could be potential factors sufficient to endanger the patient's life, however this mechanism has been studied by other authors

Therefore, it is believed that malnutrition alone is a major factor in poor prognosis and sur‐ vival of patients with ALL, however, it is noteworthy that most of the studies performed, are from developed countries and / or where it is mainly evaluated the impact of malnutri‐ tion on long-term survival, so it is necessary to know whether the association also exists in developing countries, because these populations have certain characteristics, such as fre‐ quencies malnutrition and deaths occur primarily during the first year of treatment much higher, and it also has been reported as one of the main obstacles to improved survival rates

P450. [28-37]

**3.2. Survival**

among others. [28,38-40]

who found no such effect. [23-39]

in patients with ALL. [39,42-45]

Early mortality can be defined as death during the first year of treatment, and it includes treat‐ ments as chemotherapy of induction to remission, central nervous system prophylaxis and con‐ solidation. In several cases around the globe, the early mortality rate for developed countries is significantly lower than the one presented in developing countries. Main causes for early mor‐ tality include complications during chemotherapy treatment, such as infections, hemorrhages and toxicity, since their presence often represent an interruption in the treatment.

A 1999 study conducted by Silverman and collaborators in the Dana-Farber Cancer Institute, United States; a mortality rate of 2% in the first stage of treatment was reported, mainly caused by infections. [46] Another study conducted in the UK in 1997 also measured the rate of early mortality in these patients, reporting a mortality rate of barely 1.2%, with infections still being the main cause of death; however, cases of brain hemorrhage and tumor lysis syn‐ drome (TSL) were also detected. [47]

The country that reports the lowest percentage of mortality in early stages of treatment is Germany, which reported only a 1% death rate in their patients between 1984 and 1996; with most of the deceases caused by hemorrhages and tumor lysis. [41]

While that's the case in developed countries, where very low mortality rates are reported; a study conducted by Rivera Luna and collaborators in Mexico's Instituto Nacional de Pedia‐ tría (INP) threw results of a 15% mortality rate during the phases of induction to remission. [37] In other developing countries like Honduras, El Salvador, Brazil, and India mortality al‐ so shows a spike in rates compared to developed countries, with an early mortality rate of 20.8%, 12.5%, 14.9% and 17% respectively, as you can see in Graph 1. [48-51]

**Graphic 1.** Incidence of early mortality in patients with ALL around the world.

A possible explanation for this marked difference might be that malnutrition, poverty and lack of access to public health services are frequent problems in developing coun‐ tries, unlike developed countries where children with leukemia have lower early mor‐ tality rates.

Another study realized by Pedrosa F. and collaborators in 2000, took in account indicators as weight-for-height, height-for-age and weight-for-age; comparing them to WHO data. For this study they took in account patients with any type of leukemia and patients with solid tumors. This study was collaboration between two hospitals in El Salvador and Brazil, where they were able to include 443 patients. Of that number, 151 had an ALL diagnosis. At the beginning of the study children were classified as children with malnutrition and chil‐ dren without malnutrition, and children with malnutrition were provided with a dosage of albumin 2 weeks before starting chemotherapy. The study concluded that "malnourishment

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The most recent study published on this subject was conducted with patients of Mexico's Instituto Nacional de Pediatría, with 100 patients diagnosed with ALL. Their state of nutri‐ tion was determined with indicators of weight-for-height and height-for-age and compared to the NHANES tables of the CDC in the United States. This was a retrospective study where the follow up was done during the phases of induction to remission, and the results were as follow: 14.9% of children without malnourishment died during treatment phase, while 5.1% of patients without malnourishment perished in this stage of treatment There‐ fore, it was concluded that malnutrition didn't play an important role in early mortality in

In a retrospective cohort done in El Salvador with 469 patients, besides BMI index, triceps skinfolds and Mid Upper Arm Circumference were taken into consideration. This study concluded that malnourishment had no association with mortality during treatment. [49]

A study conducted by Hijiya and collaborators demonstrated with a retrospective cohort of 621 patients of St. Jude's Hospital in United States concluded that BMI didn't affect the evo‐ lution of patients with ALL. This study took BMI as the main nutritional indicator and div‐ ided children in 3 groups: malnourished, normal and obese. The survival rates in these categories were similar, children with malnutrition presented a survivability rate of 86.1%, children with a normal nutrition state had an 86% survivability rate and in obese children

There's controversial information about the relationship between the effects of malnutrition in the evolution of patients with ALL, mostly because even with a wide range of studies, some conclude there's a significant relation between these factors [24,28,44] while others

One of the reasons is the bias in the classification of malnutrition, since in some studies like Pedroza and collaborators [38] the World Health Organization (WHO) charts are used, and in Rivera Luna and collaborators [37] they used the charts of the National Health and Nutri‐ tion Examination Survey (NHANES), while in the study conducted by Lobato Mendizabal and collaborators the charts of Ramos Galván were taken into account [44] and at last the

In the studies mentioned, the sample was taken only from one or two hospital sources, so it's important to conduct a multicentre study that can show a wider panorama of the effects

study of Mejía Aranguré and collaborators used Federico Gómez' charts. [24]

of malnourishment in the evolution of children with ALL.

doesn't have a relevant association with these patients' survival". [38]

children with ALL. [37]

the figure was of 85.9%. [39]

conclude that there's no relation. [37-39, 49]

There have been several studies that try to correlate malnutrition with the evolution of pa‐ tients with ALL. The first one was conducted in Mexico in 1989 by Lobato Mendiazabal et al., where there's a categorization of children with or without malnutrition based on weightfor-height indicators. It was found that, when measuring 5 year survival rate, 80% of chil‐ dren without malnutrition survived, while patients with malnutrition had a survival rate of barely 26% in the same period. [44]

As far as early mortality and relapses during the first year of treatment go, only 4% of children diagnosed with good nutrition suffered any of those events, while 63% of ill nurtured children experienced a relapse or death. This study was conducted in Pue‐ bla, with a sample size of 42 children of a single hospital facility (Hospital Universitar‐ io de Puebla). [44]

In a case and control study conducted by Mejia Aranguré and collaborators the state of nu‐ trition of several patients with the weight-for-height indicator was tested and compared for diagnosis with the boards of Federico Gómez. For this study 93 cases of 2 hospital sources were taken; Hospital Infantil Federico Gómez and Hospital de Pediatría de Centro Médico Nacional S XXI. [35]

It was found that children with malnutrition at the moment of diagnosis were almost 2.6 times more likely to die in comparison to children without malnutrition. Therefore, it was concluded that malnutrition is a factor that increases the mortality rate of chil‐ dren with ALL, and an association directly proportional to the severity of the nutri‐ tion was established. [24]

In a prospective cohort conducted in 63 patients by Khan and collaborators, malnutrition was classified with the index of weight-for-height, and the result was that 46% of children with malnutrition at the moment of ALL diagnose completed their treatment; only 9.8% suf‐ fered a relapse and 45% died; meanwhile children without malnutrition experienced a 59% survival to their treatment, a 21% relapse rate and 19% died. Thus, malnutrition was consid‐ ered as a bad prognosis factor for children with ALL. [36]

One of the most recent studies was conducted in Bangladesh by Hafiz MG and collaborators in 2008. This study only takes a sample of 66 patients from the Indian Pediatric Hospital, the index they used was the weight-for-height measurement, although they don't specify the ta‐ bles that results were compared to in order to classify the state of nutrition.

