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Increase in leukocyte count over time predicts thrombosis in patients with low‐risk essential thrombocythemia

2009; Elsevier BV; Volume: 7; Issue: 9 Linguagem: Inglês

10.1111/j.1538-7836.2009.03531.x

1538-7933

Francesco Passamonti, Elisa Rumi, Cristiana Pascutto, Mario Cazzola, Mario Lazzarino,

Acute Myeloid Leukemia Research

Both age (i.e. more than 60 years) and history of thrombosis are widely accepted and validated risk factors for thrombosis in patients with essential thrombocythemia (ET). Risk stratification at diagnosis is currently applied accordingly, and only patients with at least one of the two above‐mentioned risk factors are candidates for cytotoxic treatment [1Cervantes F. Passamonti F. Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL‐negative myeloproliferative disorders.Leukemia. 2008; 22: 905-14Crossref PubMed Scopus (0) Google Scholar]. Leukocytes have an emerging role in the prognostication of chronic myeloproliferative neoplasms (MPN) [2Passamonti F. Rumi E. Caramella M. Elena C. Arcaini L. Boveri E. Del Curto C. Pietra D. Vanelli L. Bernasconi P. Pascutto C. Cazzola M. Morra E. Lazzarino M. A dynamic prognostic model to predict survival in post‐polycythemia vera myelofibrosis.Blood. 2008; 111: 3383-7Crossref PubMed Scopus (0) Google Scholar, 3Gangat N. Strand J. Li C.Y. Wu W. Pardanani A. Tefferi A. Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation.Br J Haematol. 2007; 138: 354-8Crossref PubMed Scopus (120) Google Scholar, 4Gangat N. Wolanskyj A.P. McClure R.F. Li C.Y. Schwager S. Wu W. Tefferi A. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.Leukemia. 2007; 21: 270-6Crossref PubMed Scopus (0) Google Scholar]. In ET leukocyotosis at diagnosis is a further predictor of vascular complications during follow‐up. Different white blood cell count (WBC) cutoff values that predict thrombosis‐free survival have been reported (i.e. 8.7 × 109 L−1 [5Carobbio A. Finazzi G. Guerini V. Spinelli O. Delaini F. Marchioli R. Borrelli G. Rambaldi A. Barbui T. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.Blood. 2007; 109: 2310-3Crossref PubMed Scopus (281) Google Scholar], 9.4 × 109 L−1 [6Carobbio A. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Finazzi G. Rambaldi A. Barbui T. Leukocytosis and risk stratification assessment in essential thrombocythemia.J Clin Oncol. 2008; 26: 2732-6Crossref PubMed Scopus (153) Google Scholar], 11 × 109 L−1 [7Carobbio A. Finazzi G. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Ruggeri M. Rodeghiero F. Rambaldi A. Barbui T. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia.Blood. 2008; 112: 3135-7Crossref PubMed Scopus (79) Google Scholar] and 15 × 109 L−1 [8Wolanskyj A.P. Schwager S.M. McClure R.F. Larson D.R. Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long‐term complication rates, and prognostic factors.Mayo Clin Proc. 2006; 81: 159-66Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]). The most powerful prediction of vascular complication by WBC count seems limited to patients with ET at low‐risk of thrombosis (i.e. below 60 years of age, no prior thrombosis). Conversely, two independent large studies on patients with ET did not shown a relationship between leukocyte count at diagnosis and thrombosis [9Tefferi A. Gangat N. Wolanskyj A. The interaction between leukocytosis and other risk factors for thrombosis in essential thrombocythemia.Blood. 2007; 109: 4105Crossref PubMed Scopus (0) Google Scholar, 10Passamonti F. Rumi E. Arcaini L. Boveri E. Elena C. Pietra D. Boggi S. Astori C. Bernasconi P. Varettoni M. Brusamolino E. Pascutto C. Lazzarino M. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients.Haematologica. 2008; 93: 1645-51Crossref PubMed Scopus (198) Google Scholar]. To date, the relationship between leukocyte count at diagnosis and thrombosis has been studied, but such an analysis does not take into account the variation in leukocyte count over time. Based on this rationale, we studied whether changes of leukocyte count over time predict thrombosis during follow‐up. For this reason, we studied patients with two sequential evaluations of WBC count within two years from diagnosis. Thrombosis‐free survival was calculated as the time between the date of diagnosis and the date of the first thrombosis after the second WBC assessment. This is a retrospective study that was approved by the Institutional Ethics Committee of Pavia and the procedures were in accordance with the Helsinki Declaration of 1975, as revised in 2000. The study included 359 consecutive ET patients (period 1976–2008) with the above‐mentioned requirements. Patients underwent follow‐up with regular evaluation of blood cell counts at the Outpatient Section of the Division of Hematology, University of Pavia. Diagnosis of ET was done according to the criteria in use at the time of the first observation [11Murphy S. Peterson P. Iland H. Laszlo J. