Prognostic Factors for Leukemic Transformation and Survival in Essential Thrombocytosis
Prognostic Factors for Leukemic Transformation and Survival in Essential Thrombocytosis
Abstract & Commentary
By Andrew S. Artz, MD, MS, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Prognostic factors for essential thrombocytosis (ET) generally relate to the most common clinical complication, thromboembolic events. Because of the good long-term survival and low probability of leukemic transformation (LT), prognostic factors for these important clinical outcomes have been poorly characterized. In this observational study of 605 ET patients seen at one institution over 50 years, anemia (hemoglobin < 13.5 g/dL for men and < 12 g/dL for women), high leukocyte count, and age over 60 years independently worsened mortality. In the 20 (3.3%) LT patients, only anemia and platelet count > 1000 K/uL were risk factors. Absent these two risk factors, the LT rate of 0.4% was highly different from the 6.5% rate in the presence of both risk factors (P < 0.0001). The JAK2V617F mutation had no impact on survival or LT. Similarly, drug therapy did not increase the chance of LT. Prognostic stratification in ET is feasible and may improve patient counseling and designing clinical trials.
Source: N. Gangat, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients. Leukemia. 2007;21:270-276.
As opposed to the other chronic myeloproliferative disorders, essential thrombocytosis (ET) uniquely remains a diagnosis of exclusion, as opposed to chronic myeloid leukemia, chronic idiopathic myelofibrosis, or polycythemia vera. Most patients enjoy a normal life expectancy. The common disease-related complications include thrombosis and clonal evoluation into either AML or myelofibrosis.1 Prognostic models primarily stratify based upon thrombosis risk. Age over 60 years and prior thrombosis are strong risk factors for thrombosis and warrant consideration of platelet lowering therapy. Owing to the prolonged survival and low risk of leukemic transformation (LT), prognostic factors for these outcomes have been less well substantiated.2 Further, the controversy of whether or not drug therapy for ET promotes leukemogenesis persists, confounded by the potential that medical treatment is preferentially employed in advanced cases that have a greater proclivity toward clonal evolution.
Researchers from the Mayo Clinic in Rochester assessed prognostic factors for LT and survival by studying a cohort followed at their institution. From 1956 to 2006, they extracted medical records from patients having ET or myelofibrosis. The WHO criteria were used. Thus, diagnoses assigned before the WHO criteria were reviewed again. Archived DNA was used for JAK2V617F mutational screening.
Among the 605 consecutive patients identified, 66% were female, the median age was 57 years, and 50% harbored the JAK2 mutation. The median follow-up was 7 years. LT occurred in 20 (3.3%) whereas 152 (26%) had died. The strongest adverse prognostic factors for survival were advanced age, anemia, and leukocyte count above 15 k/uL. Anemia and platelet count > 1000 K/uL were the strongest factors for LT. The rate of LT was 0.4%, 4.8%, and 6.5% in the presence of 0, 1, or 2 risk factors. Although drug exposure increased the risk of leukemic transformation, the differences were negated once adjusting for baseline prognostic factors. Interestingly, 4 of 20 patients with LT were never exposed to drug therapy. The median survival after LT was 4 months and the only long-term survivor received an allogeneic stem cell transplant. The JAK2 mutation did not lead to inferior survival or higher risk of LT.
Commentary
Patients having essential thrombocytosis generally have a good prognosis. As the most common serious complication, thrombosis has been the outcome for most prognostic models. Prognostic factors predicting leukemic transformation (LT) or impaired survival have been less well determined since clonal evolution is uncommon and survival relatively normal.
As the largest study to date on these outcomes, this retrospective analysis of 605 patients diagnosed with ET from one institution provides clinically relevant information. The authors found that anemia (hemoglobin < 13.5 g/dL for men and < 12 g/dL for women) was an independent risk factor for LT and worse survival. Age and elevated leukocyte count were risk factors for worse mortality while platelet count above 1000 K/uL was the only other risk factor, aside from anemia, strongly predicting for LT.
The prognostic factors identified will be valuable in counseling about long-term prognosis. Further, they could be instrumental in designing clinical trials for high risk patients or to allow adjusting in other analyses. A negative result—lack of association between ET and drug therapy—may be the most germane finding as it provides reassurance that the appropriate use of hydroxyurea with or without anagrelide appears relatively safe.
Over the past several years, the discovery of the high frequency of Janus Kinase 2 mutations (JAK2 V617F) in myeloproliferative disorders has sparked renewed interest in understanding disease biology. Although most cases of polycythemia vera have such mutations, the 50% mutational rate in this series for ET is in line with estimates from the literature of 50-60% in ET. The lack of an association between JAK2 mutational status and outcome suggests this mutation does not necessarily identify distinct groups of ET for which different treatment strategies would be needed.
Even as the largest study evaluating survival and LT in ET, the relatively few number of events, especially for LT (n = 20), hampers the statistical power to find independent risk factors. Validating prognostic factors and understanding disease biology would be greatly facilitated by establishing a disease registry and/or design of large multi-institutional trials that included correlative studies.
In summary, this report highlights that anemia as well as several other prognostic factors impact survival and leukemic transformation in ET. Evolution into AML is uncommon and not clearly related to drug therapy employed for ET.
References
1. Rozman C, et al: Cancer. 1991;67:2658-2663.
2. Passamonti F, et al: Am J Med. 2004;117:755-761.
Prognostic factors for essential thrombocytosis (ET) generally relate to the most common clinical complication, thromboembolic events.Subscribe Now for Access
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