Acute Leukemia

Both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are an acute form of leukemia characterized by proliferation of early lymphoid/myeloid precursor cells which replace the normal hematopoietic cells of the bone marrow.

The disease is related to the following processes:  neoplastic and has an incidence of about  1 / 100.000.

Presentation

Patients with ALL and AML may present with symptoms related to either infiltration of the bone marrow with leukemic cells or symptoms related to infiltration of leukemic cells in extramedullary organs. Fever is a universal complaint even in the absence of any infection. Any fever in a leukemia patient should be considered to be from an infection until proven otherwise. Infections remain the most common cause of death in these patients and should not be taken lightly.

Symptoms of anemia may include palpitations, general malaise, dizziness, shortness of breath and even fatigue. Signs of bleeding may include presence of petechiae, ecchymosis and swollen gums.

Some individuals with ALL and AML may develop localized or generalized lymphadenopathy, or even shortness of breath as a result of enlarged mediastinal nodes. Infiltration of the marrow by leukemic cells can also present with moderate to severe bone pain. If splenomegaly is present, the individual may have early satiety and complain of left upper quadrant fullness.

In advanced cases, patients may even present with altered mental status and renal failure (due to hyperuricemia). Some AML patients may complain of severe bone pain due to the pain caused by pressure from the expanding pool of cells. In such scenarios, urgent bone marrow decompression is required for pain relief.

Physical examination

Common features in a patient with ALL or AML may include fever, signs of anemia (eg. pallor, tachycardia), petechiae, ecchymosis and adenopathy. Rarely a red rash may be seen due to infiltration of leukemic cells under the skin.

Workup

Workup of a patient with suspected ALL and AML includes the following:

  • Blood cultures need to be done in patients with a fever.
  • Bone marrow aspiration and biopsy is the definitive diagnostic test to confirm the diagnosis of leukemia. Cells obtained should be sent for flow cytometry and immunophenotyping to determine the subtype. Cytogenetic studies can help determine presence of the Philadelphia chromosome and other chromosomal abnormalities.
  • Chest X-ray may reveal presence of an infiltrative process or a prominent mediastinal mass.
  • Chest CT scan is often used to further evaluate a mediastinal mass or hilar adenopathy.
  • Complete blood count may reveal neutropenia. When the neutrophil count is < 500/ul, the risk of infection is high.
  • Coagulation profile is necessary as it may reveal abnormalities in prothrombin time, activated partial thromboplastin time, fibrinogen and fibrin degradation products, which is suggestive of concomitant disseminated intravascular coagulation (DIC).
  • A chemistry profile as well as uric acid and lactic dehydrogenase levels are recommended. In addition, liver function and renal function tests are necessary before the initiation of chemotherapy.
  • A baseline ECG is recommended before initiation of chemotherapy.
  • Because of cardiotoxicity of some chemotherapeutic drugs, it is important to perform some type of cardiac stress test to determine presence of ischemia.
  • Peripheral blood smear can help confirm results of the CBC and also reveals presence of blasts. If DIC is present, schistocytes will be present.

National Comprehensive Cancer Network (NCCN) guidelines to make a diagnosis of ALL include the following [2]:

  • Presence of ≥20% lymphoblasts in bone marrow
  • Morphologic presence of blasts cells on stained bone marrow aspirate smears
  • Stained bone marrow core biopsy and clot sections
  • Complete immunophenotyping, cytogenetic and flow cytometric studies

In the older literature, ALL was classified by the French-American-British (FAB) classification. Today, the newer World Health Organization (WHO) classification is utilized.

Treatment

Both AML and ALL treatment requires considerable expertise in oncology and hematology. Because of the need for blood products, patient should receive care where both leukapheresis and excellence in blood banking is available. These individuals require frequent hospital admissions and need to be looked after a team of healthcare professionals [8] [9] [10]. Overall less than 1/3rd of patients with ALL are cured with conventional chemotherapy regimens [1] [2].

The treatment of ALL has 4 basic components that include:

  1. Induction
  2. Consolidation
  3. Maintenance
  4. CNS prophylaxis

Hospital admission is required for treatment and for the management of adverse effects from chemotherapy [11]. Most patients need a semi-permanent IV line like a triple lumen or a Hickman catheter for administration of chemotherapy.

Induction chemotherapy usually involves the use of a 4-5- drug regimen which include prednisone, vincristine, cyclophosphamide and anthracycline, or L-asparaginase [6]. The treatment is administered over a course of 4-6 weeks. Complete remission occurs in about 60-85% of patients. Those patients who rapidly enter remission within 4 weeks tend to have good outcomes compared to those who remission occurs later.

CNS prophylaxis

Patients with ALL frequently develop leukemic meningitis following relapse. As a result intrathecal chemotherapy is required. The number of intrathecal treatment varies depending on severity but most individuals require a minimum of 4-6 treatments [1] [2] [9].