They concluded that children that present malnutrition have 2 to 3 times the risk of infection in comparison to children without malnutrition. It was also observed that children with mal‐ nutrition needed more time for induction therapy since their dosage has to be lowered, or their treatment was interrupted for toxicity. [28]

Another study realized by Pedrosa F. and collaborators in 2000, took in account indicators as weight-for-height, height-for-age and weight-for-age; comparing them to WHO data. For this study they took in account patients with any type of leukemia and patients with solid tumors. This study was collaboration between two hospitals in El Salvador and Brazil, where they were able to include 443 patients. Of that number, 151 had an ALL diagnosis. At the beginning of the study children were classified as children with malnutrition and chil‐ dren without malnutrition, and children with malnutrition were provided with a dosage of albumin 2 weeks before starting chemotherapy. The study concluded that "malnourishment doesn't have a relevant association with these patients' survival". [38]

A possible explanation for this marked difference might be that malnutrition, poverty and lack of access to public health services are frequent problems in developing coun‐ tries, unlike developed countries where children with leukemia have lower early mor‐

284 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

There have been several studies that try to correlate malnutrition with the evolution of pa‐ tients with ALL. The first one was conducted in Mexico in 1989 by Lobato Mendiazabal et al., where there's a categorization of children with or without malnutrition based on weightfor-height indicators. It was found that, when measuring 5 year survival rate, 80% of chil‐ dren without malnutrition survived, while patients with malnutrition had a survival rate of

As far as early mortality and relapses during the first year of treatment go, only 4% of children diagnosed with good nutrition suffered any of those events, while 63% of ill nurtured children experienced a relapse or death. This study was conducted in Pue‐ bla, with a sample size of 42 children of a single hospital facility (Hospital Universitar‐

In a case and control study conducted by Mejia Aranguré and collaborators the state of nu‐ trition of several patients with the weight-for-height indicator was tested and compared for diagnosis with the boards of Federico Gómez. For this study 93 cases of 2 hospital sources were taken; Hospital Infantil Federico Gómez and Hospital de Pediatría de Centro Médico

It was found that children with malnutrition at the moment of diagnosis were almost 2.6 times more likely to die in comparison to children without malnutrition. Therefore, it was concluded that malnutrition is a factor that increases the mortality rate of chil‐ dren with ALL, and an association directly proportional to the severity of the nutri‐

In a prospective cohort conducted in 63 patients by Khan and collaborators, malnutrition was classified with the index of weight-for-height, and the result was that 46% of children with malnutrition at the moment of ALL diagnose completed their treatment; only 9.8% suf‐ fered a relapse and 45% died; meanwhile children without malnutrition experienced a 59% survival to their treatment, a 21% relapse rate and 19% died. Thus, malnutrition was consid‐

One of the most recent studies was conducted in Bangladesh by Hafiz MG and collaborators in 2008. This study only takes a sample of 66 patients from the Indian Pediatric Hospital, the index they used was the weight-for-height measurement, although they don't specify the ta‐

They concluded that children that present malnutrition have 2 to 3 times the risk of infection in comparison to children without malnutrition. It was also observed that children with mal‐ nutrition needed more time for induction therapy since their dosage has to be lowered, or

bles that results were compared to in order to classify the state of nutrition.

tality rates.

barely 26% in the same period. [44]

io de Puebla). [44]

Nacional S XXI. [35]

tion was established. [24]

ered as a bad prognosis factor for children with ALL. [36]

their treatment was interrupted for toxicity. [28]

The most recent study published on this subject was conducted with patients of Mexico's Instituto Nacional de Pediatría, with 100 patients diagnosed with ALL. Their state of nutri‐ tion was determined with indicators of weight-for-height and height-for-age and compared to the NHANES tables of the CDC in the United States. This was a retrospective study where the follow up was done during the phases of induction to remission, and the results were as follow: 14.9% of children without malnourishment died during treatment phase, while 5.1% of patients without malnourishment perished in this stage of treatment There‐ fore, it was concluded that malnutrition didn't play an important role in early mortality in children with ALL. [37]

In a retrospective cohort done in El Salvador with 469 patients, besides BMI index, triceps skinfolds and Mid Upper Arm Circumference were taken into consideration. This study concluded that malnourishment had no association with mortality during treatment. [49]

A study conducted by Hijiya and collaborators demonstrated with a retrospective cohort of 621 patients of St. Jude's Hospital in United States concluded that BMI didn't affect the evo‐ lution of patients with ALL. This study took BMI as the main nutritional indicator and div‐ ided children in 3 groups: malnourished, normal and obese. The survival rates in these categories were similar, children with malnutrition presented a survivability rate of 86.1%, children with a normal nutrition state had an 86% survivability rate and in obese children the figure was of 85.9%. [39]

There's controversial information about the relationship between the effects of malnutrition in the evolution of patients with ALL, mostly because even with a wide range of studies, some conclude there's a significant relation between these factors [24,28,44] while others conclude that there's no relation. [37-39, 49]

One of the reasons is the bias in the classification of malnutrition, since in some studies like Pedroza and collaborators [38] the World Health Organization (WHO) charts are used, and in Rivera Luna and collaborators [37] they used the charts of the National Health and Nutri‐ tion Examination Survey (NHANES), while in the study conducted by Lobato Mendizabal and collaborators the charts of Ramos Galván were taken into account [44] and at last the study of Mejía Aranguré and collaborators used Federico Gómez' charts. [24]

In the studies mentioned, the sample was taken only from one or two hospital sources, so it's important to conduct a multicentre study that can show a wider panorama of the effects of malnourishment in the evolution of children with ALL.


