Myeloid Leukemias

Consist of AML, CML (which is an MPN), and CMML. All myeloid disorders can evolve into AML.

Acute Myeloid Leukemia (AML)

A disorder of too many immature myeloid cells (i.e. blasts).

Etiology

De novo vs secondary (chemotherapy, transformed MDS/MPN, congenital disorders such as Fanconi anemia or Down syndrome, benzene exposure).

Presentation

1. BM failure - cytopenias
   1. Anemia (fatigue)
   2. Thrombocytopenia (bleeding)
   3. Neutropenia (infections)
2. Systemic symptoms
   1. Leukostasis
   2. DIC
   3. TLS
3. Organ dysfunction
   1. Skin --> rash
   2. Mucosa --> gum hypertrophy
   3. CNS --> neurologic symptoms

Diagnosis

• >= 20% blasts in PBS or BM (unless there are the presence of leukemia defining mutations such as PML-RARA in APL)
• WHO classification depends on genetic mutation analysis
• Differentiating AML from ALL: based on BM biopsy, flow cytometry, cytogenetics, molecular studies. Auer rods are only present in myeloid neoplasms and are NEVER non-pathologic.

French-American-British (FAB) Classification of AML

Developed in the 1970s. Based on progenitor lineage and maturity of cells. Subtypes M0 through M5 all start in immature forms of white blood cells. M6 AML starts in very immature forms of red blood cells, while M7 AML starts in immature forms of cells that make platelets. From Cancer.org

FAB Subtype	Name
M0	Undifferentiated acute myeloblastic leukemia
M1	Acute myeloblastic leukemia with minimal maturation
M2	Acute myeloblastic leukemia with maturation
M3	Acute promyelocytic leukemia (APL)
M4	Acute myelomonocytic leukemia
M4 eos	Acute myelomonocytic leukemia with eosinophilia
M5	Acute monocytic leukemia
M6	Acute erythroid leukemia
M7	Acute megakaryoblastic leukemia

M3 subtype (Acute promyelocytic leukemia)

• presents as Blasts + Auer rods + DIC
• Requires urgent (overnight) treatment with ATRA (watch out for differentiation syndrome after treatment initiation)

Treatment of AML

• Curative intent with (1) induction chemotherapy and then (2) either consolidation chemotherapy for low-risk disease or allogenic HSCT for high-risk disease.
• APL specifically: ATRA + arsenic +/- chemotherapy

Chronic Myeloid Leukemia (CML)

This is an MPN characterized by overproliferation of mature myeloid cells, in this case, granulocytes (neutrophils, basophils, eosinophils).

Etiology

• BCR-ABL +ve (Philadelphia chromosome) which produces a constitutively active TKR

Diagnosis

• Peripheral blood PCR for BCR-ABL t(9;22) Philadelphia chromosome
• BM to confirm the phase/prognosis

Phase of CML

Chronic --> accelerated --> blast.

Chronic Phase

• Increased WBC, mostly neutrophils and its precursors. Anemia, +/- thrombocytosis.
• Splenomegaly, mild constitutional symptoms.
• BM + peripheral blast count < 10%
• Peripheral blood will show left shift + basophils + eosinophils
• Treatment: TKIs (imatinib)
• Prognosis: life expectancy equivalent to general population (i.e. NORMAL)

Accelerated Phase

• characterized by 10-19% of blasts in the peripheral blood or BM.
• Presents as worsening blood counts despite therapies (WBC > 10, plt > 1000, or Plts < 100 on therapy)

Blast Phase

• characterized by >= 20% blasts in the peripheral blood or BM
• this is essentially acute leukemia (70-80% AML, 20-30% ALL)
• Treatment is per acute leukemia (chemotherapy) + TKI

Chronic Myelomonocytic Leukemia (CMML)

This is characterized by features of both MPN (monocytosis) and MDS (dysplasia --> cytopenias).

Presentation

Patients will present often with cytopenias and splenomegaly, constitutional symptoms, rashes, lymphadenopathy.

Diagnosis

• peripheral blood monocytes >= 1 x 10^9/L and >= 10% of total WBC
• Blast count < 20% (once again, below the cutoff for AML)
• Dysplasia in at least 1 myeloid lineage
• Exclusion of other MPN (CML, ET, PV)

Prognosis

• 15-30% progress to AML
• The most important prognostic factor is blast %

Treatment

• higher risk CMML
  • medically fit
    • low blast % -- allogeneic HSCT
    • high blast % -- hypomethylating agent (HMA) then SCT
  • frail patients -- symptom-driven therapy
• lower risk CMML -- symptom-driven therapy
  • asymptomatic -- monitoring
  • symptomatic
    • hydroxyurea -- for proliferative symptoms (splenomegaly, B symptoms)
    • hypomethylating agent (HMA) -- for cytopenias

References

1. IM Review Slides, 2021