Newer induction approaches

In the past there were fewer antibiotics available and transfusion medicine was still not well developed. With advances in blood baking and availability of newer antibiotics, more aggressive chemotherapeutic regimens are being used to treat ALL and AML. Today there are several chemotherapy protocols for treatment of ALL and AML including the use of protein based therapies like imatinib and dastinib [13][14] [15].

Treatment of Ph chromosome–positive ALL

Today, patients with Philadelphia chromosome–positive (Ph+) ALL are treated with tyrosine kinase inhibitors like nilotinib and dasatinib in combination of standard chemotherapy regimens. Unfortunately the tyrosine kinase inhibitors also have serious adverse effects like liver dysfunction, pleural effusion, pulmonary artery hypertension and prolonged QT interval. Their use requires clinical judgment and the benefits must outweigh the adverse effects [7].

Transplantation

Allogeneic transplantation is now performed for young patients who have high risk features whose ALL and AML is in the first remission. In patients without high risk features allogeneic transplantation is reserved for those who relapse [16] [17].

Another newer option is use of stem cell transplant in patients with ALL and AML who have poor prognostic features such as age less than 6 months and poor repose to steroids or a high level of leukocytes. Some studies indicate that in high risk patients allogeneic bone marrow transplant may be superior to chemotherapy in achieving long term remissions.

Treatment of relapsed ALL & AML

ALL patients who relapse tend to have a poor prognosis and most of them are referred only for investigational treatments.

Blood broducts

Since ALL and AML patients regularly develop an inability make normal blood cells, they constantly need blood replacement products. All blood products given to leukemic patients must be irradiated to prevent transfusion-related graft versus host disease, which is frequently fatal.

Therapy and prophylaxis for infection

Febrile patients with ALL and AML are routinely given antibiotics including antifungal agents. Steroids should be given with great care to leukemic patients as they may mask any signs of infections. The role of antibiotics in afebrile patients is controversial.

Growth factors

The use of granulocyte colony stimulating factors is now routine during induction chemotherapy. These factors help prevent the abrupt decline in white cells and decrease the risk of infections. While many studies indicate that CSF reduces febrile neutropenia, the survival of ALL and AML patients is not altered.

Hyperuricemia and tumor lysis syndrome

A potentially life threating complication of chemotherapy is tumor lysis syndrome. The syndrome is characterized by elevated levels of potassium, uric acid and phosphate. In addition the patient may develop depressed levels of calcium and acute renal failure. Allopurinol is recommended during chemotherapy and some patients with infiltration of the kidneys by leukemic cells may benefit from rasburicase.

Long-term monitoring

All patients with ALL or AML need close monitoring on an outpatient basis. Maintenance therapy is usually administered in an outpatient setting. Further patients are also treated with trimethoprim-sulfamethoxazole to prevent pneumocystis jiroveci pneumonia. To reduce the development of candida, patients should be prescribed am antifungal drug like oral nystatin or clotrimazole troches. Patients who are severely neutropenic and at a high risk of relapse may require supplemental antifungal therapy with agents like amphotericin or itraconazole.

Prognosis

Overall only 20-40 percent of individuals with ALL are cured with current treatment protocols [5] [6]. The prognosis of patients is based on risk assessment as follows:

Good risk

  • Age less than 30
  • Complete remission within 4 weeks
  • No adverse cytogenetics findings
  • WBC count of < 30,000/ul

Intermediate risk includes those patients who do not fall into the good or poor risk criteria.

Poor risk

  • Age 60 years
  • Failing to achieve complete remission within 4 weeks of therapy
  • Presence of chromosomal aberrations like translocations t(9;22), t(4;11)
  • Presence of precursor B-cells
  • WBC count > 100,000/μL
  • Failure to achieve complete remission within 4 weeks

Despite autologous transplantation or conventional chemotherapy, individuals who have precursor B-cell ALL tend to have the worst prognosis. Several studies indicate the expression of myeloid antigens may be associated with a decreased survival.

In patients who survive ALL, other impairments include decreased physical performance, neuromuscular deficits and vision loss. These neurological deficits have been linked to intrathecal use of drugs like methotrexate and vincristine.

The prognosis for patients with AML depends on several factors such as advanced age, any comorbid condition and prior myelodysplastic syndrome. The best prognosis is in patients with t(15;17) or t(8:21) with long term survival rates of about 60%. Patients with normal cytogenetic studies have a survival rate of 15% and patients with poor cytogenetic findings like FLT3 mutation have the worst survival of only 10%. Overall, about 1/3rd of AML patients less than 60 years survive 5 years. Less than 10% of patients older than 60 survive long term [7].

Death in patients with ALL and AML is usually due to uncontrolled sepsis or hemorrhage.

