**Abstract**

The management of acute lymphoblastic leukemia is a challenge in patients of any age range. In the elderly patient, this challenge is further complicated by having to take into account the physical, social, psychological, and emotional factors of this age group, which, together with the complex nature of the disease's biology, give rise to many questions. Although the diagnostic approach of the disease does not differ from that performed in pediatric or young patients, it does in the determination of risk factors and treatment, since many of the determinants of risk have a different value to that assigned in other patients, and, therefore, we cannot apply all available resources in younger patients to facilitate our work. The genetic alterations of ALL are found more frequently in elderly patients, since age is a factor that increases the risk of presenting these alterations. As an example, the prognostic value of the presence of Philadelphia chromosome (t (9:22)) cannot be weighted at the same scale as in pediatric patients. Comorbidities play another important role when it comes to making therapeutic decisions, and there is currently controversy regarding the use of scores designed to determine the physical and physiological status of elderly subjects. Several analyzes have been carried out to define the value and usefulness of these tools in the older patients with ALL; however, work must still be done in this area. The treatment schemes should be adjusted to the needs and specific characteristics of each individual in advanced age. The use of intensive chemotherapy should be discussed within a multidisciplinary team, always considering the benefit of our patients. In the present chapter, the diverse differences in ALL biology will be addressed when compared with those of children and young adults, and with the impact on the different prognostic determinants and their weight at the time of deciding treatment. The need to apply geriatric tools for decision-making and the therapeutic schemes used around the world for elderly people will also be discussed.

**Keywords:** acute lymphoblastic leukemia, long-term survival, older adults, remission, leukemia-free survival, overall survival, death

#### **1. Introduction**

Acute lymphoblastic leukemia (ALL) is a rare disease in the elderly. The prevalence of ALL in patients >60 years of age is reported to be between 16 and 31% of all adult cases. In adults, it represents approximately 20% of all leukemia [1].

The age-adjusted incidence rate of ALL in the United States is 1.58 for every 100,000 persons per year. About 57.2% of the patients diagnosed are under 20 years of age, 26.8% of patients diagnosed are over 45 years of age, and 11% of patients diagnosed are over 65 years of age [2]. The biology of ALL in older patients seems

to be significantly different from that in younger patients and may, at least in part, explain the poor treatment outcome. Immunophenotyping and cytogenetic characteristics are among the most important biological differences in comparison with younger adults. The frequency of pre-B-cell ALL and common ALL is higher, and T-cell ALL subtype is under-represented in elderly populations compared with younger patients. The frequency of the Philadelphia chromosome also seems to increase with age and adversely influences complete remission rate and survival. Few reports on the effectiveness and toxicity of therapeutic programs concerning exclusively older patients with ALL have been published so far and only some of them were prospective studies [3].

In some of the studies, age-adapted approaches have been applied in which protocols processed earlier for younger patients have been adopted for older patients. In such modified protocols, chemotherapy was usually less aggressive, especially if it was given for patients with comorbidities and poor performance status. Consequently, in several studies, elderly patients received suboptimal treatment. Death during induction chemotherapy was observed in 7–42% of the patients in particular reports. The overall response rate varied from 12 to 85%. The median overall survival (OS) durations in patients who received a curative approach ranged from 3 to 14 months and from 1 to 14 months in patients treated with palliative therapy. Poor performance status, comorbidities, and high early mortality during intensive chemotherapy are the main reasons for poor treatment results and short OS time. New therapeutic approaches are necessary to improve the outcome in this age group of patients with ALL [4].

The implementation of tools aimed to determining the safety of treatments in elderly patients based on protocols that have previously been applied and validated in younger patients is a common practice today. A recently identified problem when applying these tasks is the underutilization of treatments with curative purposes in this group. An example of this is the CIRS-G scale, widely used to determine the risk of complications in patients with various comorbidities [4]. This phenomenon has been recorded in various efficacies and safety analyzes of treatment for acute lymphoblastic leukemia in elderly patients based on similar scales, where an important survival difference has been observed between the groups treated for curative purposes and those who received reduced therapy. Of course, comorbidities play an important role in these poor results, which forces us to search for new therapeutic options [5].

