Author: Mirando Mrsić
MD, PhD, Specialist of Internal Medicine, Hematology, Department of Hematology, Clinic for Internal Disease, KBC Zagreb
Leukemia is a malignant disease of the bone marrow and lymph nodes. The word leukemia means white blood in Greek. Among Croatian people, it is a custom to describe leukemia as a disease in which the blood turns to water. In most cases, the malignant transformation happens in the white blood cells, although it can also happen in the other cells which participate in the blood formation. White blood cells, leukocytes, are responsible for defending the organism from possibly infectious and other pathogenic organisms. The formation and destruction of bone marrow cells is a strictly controlled process which involves many mechanisms, some of which are still unknown to modern science.
The onset of leukemia is associated with a breakdown in the regulation mechanisms, which is manifested in the abnormal growth and proliferation of white blood cells and their stem cells. Malignant white blood cells do not look normal nor do they carry out their normal functions. Due to the uncontrolled proliferation of the malignant cells, the normal cells in the bone marrow are suppressed, which results in a lower rate of production of normal cells and their deficiency in the peripheral blood. A shortage of normal cells in the blood gives rise to symptoms which are not characteristic only of leukemia. The most common symptoms observed in leukemia patients are listed in Table 1.
Table 1. Most common symptoms in patients with leukemia:
- chills, fever, shivering
- weakness and fatigue
- frequent infections
- loss of appetite and weight
- tiny pinpoint-sized red spots under the skin (petechiae)
- excessive bruising
- pale color of the skin and mucous membranes
- shortness of breath during physical activity
- painless swelling of the lymph nodes
- enlarged spleen and/or liver
- night sweats
- bone pain.
Most symptoms depend on the number of malignant leukemia cells and their primary location. Leukemia can develop at every stage of your life, practically from birth until death.
Classifications of Leukemia
Leukemia is primarily divided into two large groups. One group is acute leukemia, and the other is chronic. Each of these groups is split into two types – lymphocytic or myelogenous, depending on the type of bone marrow cells which are affected by the malignant transformation.
Acute and chronic lymphocytic leukemia develops from lymphocytes in the blood and bone marrow and in the cells of the lymph nodes. The illness is characterized by the swelling of those organs which partake in the operation of the immune system whose main components are the lymphocytes. Patients with acute or chronic leukemia can suffer from swollen lymph nodes, spleen or tonsils.
Acute and chronic myelogenous leukemia affects the cells which form granulocytes, the cells which defend our organism from bacteria, fungi and other infectious factors. Those patients, generally, do not have swollen lymph nodes or tonsils. A typical finding in patients with chronic myelogenous leukemia is an enlarged spleen. In some cases this is the first sign of illness and the reason patients go to a doctor.
Bone Marrow (MGG, 1:1000): acute lymphocytic leukemia, ALL-L1
Bone Marrow (MGG, 1:1000): acute myelogenous leukemia, AML-M2
Peripheral Blood (MGG, 1:1000): exceptionally increased number of leukocytes (granulocytes) in peripheral blood of patients with chronic myelogenous leukemia
Peripheral Blood (MGG, 1:1000): number of mature leukocytes in patients with chronic lymphocytic leukemia
The cause of leukemia is unknown, but it is always connected with damaged deoxyribonucleic acid (DNA). That damage can be invisible on the level of the gene or caused by changes in either the entire chromosome or in its parts. For the time being, it is known that the malignant mutation is caused by the activation of the genes which promote cell division, the so called oncogenes, or the removal of the part of the genes that slow down cell division, the so called suppressor genes. A failure in the function of one or both genes leads to the uncontrolled growth of cells in the bone marrow. It is still not known what causes changes in DNA, but we know that exposure to cytostatics or some chemicals can induce leukemia.
The risk of leukemia developing increases with age, except in acute lymphocytic leukemia which has the highest incidence in childhood. Other risk factors are: administration of chemotherapy, exposure to certain chemicals or radiation, the development of damaged bone marrow – myelodysplastic syndrome (formerly known as preleukemia), some genetic disorders such as Down Syndrome.
The diagnosis of leukemia is based on an examination of a peripheral blood smear, the results of a bone marrow aspiration, immunophenotyping of the peripheral blood cells and/or bone marrow, and cytogenetic analysis.
A bone marrow aspiration is performed under a local anesthetic in the area of the sternum or pelvis. In some cases it is also necessary to do a biopsy of the bone along with the bone marrow aspiration. Besides these specific tests, it is necessary to do a routine check of biochemical results, an EKG and X-ray of the heart and lungs. In cases when the patients have high temperatures a hemoculture is taken which can confirm whether or not there is a breakout of bacteria or fungus in the blood. In patients with acute lymphocytic leukemia it is routine to perform a lumbar puncture to confirm the presence of malignant leukemia cells in the central nervous system. Since cytostatics don’t penetrate through the blood-brain barrier, in patients with acute lymphocytic leukemia, prophylactics can be infused directly into the CSF (cerebrospinal fluid area).
Subtypes of Leukemia
Acute leukemia is divided into subtypes.
Tables 2 and 3 show the types of acute myelogenous and acute lymphocytic leukemia according to the existing classifications.
