AML

Clinical Presentations in Acute Leukaemia (both)

  • cancerous cells within bone marrow proflifferate

  • Patients often present with generic/non-specific symptoms.

    • Lethargy

    • Bruising

    • Nausea

  • Symptoms primarily associated with bone marrow failure.

    • Thrombocytopenia is present in a majority of cases.

    • Anaemia can also be present.

  • White blood cell count may vary across patients, depends on what stage

    • low count when early as wbc production is halted

    • normal count as the cancer cells within the bone marrow start leeking out into surrounding blood

    • high count in further stages, as cancer cells leak out a lot

    • increase in wbc count starts becuase the count is low, so body increases amount of pro-inflammatory cytokines

  • Other symptoms result from:

    • Infiltration of organs

      • “pseudo-tumours” - hepatosplenogamy

    • Metabolic imbalance

Blasts

  • immature wbc

  • cant always see nucleoli (pale regions)

    • areas of increadibly active transcription

  • myeloid blasts have auer rods (not in all, but will def have some. if none there then not myeloid)

FAB: Distinguishing Between Myeloid and Lymphoid Progenitors

  • Early staining techniques relied on the relative differences in carbohydrates and lipids between lineages.

    • Sudan Black B is an example. (bad cause its carcinogenic, phased out in wales)

    • Enzymatic dyes were developed in the 1940s for this purpose. (bad cause of time contraints)

    • Other dyes include Azo dyes.

  • Current methods include immunohistochemistry and flow cytometry.

    • looks for chromasome and DNA abnormalities

Problems with the FAB System

  • The FAB system is based solely on morphological observations.

  • Potential Issues:

    • Poor correlation with clinical outcomes (lack of knowledge of how many types there were)

    • Limitations arise because of its reliance on morphology alone, lacking comprehensive predictive power.

    • all done via a human looking in a microscope

Epidemiology of Acute Myeloid Leukaemia (AML)

  • AML accounts for approximately 33% of all leukaemia cases in adults.

    • Annually, there are about 18,300 cases in the EU.

  • About 95% of all AML cases occur in adults (increases after 50)

  • There is a slight male prevalence in cases of AML.

    • due to historical jobs being male-lead

  • The incidence rate is higher in developed countries.

    • Specific rates in Western Europe range from 2-4 per 100,000.

  • Rates have increased by 70% since 1971.

  • The median age of diagnosis for AML is 68 years.

Aetiology of AML

  • Multiple environmental factors have been strongly linked to the development of AML.

    • Benzene exposure is a notable risk factor.

      • used to be used to detect gas leaks as has specific smell

    • A strong association with tobacco use exists regarding the risk of developing AML.

    • Ionizing radiation is another significant environmental factor.

      • Example: Exposure from the Atom Bomb.

    • Certain forms of cancer and specific alkylating agents are also linked to increased risk of AML.

      • not cancer itself, but the treatment - chemotherapy breaks crosslinks between DNA, risk of mutation when its repaired - possible gradual accumilation of more over time

FAB Classification of AML

  • The FAB classification system categorizes AML based on the maturation of blasts and/or the lineage of cells involved.

  • More types of myeloid cells than lymphoid cells

    • FAB subtypes include:

    • MO: Undifferentiated

    • M1: Myeloblastic without maturation

    • M2: Myeloblastic with maturation

    • NG: Promyelocytic

    • M3: Myelomonocytic

    • M4: Myelomonocytic with bone marrow eosinophilia

    • M5: Monocytic

    • M6: Erythroleukaemia - rare

    • M7: Megakaryoblastic - rare

Molecular Genetics of AML

  • Certain inherited conditions that cause poor genome stability can predispose individuals to develop AML (every round of mitosis is a risk for mutation):

    • Fanconi Anemia

    • Ataxia Telangiectasia

    • Li-Fraumeni Syndrome

  • Cytogenetic abnormalities are common in AML, often characterized by translocations.

    • Such abnormalities form the basis of WHO classification for AML.

