**2. Physiopathology**

*Geriatric Medicine and Gerontology*

them were prospective studies [3].

age group of patients with ALL [4].

hepatomegaly or splenomegaly [5].

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

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

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

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 clini-

cally 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

**136**

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


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

single genetic rearrangement is not enough to induce leukemia. Cooperative mutations are necessary for leukemic transformation and include genetic and epigenetic changes in regulatory growth pathways. Candidate genes identified include deletion of the tumor suppressor locus CDKN2A/CDKN2B and NOTCH1 mutations in T cells. The use of single nucleotide polymorphism (SNP) microarrays suggests that genomic instability is not characteristic of most cases. There is a great variation in the number of alterations in different subtypes of leukemia. The infant cases with rearrangements of the MLL gene had less than one copy number alterations (CNA) per case, suggesting that few genetic lesions are required. Conversely, cases with ETV6-RUNX1 [25] and BCR-ABL1 had more than six CNAs, some containing more than 20 lesions, which support the concept that despite the initiating events that may occur in early infancy, additional lesions are required for the subsequent development of ALL. The lymphoid transcription factor PAX5 encodes a protein involved in evolution and fidelity of the B-cell lineage. The second most frequently affected gene was IKZF1, which encodes the protein IKAROS, required for lymphoid differentiation. IKZF1 is absent in most cases with BCR-ABL1. Approximately, half of the patients expressing BCRABL1 also had deletions in CDKN2A/B and PAX5. This finding suggests that alterations in different signaling pathways are needed to induce leukemia [15]. A special role in this disease is played by the presence of the Philadelphia chromosome t (9; 22), which expresses the BCR-ABL fusion gene, and this has diagnostic, prognostic, and therapeutic implications [3, 6–11].