**Autor (Year)**

**Lobato Mendiazabal et al. (1989)**

Classification CDC tables Waterlow`s

divided in 3 categories: <10° malnourished; >ó= 85° well nourished; > 85 < 95° overweight; >95 Obesity; Note: Chemotherapy dosage was not adjusted by BMI. Survival rate: 86.1%, 86.0%, 85.9% and 78.2% respectively BMI has no effect on the survival of LLA

children.

**leukemia**

Results Children were

**Mejía Aranguré et al. (1999)**

Age 1-16 years <14 years 1-15 years 0-16 years Parameters used BMI Weight-for-height Weight for age BMI, MUAC,(TSF)

Classification

Malnourished children: 46% complete treatment and were alive, 9.8% relapse and 45% died. Well nourished children: 59% complete treatment and were alive, 21.3% relapse and 19% died. " Malnutrition is a prognosis factor in LLA children"

**Table 8.** Studies about the effect of malnutrition at time of diagnosis and early mortality in children with ALL.

**4. Overweight and obesity in survivors of childhood acute lymphoblastic**

Concern about children who suffered from ALL is the long-term consequences that therapy may bring after the leukemia has been overcome. Various studies have shown that nutri‐ tional abnormalities like obesity and overweight are commonly found in ALL survivors, with a prevalence of 20-34% depending on the country where it has been studied. [52,53]

van Waas et al, conducted a study in 2004 in the Netherlands during the period from 2002 to 2007 in a single-center cohort of 500 survivors of childhood ALL. The ages of these patients at the time of the study ranged from 18 to 59 years, of which 288 were females and 212 were males, measured variables corresponded to the levels of total cholesterol, HDL cholesterol, systolic and diastolic blood pressure, BMI, and the authors finally concluded that patients who had been treated with cranial radiotherapy (CRT) had a higher frequency of over‐

weight (59% versus 34%, P = 0.003) than those who had not received CTR. [54]

**Pedrosa F. et al. (2000)**

Alterations of Nutritional Status in Childhood Acute Leukemia

Malnourished children are 3 times more likely to present infections tan well nourished ones. Malnourished children need more time of induction to remission treatment due to the dose reduction caused by

toxicity.

Not specified CDC Tables

**Rivera Luna et al. (2005)**

287

http://dx.doi.org/10.5772/52715

Malnutrition has no association with early mortality in children

with LLA.


**Autor (Year)**

Hospitals Centro de

Classification Ramos- Galvan's

Results 5-year survival in well

Hospitals St. Jude´s

Tables

nourished versus malnourished patients: 83% in well nourished Vs 26% in malnourished. Death and relapses: 4% in well nourished vs. 63% malnourished. Reduction of chemotherapy treatment: 75% in well nourished Vs. 56% malnourished.

Children Research

Hospital

**Lobato Mendiazabal et al. (1989)**

286 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

Hematología Medicina Interna and Hospital Universitario

de Puebla

Sample size 43 patients 93 patients,

**Mejía Aranguré et al. (1999)**

Hospital de Pediatría S. XXI and Hospital Infantil de México Federico Gómez

Type of study Prospective cohort Case- control Retrospective Cohort Retrospective Cohort

17 cases and 76 controls

Age 1-15 years <16 years 0-17.8 years 0-15 years

Federico Gómez

Children who had malnutrition at the time of diagnosis were 2.6 more likely to die than children without malnutrition;

Tables

therefore malnutrition increases mortality in children with LLA.

Country USA Pakistan Bangladesh El Salvador

Shaukat Khanum memorial Hospital

Type of study Retrospective cohort Prospective cohort Prospective cohort Prospective Cohort Sample size 621 patients 163 patients 66 patients 469 patients

Parameters used Weight-for-age Weight-for-height Weight-for-age,

Country Mexico Mexico El Salvador and Brazil Mexico

**Pedrosa F. et al. (2000)**

Hospital de niños Benjamín Bloom and Instituto Materno-Infantil de Pernambuco

443 patients 151 with ALL

Height-for-age Weight-for-height

Malnutrition has no association with survival of patients Note: A dose of Albumin was applied to malnourished children 2 weeks before they started treatment.

Pediatric Hematology and Oncology

**Rivera Luna et al. (2005)**

Instituto Nacional de

Pediatría

100 patients

Height-for-age, Weight-for-height

Nutrition

NHANES

15.1% of malnourished children died during the same stage of treatment, "Malnutrition does not play a role in early mortality in children with ALL".

Hospital de niños Benjamín Bloom

14.9% of well nourished children died during the induction to remission therapy;

examination survey

WHO`s Tables National Health and

**Table 8.** Studies about the effect of malnutrition at time of diagnosis and early mortality in children with ALL.

## **4. Overweight and obesity in survivors of childhood acute lymphoblastic leukemia**

Concern about children who suffered from ALL is the long-term consequences that therapy may bring after the leukemia has been overcome. Various studies have shown that nutri‐ tional abnormalities like obesity and overweight are commonly found in ALL survivors, with a prevalence of 20-34% depending on the country where it has been studied. [52,53]

van Waas et al, conducted a study in 2004 in the Netherlands during the period from 2002 to 2007 in a single-center cohort of 500 survivors of childhood ALL. The ages of these patients at the time of the study ranged from 18 to 59 years, of which 288 were females and 212 were males, measured variables corresponded to the levels of total cholesterol, HDL cholesterol, systolic and diastolic blood pressure, BMI, and the authors finally concluded that patients who had been treated with cranial radiotherapy (CRT) had a higher frequency of over‐ weight (59% versus 34%, P = 0.003) than those who had not received CTR. [54]

Obesity and overweight are defined are the result of varying degrees of abnormal or excessive accumulation of fat. The World Health Organization defines overweight as a BMI of 25 to 29.9, and obesity as a BMI of ≥30. The BMI modifications in survivors of childhood ALL are notewor‐ thy because they are associated with insulin resistance, diabetes mellitus, hypertension, dysli‐ pidemia and with an increased cardiovascular risk. [55]

Among many other physiological functions of the GH, this hormone promotes utilization of fats as source of energy, inducing the liberation of fatty acids into the bloodstream. At the same time,

