Page created on April 8, 2022. Last updated on April 20, 2022 at 16:25

Written by ms. Worldwide, edited by Nikolas.

Acute myeloid leukaemia

Introduction and epidemiology

Acute myeloid leukaemia (AML) is a malignant disease of the myeloid cell line in the bone marrow. There is uncontrolled clonal cell proliferation which infiltrates the normal bone marrow and displaces the normal haematopoiesis. It is characterised by acute neoplastic proliferation of myeloid blast cells in the bone marrow. There is at least 20% blast rate in bone marrow and/or peripheral blood, and the cells are proven to be of myeloid origin.

Peak incidence is 65 years, and 80% of acute leukaemia during adulthood are myelogenous.

Etiology

De novo AML:

• Pre-existing hematopoietic disorders that can progress into AML
  • Myelodysplastic syndromes
  • Aplastic anaemia
  • Myeloproliferative disorders (CML)
• Environmental factors
  • Alkylating chemotherapy
  • Ionizing radiation
  • Tobacco
• Genetic or chromosomal factors
  • Down syndrome
  • Fanconi anaemia

Secondary AML results from chemo- or radiotherapy and occur in most cases 5-10 years after treatment.

Pathomechanism

Acquired somatic mutations in early hematopoietic precursors lead to rapid proliferation of abnormal and dysfunctional blasts. This disrupts the normal haematopoiesis leading to leukopenia, thrombocytopenia, and anaemia.

Clinical features

General features of acute leukaemia (both AML and ALL) are characterized by subacute onset and rapid progression. They include:

• Symptoms of anaemia
  • Fatigue
  • Pallor
• Symptoms of thrombocytopenia
  • Epistaxis
  • Bleeding gums
  • Petechiae, purpuras
• Frequent infections and fever due to immature leukocytes
• Hepatosplenomegaly
  • Not as common as in ALL but might occur

Some present with oncological emergencies like tumour lysis syndrome or DIC.

Diagnosis and evaluation

Some cell lines may be normal at the time of diagnosis.

• Normocytic normochromic anaemia
• Thrombocytopaenia
• WBC may be low or high
• Blasts on blood smear
• Increased LDH and uric acid
• Abnormal electrolytes

Diagnosis is confirmed on detection of >20% blasts in the bone marrow or finding specific genetic mutations on cytogenic examination (PCR). This requires a bone marrow aspiration and biopsy. If it’s not possible, a peripheral blood smear might be used.

Immunophenotyping is achieved with flow cytometry to determine the origin of the leukemic cell line. For example, precursor cells are CD34+, while monocytic markers are CD14 and CD36. Certain subtypes of AML can only be diagnosed by this method.

Immunophenotyping, molecular diagnostics, and cytogenic examination are important to determine the exact subtype, which is important for prognosis and to guide treatment.

Treatment

At first, induction therapy is initiated. High doses of chemotherapy are given to achieve massive reduction of tumor cell count. This step also carries the highest risk of infection and death caused by the toxic damage to bone marrow and GIT. A 7+3-day scheme is usually used. Cytarabine and idarubicin are the preferred agents.

After induction, consolidation therapy is the next step. 2-4 cycles high dose cytarabine therapy for 5 days. This destroys any remaining tumor cells after induction.

Maintenance chemotherapy is not a part of AML treatment due to lacking evidence of benefits.

For those who don’t achieve remission with chemotherapy or have unfavourable cytogenetic factors, allogenic stem cell transplantation might be an option.

Complications such as neutropenia and tumor lysis syndrome are common during and sometime after the treatment. Some prophylactic measures:

• Acyclovir for reactivation of HSV and HZV.
• TMP-SMX for PCP
• Allopurinol and IV fluids for tumor lysis syndrome
• Granulocyte colony-stimulating factor (Filgrastim) to decrease the duration of aplasia and neutropenia.
• Isolation to prevent infections while being neutropenic.
• Broad-spectrum antibiotics if neutropenic fever. NB: find the source of infection if possible!
• Transfusion of erythrocytes or platelets if needed.

Prognosis

Age is an independent and a bad prognostic factor. It is also important to consider the overall health status of the patient and comorbidities. The ECOG scale is a good indicator of this. AML associated with genetic abnormalities increases with age and might make the disease resistant to therapy.

