Acute promyelocytic leukemia natural history, complications and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
Natural History
Acute promyelocytic leukemia typically begins with a prodrome of symptoms including fatigue, bleeding, and infections (such as upper respiratory tract infection). Patients typically present to their primary care physician with such symptoms, and a complete blood count usually reveals a low white blood cell count, low hemoglobin, and low platelet count. A bone marrow biopsy is usually done to work up the abnormal laboratory values, and a diagnosis of acute promyelocytic leukemia is made. In the first few days to weeks of the disease, there is a high risk of bleeding due to disseminated intravascular coagulation, a condition characterized by abnormal thrombus formation and breakdown. The high early mortality rate was previously a major part of the natural history of the disease, prior to the advent of rapid diagnostic and therapeutic interventions for this disease.[1] In areas of the United States with limited healthcare or highly specialized academic centers, bleeding diathesis continues to remain a major part of the natural history of the disease. Such bleeding complications include gingival bleeding (very common), bruising (very common), epistaxis, menorrhagia (less common). In areas of the United States with readily available healthcare and specialized academic medical centers, the natural history of the disease takes a favorable trajectory, as the cure rate is quite high if appropriate induction therapy is initiated.[1]
Complications
- Hemorrhage: Acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC).
- Venous thromboembolism: Thrombus formation is a major cause of morbidity in acute promyelocytic leukemia. In a 2015 study from MD Anderson Cancer Center, it was shown that the annual incidence of venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, was 6.1-42%, which is the highest amongst all leukemia subtypes.[2] In contrast, the incidence of venous thromboembolism in acute lymphoblastic leukemia was only 2.1-13%. Thrombosis in the setting of acute promyelocytic leukemia is associated with a worse outcome compared to non-cancer-related thrombosis.[2] Studies have shown that nearly 80% of patients with venous thromboembolism and cancer die within 6 months of the diagnosis of venous thromboembolism. The reason for this correlation between thrombosis and death in acute promyelocytic leukemia is that thrombosis is a surrogate marker for disease progression, There are multiple reasons for the high thrombotic complication rate in acute promyelocytic leukemia:[2]
- Procoagulants: There is increased production of procoagulant molecules such as thrombin from cancer cells. Furthermore, mucins and cytokines produced by malignant promyelocytes can induce endothelial cells to increase tissue factor production, and tissue factor functions in the extrinsic pathway to promote coagulation.
- Platelets: There is a increased platelet activation in acute promyelocytic leukemia.
- Fibrin homeostasis: There is decreased fibrinolytic activity in acute promyelocytic leukemia, and this results in presence of excess fibrin. Fibrin is also known as factor I of the coagulation cascade and functions to binds platelets together via their GpIIb/IIIa receptors. This is one of the final steps in coagulation.
- Natural anticoagulants: There is decreased production of natural anticoagulants, and this results in increased propensity for thrombosis.
Prognosis
Prior to the introduction of readily available diagnostics and targeted therapeutics, the prognosis of acute promyelocytic leukemia was previously very poor, especially in the early phase of the disease. The poor prognosis was due to high bleeding risk and death from hemorrhagic complications due to disseminated intravascular coagulation. Death typically occurs with a few days to weeks. In the current era of medicine, the prognosis of acute promyelocytic leukemia carries a much better prognosis.[1] Patients can achieve long-term, durable remission if treated appropriately in an expedited manner with medications such as all-''trans'' retinoic acid, arsenic trioxide, or cytotoxic chemotherapy.
References
- ↑ 1.0 1.1 1.2 Coombs CC, Tavakkoli M, Tallman MS (2015). "Acute promyelocytic leukemia: where did we start, where are we now, and the future". Blood Cancer J. 5: e304. doi:10.1038/bcj.2015.25. PMC 4450325. PMID 25885425.
- ↑ 2.0 2.1 2.2 Vu K, Luong NV, Hubbard J, Zalpour A, Faderl S, Thomas DA; et al. (2015). "A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center". Cancer Med. 4 (1): 27–35. doi:10.1002/cam4.332. PMC 4312115. PMID 25487644.