Etiology

The cause of ALL and AML remains a mystery. However, some data from the atomic bomb in Hiroshima seems to suggest that radiation exposure may be a risk factor for both ALL and AML. Recently use of topoisomerase 11 inhibitors has resulted in ALL in some patients due to alterations in certain chromosomes. Nearly 10-15 percent of individuals with ALL have a t(9;22) translocation (ie, Philadelphia [Ph] chromosome). However, several other chromosomal abnormalities have also been identified such as t(2;8), t(4;11), and t(8;14) [1].

Risk factors for AML include myelodysplastic syndrome (the most common), aplastic anemia, myelofibrosis toxin (benzene), chemotherapeutic drugs or environmental exposure. Congenital disorders that are linked to an increased risk of AML include Down syndrome, Bloom syndrome and Fanconi anemia. There are also some germline mutations in the AML1 gene that predispose people to AML. People who smoke tend to have a higher risk of AML than those who do not. However, the majority of patients with AML have no identifiable risk factor [3].

Epidemiology

In children, ALL is the most common malignancy accounting for nearly 1/4th of all cancers in children up to age 14 and nearly 3/4rd of all cancers in infants and small children. ALL is not common in adults. Overall, ALL is slightly more common males than females. Globally the highest incidence of ALL is observed in the US, Italy, Costa Rica and Switzerland.

AML occurs in both young people and elderly. The malignancy is more frequently seen in developed countries and is more common in Caucasians compared to other populations. The risk of AML increases with age, with the median age of diagnosis in the 7th decade of life. AML is more common in men compared to women at all ages. It is believed that AML is higher in males because of possible occupational exposure to toxins [3].

Sex distribution
Age distribution

Pathophysiology

In acute leukemia, lymphoid or myeloid precursor cells that have arrested during the phase of maturity and development become prominent in the marrow and systemic circulation. The exact cause of this malignant clonal proliferation is not known but believed to be due to some type of DNA rearrangement.

After chromosomal rearrangement occurs, this leads to faulty regulation of oncogenes that control development of white cells. Once the abnormal cell lines proliferate, the bone marrow gets congested and starts to function poorly. There is physical replacement of bone marrow cells by immature cell. In addition, the abnormal white cells also secrete cytokines that also inhibit normal hematopoiesis in bone marrow.

As the bone marrow becomes congested with abnormal cells, there is spillage of cells into the circulation and infiltration of other organs, such as the liver, spleen, and eye. The clinical features of ocular infiltration may be:

  1. Secondary to direct infiltration by leukemic cells
  2. A result of abnormal systemic coagulation and hematological factors
  3. Development of opportunistic infections
  4. Iatrogenic complications arising from chemotherapeutic agents [1] [2].

Prevention

Because the cause of ALL and AML are not known it it difficult to make any firm recommendations on prevention. Even though radiation exposure has been linked to ALL and AML, this is by no means a direct correlation. In any case, if possible, one should avoid buying a home near any major power lines or a nuclear facility.

Summary

Acute lymphoblastic leukemia (ALL) is a malignancy of the bone marrow which is characterized by proliferation of early lymphoid precursor cells. Over time, these abnormal cells replace the normal hematopoietic cells of the bone marrow. ALL is the most common type of cancer in children in the United States. ALL is differentiated from several other related malignancies of the bone marrow using a variety of cytochemistry, immunochemistry and cytogenetic markers. The majority of cells in ALL are premature lymphoid precursor cells that have arrested during the early stage of development.

The exact cause of ALL is not known but there appears to be chromosomal translocations which results in an abnormal expression of certain oncogenes. As the premature lymphoblasts replace the normal bone marrow, this results in a marked decreased in production of normal blood cells. Classic features of ALL include neutropenia, anemia and thrombocytopenia. The lymphoblasts also proliferate and infiltrate other organs of the body including the liver, spleen, central nervous system (CNS), lymph nodes and eye [1] [2].

Acute myeloid leukemia (AML) is a hematological malignancy disorder that affects the bone marrow. AML is differentiated from other related malignancies by the presence of > 20% blasts in the bone marrow. Like ALL, in AML there is arrest of maturation of certain bone marrow cells. Several factors have been associated with this malignancy include exposure to radiation, genetic mutations, environment and toxin exposure and familial syndromes. AML patients present with symptoms resulting from bone marrow failure and infiltration of organs with leukemic cells [3] [4].

Patient Information

Acute leukemia is a type of cancer in which the bone marrow makes abnormal blood cells. Forms of acute leukemia include acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Once ALL or AML has been diagnosed, the patient and the family must be thoroughly educated about the disease and the symptoms. The patient should be instructed to seek emergent care if there are signs of a fever or bleeding. In addition, patients who receive chemotherapy should be told to avoid exposure to other people with illness, especially children with viral infections. Even though leukemic patients can resume all activities but most do not have the physical endurance to participate in intense physical activity. Finally all ALL and AML patients should adhere to a neutropenic diet that includes the following:

  • All food must be cooked.
  • No vegetables or fresh fruit is to consumed.
  • All meals are to be cooked until well done.

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References

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