Despite the advancement in therapy for AML, the long-term survival rate remains 20-40 %, and with cell stem transplantation up to 40-50%.

Acute promyelocytic leukaemia

Introduction and epidemiology

Acute promyelocytic leukaemia (APML) is a subtype of AML that differs from AML in prognosis. If discovered and treated in time, the prognosis is excellent, but it is very deadly if not due to the high risk of bleeding. Treatment should be started immediately if APL is suspected before diagnosis. The genotype is t(15;17) PML-RARA.

Diagnosis:
Leukopenia and promyelocytes in the peripheral blood. T(15;17) and PML-RARA fusion transcript. High risk disease is when the WBC count is below 10 G/L.

Treatment:
All-trans retinoic acid (ATRA) must be given as soon as possible. New is that Arsenic trioxide (ATO) is added into the early phase treatment together with ATRA, resulting in synergy and potential curative treatment. The effect of these agents is to force the malignant promyelocytes to mature. In high-risk disease cytarabine is added.

Maintenance therapy is obligatory. ATRA and low doses of MTX are usually enough.

Acute lymphoblastic leukaemia

Definition and epidemiology

Acute lymphoblastic leukaemia (ALL) is a malignant disease of the lymphoid cell line in the bone marrow. There is uncontrolled clonal cell proliferation which infiltrates the normal bone marrow and displaces the normal haematopoiesis. There is also extramedullary infiltration to CNS, liver, testes, and skin. There is at least 20% blast rate in bone marrow and/or peripheral blood, and the cells are proven to be of lymphoid origin.

It occurs mostly in children between ages 2-6 years, and 60% of the patients are younger than 20 years. However, it might occur in adults also, and the median age for adults is 35 years. More common in males.

Clinical features

Clinical features are mostly similar as with AML. Hepatosplenomegaly and lymphadenopathy are more common in ALL than AML. CNS and meningeal infiltration are common, causing headache, altered mental status, or other neurological symptoms. Infiltration of the bone marrow and periosteum can cause bone pain.

B-symptoms (fever, DRENCHING night sweat, unintentional weight loss >10% last 6 months) are common in ALL, but not AML. Testicular enlargement is a rare but significant finding of testicular infiltration.

Diagnosis and evaluation

Some cell lines may be normal at the time of diagnosis.

• Normocytic normochromic anaemia
• Thrombocytopaenia
• WBC may be low or high
• Blasts on blood smear
• Increased LDH and uric acid
• Abnormal electrolytes

Diagnosis is confirmed on detection of >20% blasts in the bone marrow or finding specific genetic mutations on cytogenic examination (PCR). This requires a bone marrow aspiration and biopsy. If it’s not possible, a peripheral blood smear might be used.

Immunophenotyping is achieved with flow cytometry to determine the origin of the myeloid cell line. Immunophenotyping, molecular diagnostics, and cytogenic examination are important to determine the exact subtype, which is important for prognosis and to guide treatment.

Philadelphia translocation (t(9;22)) is present in 20-30 % of adults. PCR is also useful for confirming subtype. Lumbar puncture to check for CNS infiltration in addition to brain and spine CT or MRI. This should be done in all patients.

Treatment

The goal is to achieve and maintain complete remission, meaning that there is recovery of normal bone marrow function and <5 % blasts.

It takes nearly 2-3 years with treatment to reach complete remission. Induction therapy is usually with agents such as vincristine, doxorubicin, dexamethasone. This last for 4-8 weeks. Consolidation with methotrexate for 4-8 weeks. Maintenance by methotrexate weekly and 6-mercaptopurine daily for 2 years.

CNS prophylaxis is a must as the relapse rate is 60 % if not given. Intrathecal chemotherapy with methotrexate or cytarabine is given, and CNS irradiation might be considered in some cases too.

In case of relapse or high-risk disease, allogenic stem cell transplant is considered.

Same prophylactic therapy as in AML.

Prognosis

BCR-ABL1 positivity means very poor prognosis.

The prognosis is way better for children than for adults. Complete remission is 97 % for children, and 5-year survival is 80-90 %, while for adults 5-year survival is 35 %.