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Received: 16 February 2017
Revised: 20 March 2017
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Accepted: 22 March 2017
DOI: 10.1002/ajh.24740
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RESEARCH ARTICLE
Monocytosis in polycythemia vera: Clinical and molecular correlates Daniela Barraco1
Sonia Cerquozzi2 | Naseema Gangat1 |
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Mrinal M. Patnaik1
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Terra Lasho1 | Christy Finke1 | Curtis A. Hanson3 |
Rhett P. Ketterling4 | Animesh Pardanani1 | Ayalew Tefferi1 1 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2Division of Hematology, Department of Internal Medicine, University of Calgary, Calgary, Alberta, USA; 3Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA; 4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email:
[email protected]
Abstract Monocytosis (absolute monocyte count, AMC 1 3 109/L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)-defined PV, 55 (21%) patients displayed an AMC of 1 3 109/L and 18 (7%) an AMC of 1.5 3 109/L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC 1 3 109/L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC 1.5 3 109/L). In univariate analysis, AMC 1.5 3 109/L adversely affected overall (OS; P 5 .004; HR 2.6, 95% CI 1.4-4.8) and myelofibrosis-free (MFFS; P 5 .02; HR 4.4, 95% CI 1.3-15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P 5 .05) and MFFS (P 5 .06). Other independent risk factors for OS included unfavorable karyotype (P 5 .02, HR 3.39, 95% CI 1.17-9.79), older age (P < .0001, HR 3.34 95% CI 1.97-5.65), and leukocytosis 15 3 109/L (P 5 .004, HR 2.04, 95% CI 1.26-3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.
abnormal karyotype, palpable splenomegaly, and BM fibrosis.2–4
1 | INTRODUCTION
Presence of “adverse variants/mutations” in PV, including ASXL1, Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN)
SRSF2, and IDH2, has recently been shown to adversely affect OS,
characterized by expansion of red cell mass and the almost invaria-
LFS, and MFFS.1
1
ble presence of JAK2 mutation. Median survival in PV is approxi-
The presence of absolute monocyte count (AMC) of 1 3 109/L
mately 14 years and PV-related complications affecting the survival
in the peripheral blood, sustained for >3 months, along with bone
are represented by thrombosis and disease progression into acute
marrow dysplasia defines chronic myelomonocytic leukemia (CMML), a
myeloid leukemia (AML) or myelofibrosis (MF). Multiple clinical and
clonal hematopoietic stem cell disorder with overlapping features of
genetic parameters have been evaluated with the goal of predicting
myelodysplastic syndromes (MDS) and MPN.5 However, absolute
prognosis in PV. Risk factors for overall survival (OS) in PV include
monocytosis can also been seen in other myeloid neoplasms, including
1
2
advanced age, leukocytosis, thrombosis, and abnormal karyotype ;
MDS and MPN,6 and its presence has previously been shown to indi-
myelofibrosis-free survival (MFFS) was adversely affected by leuko-
cate a worse prognosis in patients with lymphoid neoplasms,7 primary
V617F
allele burden, palpable splenomegaly,
myelofibrosis (PMF),8,9 and MDS.10 In the current study, we examined
thrombocytosis, and mild bone marrow fibrosis, whereas leukemia-
the prevalence, laboratory and molecular correlates, and prognostic
free survival (LFS) was affected by advanced age, leukocytosis,
relevance of monocytosis in PV.
cytosis, older age, JAK2
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Am J Hematol. 2017;92:640–645.
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(Sysmex America, Inc; Mundlein, IL). All results are evaluated through
2 | MATERIAL AND METHODS
Sysmex WAM, which is an information management system, ie, The current study was approved by the institutional review board of
middleware program. This program contains rules based on instrument
Mayo Clinic (Rochester, MN). Study patients were selected from our
flags, quantitative values, demographic data, previous results, and insti-
institutional database of MPN and fulfilled the 2016 World Health
tutionally derived rules to determine whether to release the automated
Organization (WHO) criteria for the diagnosis of PV9 and with special
differential results or whether a manual review and differential is
precaution to exclude cases of CMML6 or those with bone marrow
needed to provide more accurate results. For monocyte counts, all
dysplastic features. Clinical data collected were from the time of diag-
automated differential counts above 2.6 3 109/L were held for a man-
nosis. Cytogenetic analysis and reporting was done according to the
ual differential. About 100 cell manual differential counts were routine
International System for Human Cytogenetic Nomenclature.11 Assign-
for most manual differential counts, but 200 cell manual counts were
ment as “unfavorable karyotype” was according to criteria established
done at the discretion of the senior technologist in selected difficult or
12
for PMF.
Mutation screening for TET2, ASXL1, and SRSF2 was per-
complex cases. A threshold of AMC 1 3 109/L and 1.5 3 109/L (the latter
13
formed because of their known association with CMML.
