José Luis Fedele

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of lymphoid disorders that result from clonal proliferation and expansion of immature lymphocytes in bone marrow, peripheral blood, and other organs.

A better understanding of the biology of ALL has led to changes in the pathological classification of the disease, together with the emergence of new therapies adapted to the risk of each group.

Over the past decades, advances in treatment have led to long-term survival rates in children of close to 80%.

Today, rates of only 40% can be achieved in adults, by adapting the therapeutic strategies of children to the latter.

However, with better molecular knowledge of the subtypes of ALL, the development of new drugs and the knowledge of the biological differences between ALL in children and adults, it is expected that survival in adults will be comparable to pediatric survival in the coming years. .

Pathophysiology

ALL has a global incidence of 1 to 1.5 per 100,000 people / year with a bimodal distribution patent.

It has a clear peak incidence at 4 to 5 years of life, with an incidence at this age of 4 to 5 per 100,000 / person / year; followed by a second, more gradual peak at age 50, with an estimated incidence of 2 per 100,000 people / year.

ALL is the most common leukemia in childhood, representing approximately 80% of acute leukemia in this stage of life; being only 20% of Acute Leukemia in adults.

ALL is relatively rare in late childhood, adolescence, and young adults.

The causes of ALL in most patients remain unknown.

A high incidence of ALL has been observed in monozygotic and dizygotic twins of patients with ALL, reflecting a possible genetic predisposition.

Patients with Down Syndrome, Klinefelter Syndrome and diseases related to excessive chromosomal fragility such as Fanconi Anemia, Bloom Syndrome, and Telangiectatic Ataxia, are also at higher risk for ALL.

Recent studies have implicated a protective effect of the polymorphism of the Methylenetetrahydrofolate reductase (MTHFR) gene in infants and adults for ALL, pointing once again towards genetic susceptibility as part of the etiology of ALL.

Recent data indicate that the most common translocations of preleukemic genes occur in intrauterine life, during fetal hematopoiesis, with secondary genetic events that occur later in postnatal life, leading at that time to the development of the clinical picture.

Other factors such as infections have been reported as etiological in the pathogenesis of ALL.

Associations with the Human T Lymphotropic Virus (HTLV-1), Epstein-Baar virus, HIV, Varicella virus and Influenza, have been suggested in the pathogenesis of B and T lymphoproliferative processes.

Symptoms and signs

The most common clinical presentation of ALL is nonspecific.

Symptoms reflect failure of spinal function and / or other organs due to blast infiltration.

Typically, the appearance of symptoms is manifested gradually or subacute, over the course of several days or weeks.

Dyspnea, asthenia, anorexia, dizziness, and recurrent infections are common at presentation. B symptoms (fever - night sweats - weight loss), can occur.

Symptoms associated with hyperleukocytosis are rare in ALL, unlike what occurs in AML. Symptoms related to the CNS are common in some subtypes of ALL (mature B-cell ALL), and are related to meningeal infiltration with cranial nerve palsy or meningeal syndrome, but globally they are observed in only 5 to 8% of patients.

Also associated with mature B-cell ALL, abdominal masses and / or spontaneous tumor lysis syndrome can be observed.

On physical examination, it is common to find paleness, petechiae, or bruises.

Lymphadenopathy or hepatosplenomegaly, rarely symptomatic, are seen in only 20% of patients. When present they strongly orient towards a mature B or T cell subtype.

The presence of lytic bone lesions and hypercalcemia are suggestive of adult T-Lymphoma / Leukemia.

In the initial laboratory it is common to observe anemia with hemoglobin levels less than 10 g / dl in more than 80% of patients, moderate platelet penia and leukocytosis with lymphocytosis. In 50% of the patients, the initial white blood cell count is greater than 20,000 mm3, and in 15 to 20% there are levels greater than 100,000 mm3.

The almost constant elevation of serum lacticdehydrogenase and uric acid stand out.

Study methodology

For the diagnosis of ALL, it is important to obtain a careful medical history, physical examination, and exploration of peripheral blood and mainly bone marrow.