Alterations of Nutritional Status in Childhood Acute Leukemia

http://dx.doi.org/10.5772/52715

289

Moreover, it has been recently suggested that only susceptible individuals will develop obesity when treated with CRT. This susceptibility has been tracked down to a polymor‐ phism in the leptin receptor in the hypothalamus. This polymorphism (Arg/Arg) was found by Ross et al., to be associated to females having a BMI ≥25, treated with CRT. [63] Leptin is a hormone produced by adipocytes and it is involved in feeding behavior regulation and energy balance. Stored energy in adipose tissue is closely watched by the hypothalamus, through this hormone. An increase in adipose tissue will be traduced in increased leptin synthesis by adipocytes, and by negative feedback over the hypothala‐

Because corticosteroids are used to treat ALL, it is important to point out that they also pro‐ mote leptin synthesis. However, conducted studies have only shown short-term effects on increasing body weight. However, these findings strongly suggest doing more research to determine if glucocorticoids induce long-term body weight via leptin synthesis or through

After it has been released to the blood stream, leptin reaches the central nervous system and binds to its receptors found in the hypothalamic neurons of the arcuate, ventrome‐ dial, and dorsomedial nuclei. The activation of the receptors, decreases the production of orexigenic (or appetite stimulant) substances such as neuropeptide Y and agouti-related peptide. It also activates the sympathetic nervous system, increasing the metabolic index and energy consumption. As for the insulin, leptin reduces its secretion, resulting in di‐

As it has been shown leptin insensitivity, would have repercussions in the regulation of body weight and metabolism. This leptin resistance can be attributed to abnormal receptors as well as malfunctioning intracellular signaling. [61] Either way, disruption of the leptin signaling, will eventually result in metabolic modifications that would lead to a raised BMI. Furthermore, ALL survivors with CRT have higher risk of developing other components of the metabolic syndrome. [53] Gurney at al. encountered that ALL survivors who received CRT have increased total cholesterol levels, abnormally low HDL-C, altered triglycerides

As it has been shown, treatment for ALL predisposes patients to suffer from obesity and metabolic alterations, not only after, but also during it. Because of this, physicians should make patients being treated for ALL and those who have overcome ALL, aware of the possi‐

and LDL-C, compared to those who were not given CRT. [65]

it has anabolic protein effects which are traduced in an increase of lean body mass. [62]

mus food intake will be inhibited. [64,65]

*4.1.2. Corticosteroid therapy*

other mechanisms. [66]

minished energy storage. [62]

**5. Conclusions**

#### **4.1. Mechanisms involved in the development of overweight and obesity in ALL survivors**

Because of this, the processes by which these nutritional abnormalities are developed by ALL survivors are being studied, though the exact mechanisms are still uncertain, nonethe‐ less, there are some hypotheses that would explain metabolic deregulations leading to the development of altered BMI by the excessive accumulation of body fat. Here we will focus on the effects due to radiotherapy and corticosteroids. However, it is important to point out that exist other factors linked to these alterations. For example, long hospitalization periods because of inmunosuppression or vincristine-induced peripheral neuropathy may cause re‐ stricted physical activity in these patients. In addition to this, it should not be left out the usual risk factors for developing obesity of each population. [56]

#### *4.1.1. Effects attributed to cranial radiation therapy*

In one of the largest studies conducted so far related to the effect of radiotherapy for the devel‐ opment of overweight and obesity in ALL survivors by Oeffinger et al, (2003), reported that the dose and radiation site were the mainly cause. This study was conducted during the period from 1980 to 1994 the study population corresponded to 1765cases and 2588 controls aged 18-42 years old. Considering a radiation dose greater than 20Gy there was a risk factor for obesity in men with an OR 1.86 for ills (95% CI, 1.33 to 2.57, P <.001) and in women with an OR of 2.59 (95% CI, 1.88 to 3.55, P <0.001), without observing this nutritional disorder in patients who had re‐ ceived chemotherapy alone or had received cranial radiation doses of 10 to 19 Gy. [57]

Lackner H et al 1991and subsequently by Janiszewski et al., (2007), reported that the levels of growth hormone (GH), insulin-like factor (IGF1) and leptin levels were significantly low‐ er in CRT than in non-CRT. [58,59]

The mechanism proposed to explain the growth hormone deficiency, holds that cranial radi‐ otherapy (CRT) given at a young age to treat children suffering from ALL, damages the hy‐ pothalamus neurons, inducing growth hormone deficiency (GHD). [60] Deficiency in the secretion of growth hormone (GH) has been associated with the augmented percentage of body fat. Evidence that supports these hypothesis are the decreased levels of IGF-1 (also known as somatomedine C), which is a mediator of the GH action in target tissues.

Apart from their individual effects, there is evidence that relates leptin and GH. GH and IGF-1 are decreased in response to fasting. Impaired GH synthesis and secretion occurs along with a leptin deficiency or abnormality on its receptor. Leptin may also regulate GH via somatostatin synthesis inhibition and secretion, allowing GH to yield its actions over the targeted tissues. [61]

Among many other physiological functions of the GH, this hormone promotes utilization of fats as source of energy, inducing the liberation of fatty acids into the bloodstream. At the same time, it has anabolic protein effects which are traduced in an increase of lean body mass. [62]

Moreover, it has been recently suggested that only susceptible individuals will develop obesity when treated with CRT. This susceptibility has been tracked down to a polymor‐ phism in the leptin receptor in the hypothalamus. This polymorphism (Arg/Arg) was found by Ross et al., to be associated to females having a BMI ≥25, treated with CRT. [63] Leptin is a hormone produced by adipocytes and it is involved in feeding behavior regulation and energy balance. Stored energy in adipose tissue is closely watched by the hypothalamus, through this hormone. An increase in adipose tissue will be traduced in increased leptin synthesis by adipocytes, and by negative feedback over the hypothala‐ mus food intake will be inhibited. [64,65]

#### *4.1.2. Corticosteroid therapy*

Obesity and overweight are defined are the result of varying degrees of abnormal or excessive accumulation of fat. The World Health Organization defines overweight as a BMI of 25 to 29.9, and obesity as a BMI of ≥30. The BMI modifications in survivors of childhood ALL are notewor‐ thy because they are associated with insulin resistance, diabetes mellitus, hypertension, dysli‐

Because of this, the processes by which these nutritional abnormalities are developed by ALL survivors are being studied, though the exact mechanisms are still uncertain, nonethe‐ less, there are some hypotheses that would explain metabolic deregulations leading to the development of altered BMI by the excessive accumulation of body fat. Here we will focus on the effects due to radiotherapy and corticosteroids. However, it is important to point out that exist other factors linked to these alterations. For example, long hospitalization periods because of inmunosuppression or vincristine-induced peripheral neuropathy may cause re‐ stricted physical activity in these patients. In addition to this, it should not be left out the