Complete blood counts (CBC) and automated differential counts
obtained using Receiver Operator Curves analysis) were used to ana-
were initially performed on all specimens by a Sysmex XE-5000
lyze our study population. Differences in the distribution of continuous
Presenting clinical and laboratory features of 267 patients with polycythemia vera stratified by the presence or absence of monocytosis (AMC 1 3 109/L)
T A B LE 1
Variables
All patients (n 5 267)
Patients with AMC < 1000/mL (n 5 212)
Patients with AMC 1000/ml (n 5 55)
P value
Age at referral; median (range)
64 (17-94)
63 (17-89)
69 (22-94)
.02
Male
142 (53%)
111 (52%)
31 (56%)
.6
Hemoglobin, g/dL; median (range)
18 (14.8-24.3)
18 (14.8-24.3)
17.9 (15.7-24)
.4
Platelet count, 3 10 /L; median (range)
439 (37-2747)
422 (37-1640)
477 (48-2747)
.3
Leukocytes, 3 10 /L; median (range)
11.5 (4.3-59.3)
10.9 (4.3-30.2)
13.9 (4.3-59.3)
60 years (P < .0001, HR 3.34 95% CI 1.97-5.65), leukocytosis
Monocytosis (1 3 109/L) is a common finding in hematological malig-
15 3 10 /L (P 5 .004, HR 2.04, 95% CI 1.26-3.29) an unfavorable
nancies6 and has been shown to indicate a worse prognosis in patients
karyotype (P 5 .02, HR 3.39, 95% CI 1.17-9.79) retained their signifi-
with lymphoid7,14 and certain myeloid neoplasms.8,15 The prevalence
cance, whereas significance was lost for AMC 1 3 109/L (P 5 .1) and
and clinical significance of monocytosis has not been previously
9
P 5 .2
P 5 .3
WBC, 310 /L P 5 .7
NA
P 5 .01, HR 3.89, 95% CI 1.38-10.9
Unfavorablea cytogenetic
a
NA
P 5 .5
P 5 .9
Multivariate analysis considering AMC1.5 3 109/L
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AMC: absolute monocyte count; WBC: white blood count; NA: not applicable. Unfavorable karyotype: complex karyotype or sole or two abnormalities that include 18, 7/7q–, i(17q), 5/5q–, 12p–, inv(3) or 11q23 rearrangement.
P 5 .0009, HR 6.68, P 5 .007, HR 5.24, P 5 .01, HR 5.50, P 5 .01, HR 9.3, P 5 .02, HR 9.6, 95% CI 2.17-20.54 95% CI 1.58-17.36 95% CI 1.47-20.60 95% CI 1.5-56.58 95% CI 1.5-60.5
P 5 .1
Abnormal cytogenetic
P 5 .02, HR 3.39, 95% CI 1.17-9.79
P 5 .8
P 5 .8
Thrombotic events after diagnosis
P 5 .02, HR 3.39, 95% CI 1.17-9.79
P 5 .4
P 5 .008, HR 1.55, 95% CI 1.12-2.15
Thrombosis history
P 5 .7
P 5 .4
P 5 .2
Pruritus
P 5 .05
P 5 .05
P 5 .9
P 5 .25
P 5 .2
P 5 .8
P 5 .02
P 5 .4
P 5 .4
P 5 .08
P 5 .3
P 5 .05
P 5 .6
P 5 .4
Univariate analysis
Multivariate analysis considering AMC1 3 109/L
Leukemia-free survival
Splenomegaly at diagnosis
WBC 15 3 109/L P 5 .0003, HR 1.76, P 5 .0004, HR 2.82, P 5 .0004, HR 2.82, P 5 .08 95% CI 1.30-2.38 95% CI 1.60-4.98 95% CI 1.60-4.98
WBC 11 3 10 /L P 5 .004, HR 1.54, 95% CI 1.15-2.07
9
P 5 .1
P 5 .5
Platelet, 310 /L
9
P 5 .02
P 5 .06
Hemoglobin, g/dL
9
P 5 .2
P < .0001, HR 5.43, 95% CI 3.86-7.66
Age>60 years
P < .0001, HR 4.67, 95% CI 2.40-9.07
P 5 .4
P 5 .66
Sex P < .0001, HR 4.67, 95% CI 2.40-9.07
P 5 .6
P < .0001
Age (continuous variable)
P 5 .06
Multivariate analysis considering AMC1.5 3 109/L
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P 5 .02, HR 4.36, 95% CI 1.26-15.13
P 5 .004, HR 2.56, 95% CI 1.36-4.8
AMC1.5 3 109/L P 5 .05
P 5 .9
P 5 .1
P 5 .01, HR 1.88, 95%CI 1.53-3.07
AMC1 3 109/L
Univariate analysis
Multivariate analysis considering AMC1 3 109/L
Myelofibrosis-free survival
P 5 .7
Multivariate analysis considering AMC1 3 109/L
Multivariate analysis considering AMC1.5 3 109/L
P 5 .048
Univariate analysis
Overall survival
Univariate and multivariate analysis of prognostic factors for overall, myelofibrosis, and leukemia-free survivals in patients with polycythemia vera (n 5 267)
AMC
Variables
T A B LE 2
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ET AL.