The clonal origin of ALL has been established using cytogenetic analysis; restriction fragment analysis in female patients, which are heterozygous for polymorphic genes linked to the X chromosome; and analysis of T-cell receptor or immunoglobulin gene rearrangements. The clinical manifestations are very variable and insidious. The symptoms generally reflect bone marrow failure characterized by four syndromes: anemia, hemorrhage, febrile, and infiltrative. Nearly, half of the patients present with some kind of infectious process at diagnosis. Bone infiltration may produce pain and arthralgia. Additionally, close to half the patients have hepatomegaly or splenomegaly [5].

The long-term survival of older adults with acute lymphoblastic leukemia (ALL) who are intensively treated is about 40% [1]. Hematologic remissions are obtained in over 90% of patients, and the depth of these remissions using flow cytometry and molecular techniques is the subject of current studies. It is likely that, with time, new response definitions based on these tests will be established. The adult patients were divided into age 30 years and 30–60 years, because this seemed clinically relevant, and available data best dealt with these age categories. However, these divisions are not absolute or evidence-based, and an individual's biologic age and general fitness are of paramount importance. There are no randomized studies in older adults that demonstrate "pediatric" approaches to be

**137**

*Overview and Current News in Acute Lymphoblastic Leukemia*

superior, and indeed, the single-arm studies are still small scale in this age group, with insufficient follow-up. Much is unknown, but the wide variety of trials being

The development of ALL is driven by successive mutations that alter cellular

Different hereditary DNA repair disorders can play an important role in the induction of this disease. Furthermore, mutagenic environmental agents, which can be physical (ionizing radiation), chemical (benzene), and biological (HTLV-1), can also be involved. However, in most cases, there are no identifiable etiologic agents. The precise pathogenic events that lead to the development of ALL are unknown. About 5% of the cases are associated with genetic predisposition syndromes. This is the case for children with Down syndrome, who have a 10–30 times greater risk of leukemia and present genetic abnormalities such as hyperdiploidy and t (12; 21) [ETV6-RUNX1], +X, del (9), and alteration in CCAAT//enhacer-binding protein beta (CEBPD). It has been demonstrated that the fusion of P2RY8-CRLF2 and the activation of JAK mutations contribute to 50% of the ALL cases in patients with Down syndrome. Ninety percent have a deletion of IKZF12015. The disorders associated with chromosomal fragility that have been found to predispose to ALL include ataxia-telangiectasia, Nijmegen syndrome, and Bloom syndrome [7]. Patients with ataxia-telangiectasia have 70 times greater risk of leukemia and 250 times greater risk of lymphoma, particularly of T cells. The causal gene, ataxia-telangiectasia mutated (ATM), encodes a protein implicated in DNA repair and regulation of cellular proliferation and apoptosis [2, 7, 8]. Complete genome sequencing studies have identified a number of common allelic variants in four genes (IKZF1, ARID5B, CEBPE, and y CDKN2A) associated with infant ALL. The allelic variant inherited can affect the response to treatment. In utero exposure to X-rays for diagnostic use can confer a slight increase in risk for ALL, which positively correlates with exposure intensity. Data exist that support a causal role for polymorphisms in genes that encode antioxidant enzymes (for example: glutathione S-transferase, nicotinamide adenine dinucleotide phosphate (NADPH), quinone oxidoreductase), folate metabolic enzymes (serine hydroxymethyltransferase and thymidylate synthase), cytochrome 450, methylenetetrahydrofolate reductase, and cell cycle inhibitors [3, 5, 8, 9]. Specific fusion genes have been identified in leukemia, the most noteworthy being KMT2A/AFF1 (also known as MLL-AF4) and ETV6-RUNX1 or TEL-AML1; additionally, there is hyperploid and rearrangements of immunoglobulin or T-cell receptor genes. The acquired genetic anomalies are a hallmark, 80% of all cases contain cytogenetic or molecular lesions with abnormalities in chromosome number (ploidy) and structure. The mechanisms involved include aberrant expression of oncoproteins, loss of tumor suppressor genes, and chromosomal translocations, which generate fusion genes that encode transcription factors of active kinases. A

*DOI: http://dx.doi.org/10.5772/intechopen.86662*

• greater ability for self-renewal,

• blockage of differentiation, and

• resistance to apoptotic signals.

• greater proliferation,

**2. Physiopathology**

functions promoting

conducted in adults with ALL is heartening [6].

superior, and indeed, the single-arm studies are still small scale in this age group, with insufficient follow-up. Much is unknown, but the wide variety of trials being conducted in adults with ALL is heartening [6].