In one of the largest studies conducted so far related to the effect of radiotherapy for the devel‐ opment of overweight and obesity in ALL survivors by Oeffinger et al, (2003), reported that the dose and radiation site were the mainly cause. This study was conducted during the period from 1980 to 1994 the study population corresponded to 1765cases and 2588 controls aged 18-42 years old. Considering a radiation dose greater than 20Gy there was a risk factor for obesity in men with an OR 1.86 for ills (95% CI, 1.33 to 2.57, P <.001) and in women with an OR of 2.59 (95% CI, 1.88 to 3.55, P <0.001), without observing this nutritional disorder in patients who had re‐

Lackner H et al 1991and subsequently by Janiszewski et al., (2007), reported that the levels of growth hormone (GH), insulin-like factor (IGF1) and leptin levels were significantly low‐

The mechanism proposed to explain the growth hormone deficiency, holds that cranial radi‐ otherapy (CRT) given at a young age to treat children suffering from ALL, damages the hy‐ pothalamus neurons, inducing growth hormone deficiency (GHD). [60] Deficiency in the secretion of growth hormone (GH) has been associated with the augmented percentage of body fat. Evidence that supports these hypothesis are the decreased levels of IGF-1 (also

Apart from their individual effects, there is evidence that relates leptin and GH. GH and IGF-1 are decreased in response to fasting. Impaired GH synthesis and secretion occurs along with a leptin deficiency or abnormality on its receptor. Leptin may also regulate GH via somatostatin synthesis inhibition and secretion, allowing GH to yield its actions over the

ceived chemotherapy alone or had received cranial radiation doses of 10 to 19 Gy. [57]

known as somatomedine C), which is a mediator of the GH action in target tissues.

**4.1. Mechanisms involved in the development of overweight and obesity in ALL**

pidemia and with an increased cardiovascular risk. [55]

288 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

usual risk factors for developing obesity of each population. [56]

*4.1.1. Effects attributed to cranial radiation therapy*

er in CRT than in non-CRT. [58,59]

targeted tissues. [61]

**survivors**

Because corticosteroids are used to treat ALL, it is important to point out that they also pro‐ mote leptin synthesis. However, conducted studies have only shown short-term effects on increasing body weight. However, these findings strongly suggest doing more research to determine if glucocorticoids induce long-term body weight via leptin synthesis or through other mechanisms. [66]

After it has been released to the blood stream, leptin reaches the central nervous system and binds to its receptors found in the hypothalamic neurons of the arcuate, ventrome‐ dial, and dorsomedial nuclei. The activation of the receptors, decreases the production of orexigenic (or appetite stimulant) substances such as neuropeptide Y and agouti-related peptide. It also activates the sympathetic nervous system, increasing the metabolic index and energy consumption. As for the insulin, leptin reduces its secretion, resulting in di‐ minished energy storage. [62]

As it has been shown leptin insensitivity, would have repercussions in the regulation of body weight and metabolism. This leptin resistance can be attributed to abnormal receptors as well as malfunctioning intracellular signaling. [61] Either way, disruption of the leptin signaling, will eventually result in metabolic modifications that would lead to a raised BMI.

Furthermore, ALL survivors with CRT have higher risk of developing other components of the metabolic syndrome. [53] Gurney at al. encountered that ALL survivors who received CRT have increased total cholesterol levels, abnormally low HDL-C, altered triglycerides and LDL-C, compared to those who were not given CRT. [65]

## **5. Conclusions**

As it has been shown, treatment for ALL predisposes patients to suffer from obesity and metabolic alterations, not only after, but also during it. Because of this, physicians should make patients being treated for ALL and those who have overcome ALL, aware of the possi‐ bility to develop these changes, and should strongly advise them to develop healthy life‐ styles, in order to counteract this increased risk. In addition, strict medical follow-up should be set for the early detection of this alterations, so that adequate medical intervention and/or habit shifts could take place before irreversible damage has occurred.

[6] Kuvshinnikov VA. The nutritional status characteristics and the protein metabolic in‐

Alterations of Nutritional Status in Childhood Acute Leukemia

http://dx.doi.org/10.5772/52715

291

[7] Tazi I, Hidane Z, Zafad S, Harif M, Benchekroun S, Ribeiro R. Nutritional status at diagnosis of children with malignancies in Casablanca. Pediatric blood & cancer

[8] Sala A, Pencharz P, Barr RD. Children, cancer, and nutrition--A dynamic triangle in

[9] Barr RD, Ribeiro RC, Agarwal BR, Masera G, Hesseling PB, Magrath IT. Pediatric on‐ cology in countries with limited resources. In: Pizzo PA, Poplack DG. (eds.) Princi‐ ples and practice of pediatric oncology. Philadelphia: Lippincott, Williams and

[10] Dávila-Rodríguez MI, Novelo-Huerta HI, Márquez-Solís R, Cortés-Gutiérrez E, Pér‐ ez-Cortés P, Cerda-Flores RM. [Nutritional indicators in children with acute lympho‐ blastic leukemia]. Revista médica del Instituto Mexicano del Seguro Social 2010 Nov-

[11] Zalina AZ Jr, Suzana S, A Rahman AJ, Noor Aini MY. Assessing the nutritional sta‐ tus of children with leukemia from hospitals in kuala lumpur. Malaysian journal of

[12] Waterlow JC. Classification and definition of protein-calorie malnutrition. British

[13] Waterlow JC, Buzina R, Keller W, Lane JM, Nichaman MZ, Tanner JM. The presenta‐ tion and use of height and weight data for comparing the nutritional status of groups of children under the age of 10 years. Bulletin of the World Health Organization .

[14] Frisancho, A. R.; Tracer, S. P. Standards of arm muscle by stature for the assessment of nutritional status of children. American journal of physical anthropology 1987.

[15] Poskitt, E. Clinical nutritional assessant. Ed in: Practical Paediatric Nutrition. Lon‐

[16] Koskelo EK, Saarinen UM, Siimes MA. Low levels of serum transport proteins indi‐ cate catabolic protein status during induction therapy for acute lymphoblastic leuke‐

[17] Ingenbleel Y. DcVisscher M. DcNayeT P. Measurement of prealbumin as an index of

[18] Mejía-Aranguré JM, Bonilla M, Lorenzana R, Juárez-Ocaña S, de Reyes G, Pérez-Sal‐ divar ML, González-Miranda G, Bernáldez-Ríos R, Ortiz-Fernández A, Ortega-Alvar‐ ez M, Martínez-García M del C, Fajardo-Gutiérrez A. Incidence of leukemias in

mia. Pediatric hematology and oncology 1991 Jan-Mar;8(1):53-9.

protein-calorie malnutrition. Lancet 1972; 2(7768):106-9.

dices of children with acute leukemia. Voprosy pitaniia 1990;(3):24-8.

