Main syndromes

A compilation of the main syndromes in medical practice.
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José Luis Fedele

Acute leukemias (AL) are a heterogeneous group of clonal hematopoietic disorders that result from genetic alterations of the stem cell, or normal totipotential hematopoietic cell.

These alterations induce a maturation arrest or arrest with excessive proliferation of immature cells (blasts), in bone marrow and peripheral blood.

As a direct consequence of this alteration, a state of “spinal failure” occurs due to the replacement of normal hematopoiesis by immature, non-functional cells, which is ultimately responsible for the symptoms and signs of the disease.

During the past decades, the improvement of chemotherapy regimens to treat this group of pathologies, together with better supportive therapy, have resulted in a modest but significant progress in the treatment of Acute Leukemias.

For a better understanding and given notable differences between both groups, we will separate the description of LA in Acute Myeloblastic Leukemias and Acute Lymphoblastic Leukemias; both of the adult.

ACUTE MYELOBLASTIC LEUKEMIA

Acute Myeloblastic Leukemias (AML), as we mentioned before, are a heterogeneous group of diseases that, based on a greater knowledge of molecular biology, have been better characterized and, therefore, new “targets” or therapeutic targets have been identified, to achieve a better evolution of patients.

With current treatment regimens, 60–70% of patients achieve complete remission after initial induction therapy, but less than 20% of these achieve prolonged disease-free survival (DFS). Therefore, the treatments must be completed later with consolidation schemes, which can be chemotherapy again or if the conditions are appropriate Bone Marrow Transplant (BMT).

Pathophysiology

Approximately 11,000 new cases of AML are diagnosed each year in the USA.

This is equivalent to an annual incidence of 2.7 cases per 100,000 inhabitants / year.

In adults, AML is the most common type of leukemia. In children the incidence of AML is much lower (10-15%).

The mean age of the patients is 65 years and it is somewhat more common in men than in women. The incidence increases progressively with age (less than 1 case / 100,000 inhabitants / year for those under 30 years of age to 14 per 100,000 inhabitants / year at 75 years)

The incidence of "de novo" AML seems to have remained stable in recent years, but not the incidence of AML secondary to Myelodysplastic Syndrome, which seems to be increasing in number, particularly in the population over 60 years of age.

The etiology of AML is unknown.

Genetic factors are of great importance. A particularly high incidence of AML occurs in patients with syndromes associated with excessive chromosomal fragility such as Bloom syndrome, Fanconi anemia, Kostmann syndrome, Wiskott-Aldrich syndrome, etc.

Others such as Down's Syndromes, Klinefelter and Potan, have also been associated with a higher incidence of AML.

Among the external factors, radiation occupies an important place.

The survivors of the nuclear explosions in Japan showed an increase in the incidence of AML, as well as other solid tumors, with a peak of presentation between 5 and 7 years post-exposure.

Radiant therapy increases the risk of secondary AML, particularly when it is associated with the use of chemotherapeutic alkylating agents.

Other drugs, such as Chloramphenicol, Phenylbutazone, Chloroquine and Psoralens, have also been associated with an increased risk of developing AML, but this association is much less strong than with ionizing radiation, for example.

Benzol is the best known chemical leukemogen, as has been demonstrated by the increased incidence of AML among workers in industries that handle it.

Lastly, AML may be the natural progression of other diseases that affect the stem cell, such as Myeloproliferative Syndromes (Polycythemia Vera - Essential Thrombocythemia - Chronic Myeloid Leukemia - Paroxysmal Night Hemoglobinuria).

A viral etiology in the development of AML has not been convincingly demonstrated, as it occurs in some forms of Lymphoproliferative Syndromes.

As can be seen, as discussed so far, all those circumstances that can molecularly damage the DNA of the stem cell can cause or eventually increase the risk of suffering AML.

Study methodology

The classification of AML that is most widely accepted in the international arena is the one drawn up in 1976 by the French-American-British Cooperative Group (FAB).