WHO Classification

  • The WHO classification for AML relies heavily on morphological identification complemented by cytogenetic perspectives.

  • Cytogenetic abnormalities include:

    • T(15;17)(q22;q21): a mutation linked to retinoic acid receptor.

    • T(9;11)(p22;q23): connections to MLLT3-MLL mutations.

  • diagnosis is much harder than ALL

Diagnosis of AML

  • The diagnosis of AML is initially based on full blood counts and blood films.

    • Characteristics observed:

    • Possible leucocytosis (often exceeding >100\cdot10^9 cells/L).

    • Leucocytopenia (cancerous) is observed in approximately 40% of cases.

    • Thrombocytopenia is frequently present.

    • Normocytic anaemia can occur.

    • Fluorescence in-situ hybridization is utilized to detect cytogenetic abnormalities.

  • FAB is worse than WHO cause its done by human hand, but is quicker and covers more range as some DNA mutations may not have been found yet so it will cover “AML, not otherwise specified (NOS)” category

Prognosis of AML

  • AML represents the leukaemia with the poorest prognosis overall, because each person has many varying mutations so its hard to treat (no targeted theapies - companies refuse to waste so much money for a different treatment per patient)

    • Age at diagnosis significantly influences prognosis:

    • Individuals under 45 years (rare) exhibit a 5-year survival rate of 37%.

    • Those over 75 years have a 5-year survival rate of only 2%.

    • Over two-thirds of patients over 65 years will die within 12 months.

    • Various prognostic factors can be utilized for prediction of outcomes.

Case Study in Prognosis: T(15;17)

  • The translocation between chromosome t(15;17)(q22;q21) is specifically associated with acute promyelocytic leukaemia (M3).

    • This accounts for approximately 10% of all adult AML cases.

  • used to be death sentence (as short as 1 week, now has the best prognosis cause we undertsnad it)

  • A mutation causes the retinoic acid receptor alpha (RARA) gene on chromosome band 17q21 to fuse with a nuclear regulatory factor gene on chromosome band 15q24 (PML gene), resulting in the formation of a PML-RARA fusion gene product.

    • The fusion protein exhibits an enhanced binding affinity to specific DNA sites within the cell, thereby blocking transcription and differentiation of granulocytes by enhancing the interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC).

    • Historically, this condition demonstrated an exceptionally poor prognosis with a median survival of only <7 days post diagnosis before the 1990s, attributed to:

    • High doubling rate of the cells.

    • Significant association with disseminated intravascular coagulation.

    • Prognosis has since improved, offering a survival chance of approximately 80% over 10 years due to advances in treatment:

    • All-trans retinoic acid (ATRA) therapy promotes the disassociation of HDAC and NCOR from the PML-RARA fusion protein, facilitating differentiation of promyelocytes.

    • PML/RARA is regarded as the master driver of acute promyelocytic leukaemia pathogenesis and the basis of therapy response.

  • basically encourages prolifferation and stops further differentiation of the cell (bad), once figured this out we found the acne cream with retinoic acid will force the differentiation to occur, making the cell go back to normal and the body will dispose of monocytes (repurposing)

Management of AML

The management of AML is typically a two-step process:

  • Remission Induction:

    • The primary goal is to reduce bone marrow blasts to less than 5% with no detectable peripheral blasts.

    • The 7+3 regimen is a commonly used treatment protocol, involving (chemotherapy):

      • 3 days of Anthracycline.

      • 7 days of Cytosine Arabinoside (Ara-C).

    • repeated until patient either takes turn for the worst or in in reimission

  • Post-Remission Therapy:

    • Options include stem cell transplantation, immunotherapy, and continued administration of Ara-C.

    • Antimicrobial prophylaxis is crucial throughout the course of treatment to prevent infections:

      • Fluconazole (caution advised due to potential interactions with chemotherapy).

      • Cefepime.

  • can do targeted therapies if youre lucky enough to have the mutations the therapies work for