2008;51(4):495-8. ISSN:

Wilkins; 2002. p1541–1552.

nutrition 2009 Mar;15(1):45-51.

medical journal. 1972 Sep 2;3(5826):566-9.

Dec;48(6):639-44.

1977;55(4):489–498.

don; Butterworth, 1988

73(4):459-65

review. Cancer 2004;100(4):677-87.

## **Acknowledgements**

This work was funded by the Instituto Mexicano del Seguro Social through its program, Apoyo Financiero para el Desarrollo de Protocolos de Investigación en Salud en el IMSS(2005/1/I/078; FIS/IMSS/PROT/PRIO/11/017).

## **Author details**

Alejandra Maldonado-Alcázar, Juan Carlos Núñez-Enríquez, Carlos Alberto García-Ruiz, Arturo Fajardo-Gutierrez and Juan Manuel Mejía-Aranguré\*

\*Address all correspondence to: juan.mejiaa@imss.gob.mx

Research Unit in Clinical Epidemiology, Hospital of Pediatrics, National Medical Center 21st Century, Mexican Institute of Social Insurance, (IMSS), Mexico City, Mexico

### **References**


[6] Kuvshinnikov VA. The nutritional status characteristics and the protein metabolic in‐ dices of children with acute leukemia. Voprosy pitaniia 1990;(3):24-8.

bility to develop these changes, and should strongly advise them to develop healthy life‐ styles, in order to counteract this increased risk. In addition, strict medical follow-up should be set for the early detection of this alterations, so that adequate medical intervention and/or

This work was funded by the Instituto Mexicano del Seguro Social through its program, Apoyo Financiero para el Desarrollo de Protocolos de Investigación en Salud en el

Alejandra Maldonado-Alcázar, Juan Carlos Núñez-Enríquez, Carlos Alberto García-Ruiz,

Research Unit in Clinical Epidemiology, Hospital of Pediatrics, National Medical Center 21st

[1] Krebs NF, Primak LE., Haemer M. Normal Childhood Nutrition & Its Disorders. In: Hay WW, Levin MJ, Sondheimer JM, Deterding RR, (eds.) CURRENT Diagnosis & Treatment: Pediatrics. New York: McGraw-Hill; 2011. Chapter 10. Available from http://www.accessmedicine.com/content.aspx?aID=6578685 (accessed August 19

[2] Brinksma A, Huizinga G, Sulkers E, Kamps W, Roodbol P, Tissing W. Malnutrition in childhood cancer patients: A review on its prevalence and possible causes. Critical

[3] Kramárová E, Stiller CA. The international classification of childhood cancer. Inter‐

[4] Draper GJ, Kroll ME, Stiller CA. Childhood cancer. Cancer surveys

[5] Reilly JJ, Odame I, McColl JH, McAllister PJ, Gibson BE, Wharton BA. Does weight for height have prognostic significance in children with acute lymphoblastic leuke‐ mia? The American journal of pediatric hematology/oncology 1994;16(3):225-30.

Century, Mexican Institute of Social Insurance, (IMSS), Mexico City, Mexico

reviews in oncology/hematology. 2012;83(2):249-75.

national journal of cancer 1996;68(6):759-65.

habit shifts could take place before irreversible damage has occurred.

290 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

IMSS(2005/1/I/078; FIS/IMSS/PROT/PRIO/11/017).

Arturo Fajardo-Gutierrez and Juan Manuel Mejía-Aranguré\*

\*Address all correspondence to: juan.mejiaa@imss.gob.mx

**Acknowledgements**

**Author details**

**References**

2012)

1994;19-20:493-517.


children from El Salvador and Mexico City between 1996 and 2000: population-based data. BMC Cancer 2005;5:33.

New York: McGraw-Hill; 2012. Chapter 81. Available from http://www.accessmedi‐

Alterations of Nutritional Status in Childhood Acute Leukemia

http://dx.doi.org/10.5772/52715

293

[31] kumar R, Marwaha RK, Bhalla AK, Gulati M. Protein energy malnutrition and skele‐ tal muscle wasting in childhood acute lymphoblastic leukemia. Indian pediatrics

[32] Koskelo EK, Saarinen UM, Siimes MA. Skeletal muscle wasting and protein-energy malnutrition in children with a newly diagnosed acute leukemia. Cancer 1990;66(2):

[33] Lobato-Mendizábal E, Ruiz-Argüelles GJ, Marín-López A. Leukaemia and nutrition. I: Malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia. Leukemia research 1989;13(10):

[34] Shills ME, Young VR. Modern nutrition in Health and Disease. Philadelphia: Lea &

[35] Mejía-Aranguré JM, Fajardo-Gutiérrez A, Reyes-Ruíz NI, Bernáldez-Ríos R, Mejía-Domínguez AM, Navarrete-Navarro S, Martínez-García MC. Malnutrition in child‐ hood lymphoblastic leukemia: a predictor of early mortality during the induction-toremission phase of the treatment. Archives of medical research 1999;30(2):150-3. [36] Khan AU, Sheikh MU, Intekhab K. Pre-existing malnutrition and treatment outcome in children with acute lymphoblastic leukaemia. The Journal of the Pakistan Medical

[37] Rivera-Luna R, Olaya-Vargas A, Velásquez-Aviña M, Frenk S, Cárdenas-Cardós R, Leal-Leal C, Pérez-González O, Martínez-Avalos A. Early death in children with acute lymphoblastic leukemia: does malnutrition play a role? Pediatric hematology

[38] Pedrosa F, Bonilla M, Liu A, Smith K, Davis D, Ribeiro RC, Wilimas JA. Effect of mal‐ nutrition at the time of diagnosis on the survival of children treated for cancer in El Salvador and Northern Brazil. Journal of pediatric hematology/oncology 2000;22(6):

[39] Hijiya N, Panetta JC, Zhou Y, Kyzer EP, Howard SC, Jeha S, Razzouk BI, Ribeiro RC, Rubnitz JE, Hudson MM, Sandlund JT, Pui CH, Relling MV. Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lym‐

[40] Howard SC, Wilimas JA. Delays in diagnosis and treatment of childhood cancer: where in the world are they important? Pediatric blood & cancer 2005;44(4):303-4. [41] Slats AM, Egeler RM, van der Does-van den Berg A, Korbijn C, Hählen K, Kamps WA, Veerman AJ, Zwaan CM. Causes of death--other than progressive leukemia--in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch

Childhood Oncology Group experience. Leukemia 2005;19(4):537-44.

cine.com/content.aspx?aID=9114033 (accessed August 18 2012).

