Leukemia (Part One)

Leukemia (leucemia, leukosis) represents a heterogeneous group of malignant tumors (neoplasms), with varying degrees of cell proliferation, differentiation, and maturation, originating from precursor cells of blood elements in the Bone Marrow (BM). Leukemia is classified among "liquid" tumors and unlike "solid" tumors (breast, uterus, stomach, pancreas, etc.) which can be benign and malignant, are always malignant (with the ability for local infiltration and distant metastasis) and are systemic (metastatic), i.e., spread throughout the entire BM (intramedullary) and beyond it (extramedullary).

Classification

1. Lymphoid Leukemia (LL) and non-Lymphoid (Myeloid Leukemia – ML).
2. Acute Leukemia (AL) and Chronic Leukemia (CL)

BOX

Central Blood – Hematopoietic Tissue, (blood-forming), Myeloid + Lymphoid in BM (active BM) and extramedullary Lymphoid Tissue (spleen, lymph nodes, etc.). It consists of blood-forming parenchyma and the necessary microenvironment for the production of blood elements and their release into circulation. It produces peripheral blood elements (with specific structure and function that live for a certain time and are eliminated to be replaced by the same quantity – a dynamic balance between elimination and production).

BM is primarily Myeloid Tissue and includes erythropoiesis + thrombopoiesis + granulopoiesis + monopoiesis. Therefore, Myeloid Tissue (and consequently the production of erythrocytes, granulocytes, monocytes, platelets) is located only in bones (in adults in the epiphysis of long bones, ribs, clavicle, sternum, spinous processes of the vertebrae, skull, iliac crest).

While Lymphoid Tissue (therefore the production of lymphocytes) is partly in BM but also in extramedullary lymphoid tissue (the lymphatic follicles of the spleen, lymph nodes, tonsils, etc.). All blood cells originate from a small number of cells – Hematopoietic Stem Cell (hematological progenitor cells) that enter cell division as needed.

Although capable of proliferation, the hematopoietic progenitor cell is relatively resistant to "killing" by radioactive substances or chemotherapeutic agents, indicating that their regenerative capacity is low and a portion of the population of progenitor cells is in G0.

This allows them to not be affected by the action of chemotherapeutic agents, which act at different phases of the cell cycle and will ensure the repopulation of the BM after the phase of Therapeutic Aplasia achieved during Induction in the treatment of AL or in BM Transplant. Examination is done with Myelogram (BM Aspiration) and BM Biopsy. For Leukemia, often Myelogram is sufficient.

Peripheral Blood – A special connective tissue, liquid, that is distributed throughout the body (hence hematological tumors are systemic from the beginning. It consists of plasma and highly differentiated, matured (ripened - structurally and functionally) and specialized circulating cell elements, that no longer divide, but are destined to perform their function and be replaced with new ones (with the exception for the red series – reticulocytes and the white series band forms and MMCs which are slightly more immature than their corresponding final elements). The only cell with the potential to proliferate in circulation is the lymphocyte (nucleus larger than cytoplasm - inverted ratio in a mature cell).

Leukemia – literally means, white cells circulating in blood (similar to terms - glycemia, natremia, azotemia, creatinemia, etc.). Suffix -emia or -hemia also -aemia or –haemia – in blood. But this is normal. Suffix -cytosis includes all cases of an increase in the number of cells of a “physiological” and reactive nature (so if we use the terms leukocytosis, thrombocytosis, erythrocytosis we are talking about their increase with secondary, reactive causes. Suffix -cythemia includes all cases of an increase in the number of cells of an autonomous nature (so if we use the terms leukemia, erythremia, thrombocythemia, we are talking about tumoral, autonomous increase of cells).

Disease generally idiopathic, primary (de novo), in some cases secondary (post MDS, CT and RT, transformations in MPS). Be careful of secondary hematological tumors in patients who live a long time treated with CT/RT for another hematological or non-hematological disease, or hematological tumors in patients who use immunosuppressive drugs for a long time for non-malignant diseases (transplants, etc.).

If we say tumor (swelling, enlargement), the disease is:

a) monoclonal (the entire tissue/clone develops from a single tumor-origin cell, Tumor (Leukemoid) Stem Cell, but in reality, it has different subclones with secondary mutations acquired during new divisions of tumor cells). The process of tumor development is called tumorigenesis, for leukemia – leukemogenesis. The tumor cell clone - Leukemias, lymphomas, myelomas, i.e., all malignant hematopoietic tumors (liquid tumors, to distinguish them from solid tumors) originate from a single cell (the clone origin cell), where chromosomal genetic alterations (quantitative or qualitative) have occurred. This cell may be from BM or from peripheral lymphoid tissues. For leukemias, it is in BM. The entirety of cell generations formed by the mitotic division of the damaged origin cell forms a population called a “clone”. When the number of clone cells reaches a certain number, the disease appears. Each disease has one or more characteristic chromosomal anomalies. Progression of the tumor clone. Throughout all tumors, new characteristics appear during the course of the disease. This is accompanied by new chromosomal changes. The best example is CML, where the clone present in the chronic phase is replaced by a new clone, when the disease enters the acute phase. In 70% of cases, the new chromosomal changes are superimposed on the original Philadelphia chromosome. These new subclones (with new chromosomal anomalies) may have more malignant characteristics than the original clone and/or may be clones resistant to chemotherapeutic agents. Thus, the new subclones become the cause for progression, relapse of the disease, and acquired resistance to treatment.