This classification was initially based only on morphological and cytochemical criteria of the stem cells.

Subsequently, the advent of the immunological and cytogenetic study of cells provided valuable additional information, which, as mentioned above, has improved the diagnosis, prognosis and treatment of this pathology.

Immunophenotyping by Flow Cytometry studies the presence of antigens present on the cell surface, specific for a certain cell lineage and even, for a certain maturation stage of the same cell line, through a wide battery of monoclonal antibodies. The use of 2 or 3 Ac. Monoclonal for each of the 3 main cell lines (Myeloid - Lymphoid B - Lymphoid T), allows to establish an immunological classification of Acute Leukemia that correctly identifies the cell line in 98-99% of cases.

The Cytogenetics study, for its part, offers valuable information on diagnosis and, unlike the previous one, prognosis and treatment.

Almost 70% of patients with Acute Leukemia have some detectable cytogenetic alteration, and some of these are closely linked to a specific morphological variety, as in the case of promyelocytic AML (M3-FAB) with t (15; 17).

From this, a new classification was generated, called MIC, which integrates the FAB plus the data provided by this new study methodology.

In daily clinical practice, in most centers dedicated to the study of these diseases, the old FAB classification is still used with the addition of data from Flow Cytometry (immunology) and Cytogenetics.

In the following tables, both classifications are summarized and an attempt is made to correlate both for a better understanding.

TABLES 1 and 2 (Missing Image or Table)

Traditionally, the diagnosis of AML required a medullary infiltration equal to or greater than 30% by myeloid blasts. Today it is considered that 20% or more are already diagnostic of the process. Usually, spinal infiltration far exceeds this figure and is diffuse in nature, which does not offer problems for diagnosis, especially in “de novo” AML. Sometimes less than this number may be seen in AML secondary to myelodysplasia.

In any case, the diagnosis is based on the observation of bone marrow and peripheral blood, together with the support of immunostaining and cytogenetics.

The differential diagnosis must be established with various entities.

From the morphological point of view, the greatest confusion sometimes occurs with Infectious Mononucleosis, a benign viral entity that causes morphological changes in lymphocytes that match, sometimes remarkably, the morphology of the blasts. In these cases, the serology and especially the clinical evolution clarify the diagnosis.

Medullary replacement by metastatic cells can lead to a Leukoerythroblastic picture, which mimics AML.

Among other entities, Neuroblastoma, Rhabdomyosarcoma, Swing Sarcoma or Anaplastic Lung Cancer are mentioned. The absence of blasts in peripheral blood, the pathological anatomy and the immunostaining, dispel the doubts in most of these cases.

Symptoms and signs

The symptoms and signs of AML are due, as mentioned above, to marrow failure due to leukemic proliferation and also to invasion of various organs and tissues.

Medullary invasion, which is usually massive, causes cytopenias of varying degrees, with consequent systemic manifestations.

Asthenia and fatigue reveal progressive anemia, which is present in 80-100% of patients at presentation, and is usually of the normocytic, normochromic type.

Thrombocytopenia is also very common at presentation (80-90%) and half of these patients show hemorrhagic signs, more frequent and intense if the number of platelets is less than 20,000 / mm3. Hemorrhagic diathesis ranges from mucocutaneous bleeding (petechiae, ecchymosis, hematomas, to severe Disseminated Intravascular Coagulation (DIC). This last entity is especially frequent in the M3 (Promyelocytic) variety with an incidence of 75-90% of the patients at some point in their evolution. It is so frequent in this variety that its mere presence at the time of presentation makes it necessary to rule out this variant in the first place. Retinal hemorrhages are common and in their production, in addition to plaquetopenia, they involve leukemic infiltration ocular and intense anemia.