2000;37(7):720-6.

373-6.

899-906.

502-5.

Febiger;1988. p628.

Association 2006;56(4):171-3.

and oncology 2008;25(1):17-26.

phoblastic leukemia. Blood 2006;108(13):3997-4002.


New York: McGraw-Hill; 2012. Chapter 81. Available from http://www.accessmedi‐ cine.com/content.aspx?aID=9114033 (accessed August 18 2012).

[31] kumar R, Marwaha RK, Bhalla AK, Gulati M. Protein energy malnutrition and skele‐ tal muscle wasting in childhood acute lymphoblastic leukemia. Indian pediatrics 2000;37(7):720-6.

children from El Salvador and Mexico City between 1996 and 2000: population-based

[19] Draper GJ, Kroll ME, Stiller CA. Childhood cancer. Cancer surveys 1994;19-20:

[20] Mejía Aranguré JM, Ortega Alvarez MC, Fajardo Gutiérrez A. Acute leukemias epi‐ demiology in children. Part 1. Revista médica del Instituto Mexicano del Seguro So‐

[21] Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pedia‐

[22] Uderzo C, Rovelli A, Bonomi M, Barzaghi A, Strada S, Balduzzi A, Pirovano L, Ma‐ sera G. Nutritional status in untreated children with acute leukemia as compared with children without malignancy. Journal of pediatric gastroenterology and nutri‐

[23] Reilly JJ, Weir J, McColl JH, Gibson BE. Prevalence of protein-energy malnutrition at diagnosis in children with acute lymphoblastic leukemia. Journal of pediatric gastro‐

[24] Mejía-Arangure JM, Fajardo-Gutíerrez A, Bernáldez-Ríos R, Rodríguez-Zepeda MC, Espinoza-Hernández L, Martínez-García MC. Nutritional state alterations in children with acute lymphoblastic leukemia during induction and consolidation of chemo‐

[25] Delbecque-Boussard L, Gottrand F, Ategbo S, Nelken B, Mazingue F, Vic P, Farriaux JP, Turck D. Nutritional status of children with acute lymphoblastic leukemia: a lon‐

[26] Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rub‐ nitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leuke‐ mia without cranial irradiation. The New England journal of medicine 2009;360(26):

[27] Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. Lippincott Wil‐

[28] Hafiz MG, Mannan MA. Nutritional status at initial presentation in childhood acute lymphoblastic leukemia and its effect on induction of remission. Mymensingh medi‐

[29] Murry DJ, Riva L, Poplack DG. Impact of nutrition on pharmacokinetics of anti-neo‐

[30] Longo DL. Approach to the Patient with Cancer. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, (eds.) Harrison's Principles of Internal Medicine.

plastic agents. International journal of cancer 1998;11:48-51.

gitudinal study. The American journal of clinical nutrition 1997;65(1):95-100.

data. BMC Cancer 2005;5:33.

cial 2005;43(4):323-33.

tion 1996 ;23(1):34-7.

2730-41.

liams & Wilkins;2011

cal journal 2008;17(2 Suppl):S46-51.

tric clinics of North America. 2008;55(1):1-20, ix.

292 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

enterology and nutrition 1999;29(2):194-7.

therapy. Archives of medical research 1997;28(2):273-9.

493-517.


[42] Lobato-Mendizábal E, López-Martínez B, Ruiz-Argüelles GJ. A critical review of the prognostic value of the nutritional status at diagnosis in the outcome of therapy of children with acute lymphoblastic leukemia. Revista de investigación clínica 2003;55(1):31-5.

[52] Nathan PC, Jovcevska V, Ness KK, Mammone D'Agostino N, Staneland P, Urbach SL, Barron M, Barrera M, Greenberg ML. The prevalence of overweight and obesity in pediatric survivors of cancer. The Journal of pediatrics 2006 Oct;149(4):518-25. [53] Skoczen S, Tomasik PJ, Bik-Multanowski M, Surmiak M, Balwierz W, Pietrzyk JJ, Sztefko K, Gozdzik J, Galicka-Latała D, Strojny W. Plasma levels of leptin and soluble leptin receptor and polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R, in survivors of childhood acute lymphoblastic leukemia. Journal

Alterations of Nutritional Status in Childhood Acute Leukemia

http://dx.doi.org/10.5772/52715

295

[54] van Waas M, Neggers SJ, Pieters R, van den Heuvel-Eibrink MM. Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer. Annals of

[55] World Health Organization. WHO: Obesity and Overweight. Fact Sheet N°311. May 2012 http://www.who.int/mediacentre/factsheets/fs311/en/(accessed 20 August 2012)

[56] Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematology/oncology clinics of North

[57] Oeffinger KC, Mertens AC, Sklar CA, Yasui Y, Fears T, Stovall M, Vik TA, Inskip PD, Robison LL. Childhood Cancer Survivor Study. Obesity in adult survivors of child‐ hood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor

[58] Lackner H, Schwingshandl J, Pakisch B, Knoblauch S, Mutz I, Urban C. [Endocrino‐ logic function following cranial irradiation in acute lymphoblastic leukemia inchild‐

[59] Janiszewski PM, Oeffinger KC, Church TS, Dunn AL, Eshelman DA, Victor RG, Brooks S, Turoff AJ, Sinclair E, Murray JC, Bashore L, Ross R. Abdominal obesity, liv‐ er fat, and muscle composition in survivors of childhood acute lymphoblastic leuke‐ mia. The Journal of clinical endocrinology and metabolism 2007;92(10):3816-21. [60] Diller L, Chow EJ, Gurney JG, Hudson MM, Kadin-Lottick NS, Kawashima TI, Lei‐ senring WM, Meacham LR, Mertens AC, Mulrooney DA, Oeffinger KC, Packer RJ, Robison LL, Sklar CA. Chronic disease in the Childhood Cancer Survivor Study co‐ hort: a review of published findings. Journal of clinical oncology 2009;27(14):2339-55.

