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] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [3]
Overview
The natural history of acute promyelocytic leukemia is characterized by symptoms related to defective normal blood cell production. These symptoms include fatigue, bleeding, and infection. Complications include thrombosis and hemorrhage, which eventually occur in a significant proportion of patients. Early death is common and is related to bleeding complications. Therapy-related complications include differentiation syndrome, QT interval prolongation, and cardiomyopathy. The prognosis of acute promyelocytic leukemia was previously poor, but the advent of arsenic trioxide and all-trans retinoic acid has rendered the prognosis to be far more favorable in the recent years.
Natural History
- Acute promyelocytic leukemia typically begins with a combination 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.[1]
- The median survival in the absence of treatment is typically one week, due to bleeding complications contributing to mortality.[2]
- 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.[3] 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.[3]
Complications
- Hemorrhage: Acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC). Hemorrhagic and bleeding diathesis is the major cause of early complications that can lead to immediate death in patients with acute promyelocytic leukemia. For this reason, prompt treatment of the disease is required.[4][5]
- Venous thromboembolism: Thrombus formation is a major cause of morbidity in acute promyelocytic leukemia. Thrombosis in the setting of acute promyelocytic leukemia is associated with a worse outcome compared to non-cancer-related thrombosis. Studies have shown that rate of venous thromboembolism was 10.8 % in patients with acute promyelocytic leukemia . The reason for this correlation between thrombosis and death in acute promyelocytic leukemia is that thrombosis is a surrogate marker for disease progression.[6][7][8][9]
- 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.[10]
- Platelets: There is a increased platelet activation in acute promyelocytic leukemia.[4]
- Fibrin: 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.
- Catheters: Central venous catheters can serve as a nidus for thrombosis since there is localized tissue and endothelial damage at the site of catheter insertion. and along the catheter within the body.[7] Patients with acute promyelocytic leukemia are more likely to have central venous catheters, compared to patients with other conditions, since chemotherapy usually requires the presence of a central catheter to be placed.
- Immobility: Patients with acute promyelocytic leukemia are frequently confined to a hospital bed during induction therapy, and venous stasis contributes to thrombosis. Obesity can also contribute to thrombosis.
- Erythropoiesis-stimulating agents: Patients with acute promyelocytic leukemia frequently have anemia. Some patients receive erythropoiesis-stimulating agents, such as erythropoietin, which can increase red blood cell production and exacerbate thrombotic complications.
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.[7] In contrast, the incidence of venous thromboembolism in chronic myeloid leukemia was only 1.5%.
| Disease | Thrombotic Incidence |
|---|---|
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Acute promyelocytic leukemia |
6.1-48% |
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Acute myeloid leukemia |
3.7% |
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Chronic lymphocytic leukemia |
2.7% |
|
Acute lymphoblastic leukemia |
2.1-13% |
|
Chronic myeloid leukemia |
1.5% |
- Therapy-related complications:: Treatment of acute promyelocytic leukemia can result in a variety of complications which are somewhat unique to the disease.
- Differentiation syndrome: Differentiation syndrome is a clinical condition that results from treatment with all-trans retinoic acid.Differentiation syndrome[11] This condition is characterized by weight gain, peripheral edema, hypoxia, dyspnea, renal failure, fever, and hypotension. The syndrome is thought to be due to systemic inflammation induced by the release of cytokines from malignant promyelocytes. This results in endothelial cell damage with resultant capillary leakage. Malignant promyelocytes are then able to adhere to tissue that is perfused by the microcirculation.[11] Patients with a high white blood cell count are at highest risk for differentiation syndrome, since all-trans retinoic acid will result in release of a large amount of cytokines if there is a high leukemia burden. Differentiation syndrome is a major complication that must be recognized early on, such that proper corrective measures can be taken. These include the use of dexamethasone 10mg PO twice daily, plus supportive treatment for any underlying respiratory distress. Diruesis may be needed to help eliminate excess fluid accumulation.
- QT interval prolongation: Arsenic trioxide can result in prolonged QT interval, which carries a risk for cardiac-related complications such as arrhythmias. Patients who are treated with arsenic trioxide must have routine electrocardiograms (EKGs) done to ensure that the corrected QT interval remains less than 500 milliseconds. In patients who are treated with concomitant chemotherapy and arsenic trioxide, such as patients with high-risk acute promyelocytic leukemia, there is a higher risk for cardiac-related complications. Chemotherapy and intravenous fluids can alter electrolyte such as potassium levels. Hypokalemia (low potassium) can exacerbate QT prolongation.