Fever is a usual clinical characteristic at the beginning, and it is mainly due to the presence of infection. Moderate to severe neutropenia occurs in 40-50% of patients and is primarily responsible for infection. To a lesser extent, fever is not related to infection and is only part of the leukemic process. It is important to differentiate between these two entities, since if the patient begins chemotherapy with an unresolved infectious process, he has less than half the probability of achieving complete remission.

In general, at presentation, the average white blood cell count is 15,000 to 30,000 / mm3, and blasts are seen in peripheral blood in 90% of cases.

In a few patients, the number of leukocytes exceeds 100,000 / mm3 and in these patients, in addition to the above symptoms, manifestations of Tumor Lysis Syndrome and Leukostasis may appear.

The first is a severe metabolic condition characterized by marked hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, metabolic acidosis, and acute renal failure.

Leukostasis is characterized by symptoms mainly related to the Central Nervous System (CNS): changes in mental status, headache, cranial nerve palsy. In addition, chest pain, dyspnea, and priapism are usually observed.

Both are oncological emergencies and must be suspected, diagnosed and treated early as they can by themselves end the life of the patient, sometimes before reaching a specific intervention on leukemia.

As additional, less frequent signs, the following may be observed: organomegaly (hepatosplenomegaly), polyadenopathy, sternal pain or tenderness, gingival, soft tissue, meninges or skin infiltration.

The latter manifests as painless and non-pruritic maculopapular lesions (due to infiltration of the dermis), and they are more frequent in the M4 and M5 variants (monolithic), as are gingival and meningeal infiltration and hyperleukocytosis.

The goal of treating AML is to reduce the greatest number of blast cells in the bone marrow and thus to reestablish normal hematopoiesis.

Since the 1960s, the concept of Complete Remission (CR) was established as an index to assess response and as a marker of patient survival.

CR criteria are: platelet count> 100,000 / mm3; Neutrophil count> 1000 mm / 3 and <5% blasts in bone marrow.

In recent times, alternative concepts have emerged such as CR with incomplete platelet recovery (<100,000 but more than 30,000 / mm3); o Minimal Residual Disease, the latter concept determined by the presence of blasts by immunological or cytogenetic methods, but not by conventional morphological or cytochemical ones.

Regarding this last concept, it should be clarified that new molecular detection techniques such as Fluorescence and In situ Hybridization (FISH) or Polymerase Chain Reaction (PCR) are currently used as markers of minimal residual disease, with prognostic and therapeutic implications, as well as in the initial diagnosis phase.

The standard treatment of AML is divided into a first phase called Induction of remission, followed by a second phase called post-remission treatment or consolidation.

CR should be achieved with a maximum of 2 cycles of cytostatic treatment. Otherwise, AML is considered refractory and alternatives to conventional treatment should be sought.

Traditionally, a scheme is used that combines an anthracycline (Doxorubicin or Idarubicin) for 3 days plus Cytarabine in continuous infusion for 7 days. For this reason, this scheme is known as the 7 + 3 regime. In clinical practice, an evaluation of the bone marrow (aspirate) should be carried out between the 2nd and 3rd week after starting treatment. If immature elements (blasts) still persist and it is cellular, the initial scheme can be repeated, generally attenuated (5 + 2).

With this conventional scheme, complete remissions are achieved that are in the order of 50 to 70%, with a median duration of remission of one year.

For this reason, after CR, “maintenance” or “consolidation” treatments should be planned to ensure longer “disease-free” time.

The decision on which is the best post-referral treatment remains controversial. There are groups of researchers who advocate Bone Marrow Transplantation, allogeneic or anthology, as the best possible therapy, if the patient's conditions allow it; while others defend the efficacy of a consolidation with intensive and short-term chemotherapy.

It is beyond the objectives of this chapter to go into details of the scope of each of these modalities.

Finally, we will mention some concepts in relation to prognostic factors.

In recent times, with the advent of molecular and immunological detection techniques, constant and variable anomalies have been added in these areas as markers of better or worse prognosis, which are given increasing predictive value.