A Patient with Pancytopenia

Peter W. Marks, MD

Yale University School of Medicine, New Haven, CT

Copyright of the American Society of Hematology, 2012. ISSN: 1931-6860.

V. PATHOPHYSIOLOGY

Epidemiology

Acute myeloid leukemia (AML) is a relatively common hematologic malignancy. In the United States in 2010, there were about 12,000 new cases and about 9,000 deaths from the disease. It most commonly affects older individuals, with a median age of 68 years at diagnosis, but also occurs across the entire age spectrum, including children.

Risk factors for AML include exposure to certain toxins, such as benzene, and exposure to ionizing radiation. In addition, therapy-related AML occurs in a fraction of patients treated with chemotherapy agents, particularly alkylating agents and topoisomerase II inhibitors. Certain genetic abnormalities, such as Down’s syndrome and neurofibromatosis 1, are also associated with an increased incidence of AML. Several other hematologic disorders ultimately can transform into acute myeloid leukemia. These include the myelodysplastic syndromes, myeloproliferative syndromes, and chronic myeloid leukemia.

Classification

Modern classification of AML relies on complementary modalities. These include evaluation of morphology, histochemistry, flow cytometry, cytogenetics including fluorescence in situ hybridization (FISH), and molecular diagnostic testing.

Based on morphology and histochemistry, AML was traditionally classified into eight major subtypes according to the French-American-British classification scheme:

M0 Miniminally differentiated AML
M1 AML without maturation
M2 AML with maturation
M3 Promyelocytic leukemia
M4 Myelomonocytic leukemia
M5 Monocytic leukemia
M6 Erythroleukemia
M7 Megakaryoblastic leukemia

However, with the advances in the field, including a deeper appreciation of the importance of cytogenetic and molecular prognostic factors, the most recent World Health Organization (WHO) classification scheme focuses on factors that are more related to the underlying pathophysiology and outcomes. The major categories are:

Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related acute myeloid leukemia
Acute myeloid leukemia, not otherwise specified

The category of AML with recurrent genetic abnormalities encompasses both favorable and poor prognosis leukemias:

Category Prognosis
AML with t(8;21)(q22;q22); RUNX1-RUX1T1 Favorable
AML with inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11 Favorable
APL with t(15;17)(q22;q23); PML-RARA Favorable
AML with t(9;11)(p22;q23); MLLT3-MLL Intermediate
AML with t(6;9)(p23;q34); DEK-NUP214 Unfavorable
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 Unfavorable
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 Intermediate
Provisional entity: AML with mutated NPM1 Favorable
Provisional entity: AML with mutated CEBPA Favorable

The molecular pathogenesis of APL is now understood and is illustrated below. The fusion protein consists of the promyelocytic leukemia gene (PML), a tumor suppressor normally found in nuclear bodies, and the retinoid acid receptor alpha gene (RARA), a transcription factor that is normally responsive to retinoid acid. The juxtaposition of these two genes produces a protein that does not respond to the usual form of retinoic. However, it does respond to a specific type of retinoic acid, all-trans retinoid acid, leading to restoration of gene transcription and thereby to cellular differentiation. Interestingly, the substance arsenic trioxide leads to a similar effect because it leads to aggregation and degradation of the PML-RARA fusion protein, thereby promoting differentiation. Both ATRA and arsenic trioxide are now used for the treatment of APL.



Any type of AML may be associated with disseminated intravascular coagulation (DIC). However, APL is the form of AML most commonly associated with severe coagulopathy. In fact, much of the mortality today from APL is the result of early deaths due to bleeding complications, such as hemorrhage into the brain. The mechanism for the coagulopathy relates to substances that are released from the blasts into the circulation as they undergo cell death. These proteins include tissue factor and other proteins, including those involved in fibrinolysis. The release of these proteins leads to the generation of thrombin and to the formation and subsequent breakdown of fibrin strands. The resultant coagulopathy may be apparent when patients first present with APL. Alternatively, it may be manifest or can be greatly exacerbated at the time conventional cytotoxic chemotherapy is initiated, since this leads to rapid cell death. Newer treatments for APL that lead to differentiation of the blasts (all-trans retinoic acid and arsenic trioxide) greatly lessen this complication.


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