b) autonomous (autonomous proliferation – not affected by physiological inhibitory stimuli of cell proliferation). They become "immortal" cells, cells that multiply continuously.

c) Metastasis is characteristic of malignant tumors (cancer, neoplasm) tumor cells lose adhesion molecules (located on the plasma membrane) and connection with the microenvironment and enter circulation and localize in one or more sites and find the necessary microenvironment to stay and proliferate. Blood is a special connective tissue originating from mesenchyme and spread throughout the body, meaning that its microenvironment is spread throughout the body and metastasis of tumor cells of this tissue is possible throughout the body.

1. Cells that are not dividing (G0) are not affected by the action of cell cycle – dependent chemotherapeutic agents. Leukemic Stem Cells (the tumor progenitor, leukemic cell from which all other cells of the tumor clone originate) are difficult to eliminate. The possibility of elimination through BMT (Bone Marrow Transplant) and Target Therapy (personalized drugs for the leukemic tumor cell).
2. Tumor cells are continuously produced (about 10,000 cells/day), but they will develop a tumor if they escape the body's anti-tumor defense (complement, NK, Cytotoxic LT) and find the necessary microenvironment to stay and proliferate.
3. The treatment of tumors consists of destroying tumor cells and stimulating immune processes, with the aim of eliminating or limiting tumor cells (residual disease) to such a level that it does not give clinical and cytological laboratory changes (in the examination with Optical Microscope of peripheral and central blood). Complete elimination of tumor cells = cure and so far it has been achieved only in successful cases with Allogeneic BM Transplant. Reducing tumor cells to the level of "residual disease" = Complete Remission which is actually the goal of conventional chemotherapy treatment of leukemias, but this does not mean cure. Tumor cells remain and if the result is not "consolidated" and "maintained" they will start multiplying again and when they reach a certain tumor mass they appear in the laboratory and clinic (cytological and clinical relapse).
4. After each relapse, the possibility of achieving remission is smaller and the duration of remission if achieved is shorter.
5. Tissues with rapid proliferation, thus with frequent cell divisions (which includes Hematopoietic Tissue) are more often affected by tumors because there is a greater possibility for genetic mutations to occur (mutation of the proto-oncogene transforms it into oncogenes and the reduction of Tumor Suppressor Genes - anti-oncogenes). But these tissues (Hematopoietic Tissue, epithelial tissue, spermatogenesis) are the tissues that are most damaged by chemotherapy/radiotherapy.
6. What are oncogenes and anti-oncogenes? A number of normal genes when mutated contribute to the malignant transformation of a cell. It is known that proto-oncogenes (which under the action of different factors turn into oncogenes, i.e., genes that cause cancer) and anti-oncogenes are hereditary. With this, it is explained that tumors have a genetic basis. People with a family history should undergo regular check-ups. Dominant genes that when mutated cause tumors are called oncogenes. Oncogenes arise from mutations of normal genes called proto-oncogenes. Proto-oncogenes code for proteins (located on the surface, cytoplasm, or nucleus of cells) which act in cell proliferation, survival, and differentiation. Proto-oncogenes are widely distributed among human chromosomes. They are classified depending on the function of the protein for which they code. Oncogenes are dominant because only one of the proto-oncogene pair of alleles needs to mutate for it to cause cancer. Evidence that activated oncogenes are involved in malignancy (in the development of leukemias) is indirect, but it has been made possible for some types of leukemia to be reproduced in mice. E.g., if we activate the oncogene BCR –ABL in mice and produce the abnormal protein p210, CML will develop, but if from the activation of the same oncogene the abnormal protein p190 is produced, ALL will develop. The second class of genes involved in cancer is known as anti-oncogenes or tumor suppressor genes (TSG). TSG, in their normal (unmutated) state, code for proteins which inhibit cell division and proliferation processes. TSG as well as proto-oncogenes are distributed in different human chromosomes. These genes code for proteins which in most cases are located in the nucleus and control two points of the cell cycle the transition from G1-S and from S-G2. In the absence or malfunction of these proteins, cell replication cannot be inhibited by normal signals which regulate growth. The loss of their functions becomes the cause for the development of tumors. The homozygous loss or inactivation (both alleles responsible for a trait) of anti-oncogenes from different mutations, becomes the cause for the malignant transformation of a cell or for the progression of the tumor in a more malignant form. The heterozygous loss or inactivation (one of the alleles responsible for a trait) is inherited and when the other allele is lost or inactivated the tumor appears. Mutations of one of the TSG alleles (just one of the TSG genes in a pair of homologous chromosomes) will not cause a tumor, as long as the other allele gene functions normally (they are carriers of the mutant gene). These genes are recessive and to appear phenotypically a recessive homozygous state is needed, before the mutation occurs in both alleles.