- Cardiomyopathy: Patients receiving chemotherapy with anthracyclines, such as idarubicin or daunorubicin, are at risk for short-term cardiac-related complications such as arrhythmias and long-term cardiac-related complications such as systolic dysfunction and heart failure. The highest risk of these complications occurs in patients with underlying cardiomyopathy such as congestive heart failure, atrial fibrillation, or other cardiac issues. The cardiotoxicity of anthracyclines is dose-dependent and generally irreversible.
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 absence of treatment. The early death rate is estimated to be 17.3%, based on a large population-based analysis conducted in the United Stated between 1992-2007.[12] [2] The 5-year survival rate is only 30-40% after 5 years in younger patients.[11] In the current era of medicine (after the introduction of all-trans retinoic acid and arsenic trioxide, the prognosis of acute promyelocytic leukemia carries a much better prognosis.[3] 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. The current overall survival rate is 86-97%, and the complete remission rate is 90-100%.[11] In a multicenter study published in 2017 evaluating long-term outcomes of patients with acute promyelocytic leukemia, the complete remission rate was 96%.[13] Induction mortality if low at 4%.[13]
References
- ↑ Franchini M, Lippi G, Manzato F (2006). "Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation". Thromb J. 4: 4. doi:10.1186/1477-9560-4-4. PMC 1402263. PMID 16504043.
- ↑ 2.0 2.1 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). "Early mortality in acute promyelocytic leukemia: Potential predictors". Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.
- ↑ 3.0 3.1 3.2 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.
- ↑ 4.0 4.1 Choudhry, Aditi; DeLoughery, Thomas G. (2012). "Bleeding and thrombosis in acute promyelocytic leukemia". American Journal of Hematology. 87 (6): 596–603. doi:10.1002/ajh.23158. ISSN 0361-8609.
- ↑ Choudhry, Aditi; DeLoughery, Thomas G. (2012). "Bleeding and thrombosis in acute promyelocytic leukemia". American Journal of Hematology. 87 (6): 596–603. doi:10.1002/ajh.23158. ISSN 0361-8609.
- ↑ Breen, Karen A.; Grimwade, David; Hunt, Beverley J. (2012). "The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia". British Journal of Haematology. 156 (1): 24–36. doi:10.1111/j.1365-2141.2011.08922.x. ISSN 0007-1048.
- ↑ 7.0 7.1 7.2 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.
- ↑ Al-Ani, F., Ahrari, A., Wang, Y. P., Iansavitchene, A., & Lazo-Langner, A. (2017). Incidence of Venous Thromboembolism in Acute Leukemia: A Systematic Review and Meta-Analysis. Blood, 130(Suppl 1), 5634. Accessed January 15, 2019. Retrieved from http://www.bloodjournal.org/content/130/Suppl_1/5634.
- ↑ Dicke, Christina; Amirkhosravi, Ali; Spath, Brigitte; Jiménez-Alcázar, Miguel; Fuchs, Tobias; Davila, Monica; Francis, John L; Bokemeyer, Carsten; Langer, Florian (2015). "Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study". Experimental Hematology & Oncology. 4 (1). doi:10.1186/s40164-015-0018-x. ISSN 2162-3619.
- ↑ Lima, Luize G.; Monteiro, Robson Q. (2013). "Activation of blood coagulation in cancer: implications for tumour progression". Bioscience Reports. 33 (5): 701–710. doi:10.1042/BSR20130057. ISSN 0144-8463.
- ↑ 11.0 11.1 11.2 11.3 McCulloch D, Brown C, Iland H (2017). "Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives". Onco Targets Ther. 10: 1585–1601. doi:10.2147/OTT.S100513. PMC 5359123. PMID 28352191.
- ↑ Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). "Emerging new approaches for the treatment of acute promyelocytic leukemia". Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
- ↑ 13.0 13.1 Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E; et al. (2017). "Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab". Blood. 129 (10): 1275–1283. doi:10.1182/blood-2016-09-736686. PMC 5413297. PMID 28003274.