Table 2. Subtypes of AML
- AML with recurrent cytogenetic translocations
- AML with t(8;21)(q22;q22) AML1(CBF-alfa)/ETO
- Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR-alfa)
- AML with eosinobasophils in the bone marrow (inv(16)(p13;q22) or t(16;16) (p13;q11), CBF-beta/MYH11X)
- AML with 11q23(MLL) abnormalities
- AML with signs of myelodysplasia
- AML with preceding myelodysplasia
- AML without preceding myelodysplasia
- AML and MDS – secondary after treatment
- After alkylating agents
- After epipodophilotoxins (some ALL)
- Other AML
- AML not otherwise specified
- AML undifferentiated (AML-M0)
- AML with minimal maturation (AML-M1)
- AML with maturation (AML-M2)
- Acute myelomonocytic leukemia (AML-M4)
- Acute monocytic leukemia (AML-M5)
- Acute erythroid leukemia (AML-M6)
- Acute megakaryocytic leukemia (AML-M7)
- Acute basophilic leukemia
- Acute panmyelosis with fibrosis
- Biphenotypic acute leukemias
Table 3. Subtypes of ALL
- Precursor B-cell ALL
- (cytogenetic subsets)
- t(9;22)(q34;q11); BCR/ABL
- t(v;11q23); reorganization MLL
- t(1;19)(q23;p13); E2A/PBX1
- t(12;21)(p12;q22); ETV/CBF-alpha
- Precursor T-cell ALL
- Acute leukemia with Burkitt’s tumor cells
The treatment of acute leukemia falls into three phases. In the first phase, the so called induction or introductory, several types of cytostatics are applied for the purpose of putting the disease in remission. As higher doses of cytostatics are applied, the defense mechanism breaks down and the mucous tissues become swollen, especially those in the mouth and digestive tract.
With the shortage of leukocytes, the phase of neutropenia occurs, in which the patient is exposed to infections from the environment, especially by way of their skin or from their own digestive tract. Infections in these patients are very high risk, and if not immediately treated with antibiotics, can be fatal within 24 hours. The length of the neutropenia phase varies from patient to patient; however, the average is from 2 – 3 weeks. During this phase the patient is not only at risk of infections, but also exposed to the risk of uncontrolled bleeding because of the shortage of blood platelets (thrombocytopenia) and/or the disorder of blood coagulation. Therefore, patients in this phase, besides increased attention and care, have an increased need for blood transfusions and blood derivatives.
After the neutropenia phase comes the recovery phase, when the bone marrow recovers. In about 60 – 70% of patients, the bone marrow recovers to a healthy state and they reach the stage called remission. That is the stage in which the results of the blood count are normal and there are fewer than 5% blast cells (immature blood-forming cells) in the bone marrow. If the patient does not continue the treatment, the disease could quickly recur so the treatment must be continued. Induction or introductory therapy lasts about one month. Patients who achieve complete remission continue with the so-called consolidation or intensification therapy. Patients who do not achieve remission of the disease continue with the so called salvage or “salutary” therapy. Unfortunately, the success of treatment in the latter group is not as good and only 20 – 30% of patients manage to achieve remission of the disease.
After induction or introductory therapy, treatment continues with consolidation therapy with the same or different cytostatics, in the doses identical to those administered during the initial therapy.
Before the start of consolidation therapy, a blood sample is taken for HLA tissue typing from patients that are younger than 45 in order to determine if the patient has a potential bone marrow donor within their family. If a donor is not found within the family, treatment continues with a transplant of their own bone marrow. The cells used for the transplant of one’s own stem cells are collected during the phase of coming out of neutropenia, during consolidation therapy.
Bone marrow transplant or hematopoietic stem cell transplant is the third phase of treatment for patients with acute leukemia. If the patient has a HLA (Human Leukocyte antigen or the major histocompatibility system) match among siblings, treatment continues with a related transplant. When a HLA match can not be found among relatives, treatment continues with a transplant of one’s own bone marrow. In patients that are younger than 35, for whom a high risk of recurrence has been determined, and who don’t have a HLA match within the family, the search procedure is launched to find a non-related matching donor.
The rate of success of treating acute leukemia in adults by way of a bone marrow transplant is about 50%.
Treatment of Chronic Leukemia
Chronic leukemia, as the name says, has a slow course and does not require such aggressive treatment as in patients with acute leukemia. Today, chronic myelogenous leukemia is successfully controlled by applying imatinib, so we have already started dividing the history of fighting against leukemia into the time before imatinib and the time after imatinib. In those patients in whom the disease has not been put under control, treatment continues with a bone marrow transplant from a sibling, or any other HLA match within the family. For patients with chronic myelogenous leukemia that are younger than 35, who do not respond to the imatinib, and do not have a HLA match within the family, the procedure of finding a non-related matching donor begins. For patients with chronic leukemia, a transplant of their own bone marrow is not a therapy of choice.
Chronic lymphocytic leukemia is predominantly a disease of advanced age and normally has a slow course. Today it is treated with different drugs, but the drug of choice which seems to have a good control over the disease is chlorambucil. In younger patients, in whom instability or exacerbation of the basic disease is registered, a bone marrow transplant from a sibling is taken into consideration as a possible option.
Other Forms of Leukemia
For patients with acute promyelocytic leukemia M3, the medicine of choice in induction therapy is a combination of cytostatic idarubicin and all-trans retinoic acid. After the administration of cytostatics, these patients suffer from the release of the so-called procoagulant material into the blood, which results in massive and uncontrolled bleeding. Prior to the era of all-trans retinoic acid, about 50% died during induction therapy from bleeding into the central nervous system. The application of all-trans retinoic acid prevents bleeding in the early phase of treatment. For those patients with AML-M3, treatment is based only on the application of a combination of cytostatics and, in most cases, a bone marrow transplant from a related donor’s or one’s own cells is not necessary.
Great advances have been achieved in the area of ‘smart drugs’. As of recently, patients with acute myelogenous leukemia have been administered monoclonal antibody therapy, specifically targeting leukemia cells. For the time being, the agent applied in clinical practice is gemtuzumab ozogamicim. The results from this type of treatments are encouraging, but additional research is required in order to confirm the real effectiveness of the treatment.