[61] Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine sys‐

[62] Guyton AC, Hall JE. Pituitary hormones and their control by the hypothalamus. In: Textbook of Medical Physiology. Philadelphia: Saunders Elsevier; 2011. Chapter 75. [63] Ross JA, Oeffinger KC, Davies SM, Mertens AC, Langer EK, Kiffmeyer WR, Sklar CA, Stovall M, Yasui Y, Robison LL. Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Journal of clinical oncology 2004;22(17):3558-62.

of experimental & clinical cancer research 2011 Jun 1;30:64.

oncology 2010;21(5) 1121-6.

America 2009 Oct;23(5):1065-82, vi-vii.

Study. Journal of clinical oncology 2003;21(7) 1359-65.

hood]. Wiener klinische Wochenschrift 1991;103(19):581-4.

tems. Frontiers in neuroendocrinology 2000 Jul;21(3):263-307.


[52] Nathan PC, Jovcevska V, Ness KK, Mammone D'Agostino N, Staneland P, Urbach SL, Barron M, Barrera M, Greenberg ML. The prevalence of overweight and obesity in pediatric survivors of cancer. The Journal of pediatrics 2006 Oct;149(4):518-25.

[42] Lobato-Mendizábal E, López-Martínez B, Ruiz-Argüelles GJ. A critical review of the prognostic value of the nutritional status at diagnosis in the outcome of therapy of children with acute lymphoblastic leukemia. Revista de investigación clínica

[43] Weir J, Reilly JJ, McColl JH, Gibson BE. No evidence for an effect of nutritional status at diagnosis on prognosis in children with acute lymphoblastic leukemia. Journal of

[44] Marín-López A, Lobato-Mendizabal E, Ruiz-Argüelles GJ. Malnutrition is an adverse prognostic factor in the response to treatment and survival of patients with acute lymphoblastic leukemia at the usual risk. Gaceta médica de México 1991;127(2):

[45] Lobato Mendizábal E, Ruiz-Argüelles GJ. [Leukemia and malnutrition. III. Effect of chemotherapeutic treatment on the nutritional state and its repercussion on the ther‐ apeutic response of patients with acute lymphoblastic leukemia with standard risk].

[46] Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Arkin S, Declerck L, Cohen HJ, Sallan SE. Im‐ proved outcome for children acute lymphoblastic leukemia: results of Dana Farber

[47] Hargrave DR, Hann II, Richards SM, Hill FG, Lilleyman JS, Kinsey S, Bailey CC, Chessells JM, Mitchell C, Eden OB; Medical Research Council Working Party for Childhood Leukaemia. Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997

(UKALL VIII, X and XI) British journal of haematology 2001 Feb;112(2):293-9.

[48] Metzger ML, Howard SC, Fu LC, Peña A, Stefan R, Hancock ML, Zhang Z, Pui CH, Wilimas J, Ribeiro RC. Outcome of childhood acute lymphoblastic leukaemia in re‐

[49] Gupta S, Bonilla M, Fuentes SL, Caniza M, Howard SC, Barr R, Greenberg ML, Ri‐ beiro R, Sung L. Incidence and predictors of treatment-related mortality in paediatric

[50] Howard SC, Pedrosa M, Lins M, Pedrosa A, Pui CH, Ribeiro RC, Pedrosa F. Estab‐ lishment of a pediatric oncology program and outcomes of childhood acute lympho‐ blastic leukemia in a resource-poor area. The journal of the American Medical

[51] Advani S, Pai S, Venzon D, Adde M, Kurkure PK, Nair CN, Sirohi B, Banavali SD, Hawaldar R, Kolhatkar BB, Vats T, Magrath I. Acute lymphoblastic leukemia in In‐ dia: an analysis of prognostic factors using a single treatment regimen. Annals of on‐

acute leukaemia in El Salvador. British journal of cancer 2009;100(7):1026-31.

Consortium Protocol 91-01. Blood 2001 Mar 1;97(5):1211-8.

source-poor countries. Lancet. 2003;362(9385):706-8.

Association 2004;291(20):2471-5.

cology 1999 Feb;10(2):167-76.

pediatric hematology/oncology 1998;20(6):534-8.

294 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

2003;55(1):31-5.

125-31; discussion 131-2.

Sangre 1990;35(3):189-95.


[64] Garmey EG, Liu Q, Sklar CA, Meacham LR, Mertens AC, Stovall MA, Yasui Y, Robi‐ son LL, Oeffinger KC. Longitudinal changes in obesity and body mass index among adult survivors of childhood acute lymphoblastic leukemia: a report from the Child‐ hood Cancer Survivor Study. Journal of clinical oncology 2008;26(28) 4639-45.

**Chapter 13**

**Acute Lymphoblastic Leukemia (ALL) Philadelphia**

**Positive (Ph1) (Incidence Classifications, Prognostic**

ALL is a malignancy of lymphoid cells occurring at any age. Almost 5000 cases are diagnosed annually in the USA. Cell-B subtypes account for 85–90% of cases in children and 75–80% of cases in adults; T-lineage ALL accounts for a small proportion of cases. It has a bimodal incidence occurring at 2–4 years of age followed by a gradual increase after the age of 50.

In the last years much progress has been made in understanding the biology of acute lymphoblastic leukemia which is now recognized as an expanding group of heterogene‐ ous entities. Recognition of distinct gene expression patterns may identify patient sub‐ group with unique response to therapy and prognosis. Accurate definition of prognostic subgroups based on cytogenetic molecular marker has allowed institution of risk orient‐ ed therapies. [2] The Philadelphia (Ph1+) chromosome was first described in 1960 in a patient with chronic myeloid leukemia (CML). This is the product of the fusion of

The incidence is approximately 20-30 % of adult patients with ALL who present the Philadel‐ phia (Ph) Chromosome. Whereas Ph+ ALL is rare in children, comprising less than 5% of acute lymphoblastic leukemia, its incidence increases to approximately 40% in adults 40 years of age, with a 10% increment for every further decade of life with no sex difference. The majority of patients are diagnosed with de novo Ph+ ALL, although occasional cases of secondary Ph1+, ALL have been reported following chemotherapy or radiation therapy. [3, 4]. There are no known risk factors for Ph+ ALL. The associations with environmental socioeconomic infections and genetic events are being studied extensively in ALL. Few causal links have been estab‐ lished and the etiology of ALL remains obscure in most cases. The strongest associations to

and reproduction in any medium, provided the original work is properly cited.

© 2013 Enrico and Milone; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

chromosomes 9 and 22, t (9;22), which results in a BCR-ABL hybrid gene. [2]

**Factor in ALL Principles of ALL Therapy)**

Alicia Enrico and Jorge Milone

http://dx.doi.org/10.5772/55095

**1. Introduction**

Additional information is available at the end of the chapter