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment.Semin Hematol. 1997; 34: 29-39PubMed Google Scholar, 12Tefferi A. Vardiman J.W. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point‐of‐care diagnostic algorithms.Leukemia. 2008; 22: 14-22Crossref PubMed Scopus (0) Google Scholar]. Therapy was given on the basis of the physicians' clinical judgment with an agreement to be conservative with low‐risk patients. Ischemic stroke, cerebral transient ischemic attack, acute myocardial infarction, peripheral arterial thrombosis and venous thromboembolism (deep venous thrombosis of the extremities or of abdominal vein) were taken into account as severe vascular events. According to standard risk stratification at diagnosis [1Cervantes F. Passamonti F. Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL‐negative myeloproliferative disorders.Leukemia. 2008; 22: 905-14Crossref PubMed Scopus (0) Google Scholar], 194 patients had low‐risk (LR) ET (age below 60 years, no prior thrombosis) and 165 had high‐risk (HR) ET (age above 60 years, history of thrombosis). LR ET patients were followed for a median time of 4.7 years (range, 0.8–24) and HR ET patients for 6 years (range, 0.3–21). Median age was 41 years (range, 16–59) in LR and 68 (range, 20–90) in HR patients. Median haemoglobin level was 13.9 × 109 L−1 (range 12.1–16.2) in LR and 14.1 × 109 L−1 (range 10.1–17.1) in HR patients. Both patients with upper values of haemoglobin were male. Median WBC count was 9.1 × 109 L−1 (range, 4.2–20) in LR and 9.2 (range, 4.7–22.1) in HR patients. Median platelet (PLT) count was 801 (range, 462–1750) in LR and 797 (range, 475–3000) in HR patients. Splenomegaly was present in 18 (9.2%) LR and in 17 (10.3%) HR patients: spleen size never exceeded 3 cm from the costal margin. JAK2 (V617F) mutation was detected in 80 (55%) out of the 146 patients analyzed. The first stage of this study was to examine the predictive power of different WBC cut‐off levels upon thrombotic risk in ET patients. We therefore analyzed the association of WBC counts of greater than either 8.7 × 109 L−1, 9.4 × 109 L−1, 11 × 109 L−1 and 15 × 109 L−1 upon the risk of thrombosis during follow‐up. Cox proportional hazard regression did not show a relationship between leukocyte count at diagnosis and thrombosis either in LR or in HR patients. Therefore the study does not confirm the previously recognized relationship between WBC count at diagnosis and thrombosis [5Carobbio A. Finazzi G. Guerini V. Spinelli O. Delaini F. Marchioli R. Borrelli G. Rambaldi A. Barbui T. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.Blood. 2007; 109: 2310-3Crossref PubMed Scopus (281) Google Scholar, 6Carobbio A. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Finazzi G. Rambaldi A. Barbui T. Leukocytosis and risk stratification assessment in essential thrombocythemia.J Clin Oncol. 2008; 26: 2732-6Crossref PubMed Scopus (153) Google Scholar, 7Carobbio A. Finazzi G. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Ruggeri M. Rodeghiero F. Rambaldi A. Barbui T. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia.Blood. 2008; 112: 3135-7Crossref PubMed Scopus (79) Google Scholar]. We further evaluated whether a leukocyte count change within two years of diagnosis might predict subsequent thrombosis in LR ET patients. To define leukocyte count change, we calculated the difference between the two numerical evaluations of WBC (ΔWBC). A positive ΔWBC (i.e. the second WBC count higher than the first one) was found in 78 patients (40%). Among these, leukocyte count at the second evaluation was within a normal range in 58 patients (74%). Variation of WBC count was not influenced by smoking or by cytotoxic therapy. Between the two evaluations of WBC no thrombosis occurred, whereas after the second WBC count 17 (8.7%) patients developed vascular complications. Ten patients had an ischemic stroke/transient ischemic attack, two an acute myocardial infarction and five venous thromboembolism. Cox proportional hazard regression revealed that patients with a positive ΔWBC had a significantly higher risk of developing thrombosis (HR = 3.86, 95% CI: 1.4–10.5; P=0.008) than