Morphology findings, immunostaining by flow cytometry, and the identification of cytogenetic abnormalities in samples obtained from peripheral blood and bone marrow, constitute today an unavoidable tool for the correct characterization and typing of the different subtypes of ALL.

Smear aspirate smears show increased cellularity with replacement of much of the marrow by blast cells.

Simultaneously with the direct study of the blood and bone marrow, imaging studies (chest X-ray, ultrasound, Computed Axial Tomography, etc.), examination of the cerebrospinal fluid, complete analytical laboratory, with evaluation of renal function, should be started. liver, coagulation, ions and uric acid; as well as cultures for bacteria, fungi and studies of viral affections, especially if the patient is feverish at the time of presentation.

The differential diagnosis should be established with other onco-hematological and non-onco-hematological diseases.

Diseases such as Idiomatic Thrombocytopenic Purpura, Infectious Mononucleosis, Aplastic Anemia and Juvenile Chronic Arthritis should be ruled out.

Neuroblastoma, at times, can produce a massive bone marrow invasion and be confused with ALL in pediatric cases.

In some pediatric cases, medullary blast infiltration is often preceded by peripheral pancytopenia and transient medullary hypoplasia and confuses the physician. In these cases, repeated puncture at short intervals and at different sites can help clarify the diagnosis.

All these latter situations, problematic in the past, are resolved relatively easily today thanks to the contribution of immunostaining and cytogenetic studies.

Regarding the classification of ALL, the Franco-American-British Cooperative Group (FAB) distinguishes 3 subtypes of ALL (L1 - L2 - L3), based on morphological criteria (cell size, presence of nucleolus, basophilia, vacuolation, etc.).

Currently, the distinction between these three subtypes lacks prognostic relevance, which is why it is being practically abandoned and was replaced by a new one, proposed by the World Health Organization (WHO) that includes immunological criteria and molecular abnormalities.

Thus, with the immunophenotype, they can be divided into pre-pre B ALL, pre-B ALL, common ALL, and mature B-cell ALL, within B cells and pre-T ALL, and mature T-cell ALL, to the group of T-cell neoplasms.

Co-expression of markers of more than one lineage is seen in 15 to 50% of adult ALL and 5 to 35% of pediatric ALL, and has not been mentioned as important from a prognostic point of view.

With the use of flow cytometry, adequate typing of more than 95% of ALL is ensured, with which this method has become the most important in the current arsenal for the diagnosis of ALL.

The treatment of ALL is one of the most complex anticancer therapy programs. Multiple drugs are combined in different sequences of doses and times to achieve three main objectives, namely:

1. Reconstitute normal erythropoiesis.
2. Prevent the emergence of resistant clones
3. Provide adequate prophylaxis of “sanctuary” sites (CNS - Testicles).
4. Eliminate "minimal residual disease" through consolidation and maintenance programs for initial remission.

The realization of these points has led to the achievement of a cure rate or "prolonged survival rate" of more than 80% in children, making it one of the most successful treatments in modern oncology.

The usual treatment program includes three distinct phases:

• Induction
• Intensification or consolidation
• Maintenance

Although specific schemas are beyond the scope of this chapter, some important points will be briefly mentioned.

The combination of anthracyclines, vincristine and steroids was the cornerstone in the induction treatment of ALL. With this scheme, initial complete remission is achieved in 70% to 90% of patients. This induction scheme has been positively influenced by the addition of agents such as cytarabine, cyclophosphamide, methotrexate, and Rituximab, which are indicated according to different subtypes of ALL.

Although L-asparaginase is an important agent in the arsenal for pediatric ALL, its role in adult ALL has not been defined.

The use of colony stimulating factors (G-CSF), during this induction phase, has accelerated the recovery from toxic myelosuppression, thereby improving treatment time regimens.

Consolidation is based on a repetition of the induction scheme, modified in doses and times or on a Bone Marrow Transplant.

Also in this phase, different agents have been added according to different subtypes that have improved the prognosis and overall survival.

Maintenance has been the one that has undergone the least changes over time. Weekly 6-mercaptopurine and methotrexate, combined with monthly pulses of corticosteroids and vincristine continue to be the cornerstone of this part of the treatment.