evaluated in patients with PV and this was the main objective of the current study. The incidence of monocytosis 1 3 109/L and 1.5 3 109/L in our study cohort was 21% and 7%, respectively. Patients with monocytosis (both thresholds, 1 3 109/L and 1.5 3 109/L) appeared to show a specific phenotype, characterized by older age (>60 years) and leukocytosis 15 3 109/L; in particular, patients with AMC 1.5 3 109/L were also characterized by a lower incidence of microcirculatory disturbance and hyperlipidemia and with higher mutation frequencies of TET2 and SRSF2, 57% and 29%, respectively. Furthermore, monocytosis (both thresholds) was seen to negatively impact on OS in univariate analysis (Table 2) and AMC 1.5 3 109/L retained a borderline significance in multivariate analysis not including SRSF2 mutations: given its low frequency in our study, the multivariate analysis including this variable should be interpreted with caution, although its impact in terms of OS has previously been shown.1 The adverse impact of monocytosis 1.5 3 109/L was also demonstrated for MFFS, although significance was borderline in multivariable analysis. In other myeloid malignancies, especially in PMF, presence of monocytosis has been shown to be clinically relevant. In particular, monocytosis has been associated with a specific and more aggressive phenotype and identified as an independent risk factor for inferior survival.8 The development of monocytosis might indicate a disease progression, highlighting its powerful significance in those cases of PMF in which adequate genetic information are missing or “stable.”9 The current study suggests that the presence of monocytosis in PV might indicate a biologically more aggressive disease, sharing some genetic features with CMML (ie, presence of TET2, ASXL1, and SRSF2 mutations), and therefore characterized by a negative prognosis; the particular observation is consistent with previous reports in other hematological malignancies.7–10 Obviously, the findings in the current study require validation from additional studies but suggest an association between PV and CMML and raise the possibility of considering AMC in future prognostic models for PV.
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[4] Tiribelli M, Barraco D, De Marchi F, et al. Clinical factors predictive of myelofibrotic evolution in patients with polycythemia vera. Ann Hematol. 2015;94(5):873–874. doi: 10.1007/s00277-014-2257-z [5] Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2016 update on diagnosis, risk stratification, and management. Am J Hematol. 2016;91(6):631–642. doi: 10.1002/ajh.24396 [6] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. doi: 10.1182/ blood-2016-03-643544 [7] Bari A, Tadmor T, Sacchi S, et al. Monocytosis has adverse prognostic significance and impacts survival in patients with T-cell lymphomas. Leuk Res. 2013;37(6):619–623. doi: 10.1016/j.leukres.2013.01.009 [8] Elliott MA, Verstovsek S, Dingli D, et al. Monocytosis is an adverse prognostic factor for survival in younger patients with primary myelofibrosis. Leuk Res. 2007;31(11):1503–1509. doi: 10.1016/j. leukres.2006.12.025 [9] Boiocchi L, Espinal-Witter R, Geyer JT, et al. Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. Mod Pathol. 2013;26(2):204–212. doi: 10.1038/modpathol 2012;165 [10] Rigolin GM, Cuneo A, Roberti MG, Bardi A, Castoldi G. Myelodysplastic syndromes with monocytic component: hematologic and cytogenetic characterization. Haematologica. 1997;82(1):25–30. [11] Simons A, Shaffer LG, Hastings RJ. Cytogenetic nomenclature: changes in the ISCN 2013 compared to the 2009 edition. Cytogenet Genome Res. 2013;141(1):1–6. doi: 10.1159/000353118 [12] Caramazza D, Begna KH, Gangat N, et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia. 2011;25 (1):82–88. doi: 10.1038/leu.2010.234 [13] Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28 (11):2206–2212. doi: 10.1038/leu.2014.125 [14] Takasaki Y, Iwanaga M, Tsukasaki K, et al. Impact of visceral involvements and blood cell count abnormalities on survival in adult T-cell leukemia/lymphoma (ATLL). Leuk Res. 2007;31(6):751–757. doi: 10.1016/j.leukres.2006.11.013 [15] Beran M, Shen Y, Onida F, Wen S, Kantarjian H, Estey E. Prognostic significance of monocytosis in patients with myeloproliferative disorders. Leuk Lymphoma. 2006;47(3):417–423. doi: 10.1080/ 10428190500305448
Nothing to report.
REFERENCES [1] Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92(1):94–108. doi: 10.1002/ajh.24607 [2] Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874–1881. doi: 10.1038/ leu.2013.163 [3] Barbui T, Thiele J, Passamonti F, et al. Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome. Blood. 2012;119(10):2239–2241. doi: 10.1182/blood-2011-11-393819
S UPPORTING INF ORMATION Additional Supporting Information may be found online in the supporting information tab for this article.
How to cite this article: Barraco D, Cerquozzi S, Gangat N, et al. Monocytosis in polycythemia vera: Clinical and molecular correlates. Am J Hematol. 2017;92:640–645. https://doi.org/10. 1002/ajh.24740