those with a negative ΔWBC. The proportion of patients carrying the JAK2 (V617F) mutation was not significantly different between patients with positive ΔWBC and those with negative ΔWBC. To translate the significant relationship we found between ΔWBC and thrombosis into a simple prognostic parameter for clinical practice, we evaluated whether a ΔWBC greater than one‐third of baseline WBC count might be predictive of subsequent thrombosis. The one‐third increase in WBC was arbitrarily chosen on the basis of relevance and of sample size. A ΔWBC greater than one‐third of baseline WBC count was found in 18 (9.2%) patients. Ten out of 18 (55%) patients had both WBC counts within a normal range (< 10 × 109 L−1). Thrombosis occurred in 5 (27.7%) out of 18 patients with a ΔWBC greater than one‐third of baseline WBC count and in 12 (6.8%) out of 176 with a ΔWBC lower than one‐third of baseline WBC count (P=0.03). Cox proportional hazard regression revealed that patients with a ΔWBC greater than one‐third of the baseline WBC count had a significantly higher risk of developing thrombosis (HR = 3.6, 95% CI: 1.2–11.4; P=0.028) (Fig. 1). Because of the long period of observation of the patients, we considered the introduction of cytotoxic agents at any time during the follow‐up of the patients (n = 97) and the use of antiplatelet therapy (n = 166) as potential confounding factors for thrombosis. A multivariate Cox proportional hazard regression model including the level of ΔWBC, the anti platelet therapy and the cytotoxic treatment (as time‐dependent covariate) showed that the one‐third increase in ΔWBC retained the independent effect on thrombosis (HR = 7.1, 95% CI: 1.5–16.8; P=0.007). When we evaluated high‐risk ET patients, we found that a positive ΔWBC was found in 27 (16%) patients and the one‐third increase of ΔWBC was found in three (1.8%). Cox proportional hazard regression did not show a relationship between ΔWBC (expressed either as continuous or as categorical variable) and thrombosis. In this study, we studied the role of leukocyte count on thrombosis with two different models. According to the first model, we evaluated the relationship between WBC count at diagnosis and thrombosis during follow‐up and we found no relationship. We did not confirm the correlation between WBC count at diagnosis and thrombosis previously found by other investigators [5Carobbio A. Finazzi G. Guerini V. Spinelli O. Delaini F. Marchioli R. Borrelli G. Rambaldi A. Barbui T. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status.Blood. 2007; 109: 2310-3Crossref PubMed Scopus (281) Google Scholar, 6Carobbio A. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Finazzi G. Rambaldi A. Barbui T. Leukocytosis and risk stratification assessment in essential thrombocythemia.J Clin Oncol. 2008; 26: 2732-6Crossref PubMed Scopus (153) Google Scholar, 7Carobbio A. Finazzi G. Antonioli E. Guglielmelli P. Vannucchi A.M. Delaini F. Guerini V. Ruggeri M. Rodeghiero F. Rambaldi A. Barbui T. Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia.Blood. 2008; 112: 3135-7Crossref PubMed Scopus (79) Google Scholar]. The second model takes in to consideration the natural course of the disease that may entail modification of leukocyte count over time. Hence, we evaluated the impact of the increase in leukocyte count over time on the risk of thrombosis. On this basis, we demonstrated that LR ET patients with an increase in leukocyte count in the two years from diagnosis have higher risk of thrombosis than patients with stable WBC counts. We further provided evidence that a ΔWBC greater than one‐third from baseline within two years from diagnosis is associated with a significantly higher risk of developing thrombosis suggesting a role of leukocyte on vascular complications. The retrospective nature of the study represents a potential bias of the study does not allow a definite conclusion on this topic. This now warrants confirmation by prospective observations. In conclusion, this study shows that in LR ET the increase in leukocyte count over time more than the leukocyte count per se has an impact on thrombosis. Patients with this feature (about 9%) are at a higher risk of vascular complications and require a careful follow‐up. Grants from Fondazione Cariplo, Milan, Italy; Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; Fondazione Ferrata Storti, Pavia, Italy; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Ministry of University and Research, Rome, Italy. The authors state that they have no conflict of interest.