Paper Comparativa Sobrevida de PV, TE y MFP
Paper Comparativa Sobrevida de PV, TE y MFP
Paper Comparativa Sobrevida de PV, TE y MFP
CME Article
Long-term survival and blast transformation in molecularly annotated
essential thrombocythemia, polycythemia vera, and myelofibrosis
Ayalew Tefferi,1 Paola Guglielmelli,2 Dirk R. Larson,3 Christy Finke,1 Emnet A. Wassie,1 Lisa Pieri,2 Naseema Gangat,1
Rajmonda Fjerza,2 Alem A. Belachew,1 Terra L. Lasho,1 Rhett P. Ketterling,4 Curtis A. Hanson,5 Alessandro Rambaldi,6
Guido Finazzi,6 Juergen Thiele,7 Tiziano Barbui,6 Animesh Pardanani,1 and Alessandro M. Vannucchi2
1
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; 2Laboratorio Congiunto MMPC, Department of Experimental and Clinical
Medicine, University of Florence, Florence, Italy; 3Department of Statistics and Bioinformatics, 4Division of Cytogenetics, Department of Laboratory
Medicine, and 5Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN; 6Division of Hematology and Research
Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy; and 7Institute of Pathology, University of Cologne, Cologne, Germany
Submitted May 29, 2014; accepted July 8, 2014. Prepublished online as Blood The publication costs of this article were defrayed in part by page charge
First Edition paper, July 18, 2014; DOI 10.1182/blood-2014-05-579136. payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
The online version of this article contains a data supplement.
There is an Inside Blood Commentary on this article in this issue. © 2014 by The American Society of Hematology
Introduction
Janus kinase 2 (JAK2) mutations are present in .95% of patients with availability of archived DNA and no other selection bias was introduced.
polycythemia vera (PV) and also constitute the most frequent mutation Diagnoses of ET, PV, PMF, and BT were according to the 2008 World Health
(;60% incidence) in essential thrombocythemia (ET) and primary Organization (WHO) criteria.15,16 Previously published methods were used
for CALR, JAK2, and MPL mutation analyses.6
myelofibrosis (PMF).1 Calreticulin (CALR) exon 9 insertions/deletions
represent the second most frequent mutation in ET and PMF; their All statistical analyses considered clinical and laboratory parameters
obtained at diagnosis or within 1 year of diagnosis. Differences in the
mutational frequency is estimated between 15% and 32% in ET and
distribution of continuous variables between categories were analyzed by
25% and 35% in PMF.2-8 Myeloproliferative leukemia virus oncogene either Mann-Whitney or Kruskal-Wallis test. Patient groups with nominal
(MPL) mutations are also specific to ET and PMF and occur with variables were compared by x2 test. All patients, including those from the
mutational frequencies of 4% in ET and ;8% in PMF.1 JAK2, CALR, Mayo Clinic and the 2 Italian centers, were followed until death, leukemic
and MPL mutations are for the most part mutually exclusive and their transformation, or last clinic visit if they were currently alive. In addition,
pathogenetic contribution is currently believed to include upregulation follow-up information on the patients who are alive was updated by directly
of JAK2 signaling.9 contacting patients or their physicians. Survival analysis was considered from
The original descriptions of CALR mutations in myeloproliferative the date of diagnosis to date of death (uncensored) or last contact (censored).
neoplasms (MPN) suggested a significant impact on disease phenotype Leukemia-free survival (LFS) calculations considered BT as the uncensored
Table 1. Presenting clinical and laboratory features of 826 Mayo Clinic patients with ET vs PV vs PMF
P
Variables ET, n 5 292 PV, n 5 267 PMF, n 5 267 ET vs PV ET vs PMF PV vs PMF
Age, median (range), y 55 (15-91) 64 (19-95) 63 (14-87) ,.0001 ,.0001 .6
Age $60 y, n (%) 123 (42.1) 157 (58.8) 163 (61) ,.0001 ,.0001 .6
Females, n (%) 173 (59.2) 137 (51.3) 102 (38.2) .06 ,.0001 .002
Hemoglobin, median (range), g/dL 13.9 (6.9-17.9) 18.4 (15.1-24.5) 10.6 (5.8-16.1) ,.0001 ,.0001 ,.0001
Leukocytes, median (range), 3109/L 9.6 (2.8-53.4) 11.8 (3.8-171.6) 8.6 (0.8-146.6) ,.0001 .1 ,.0001
Platelets, median (range), 3109/L 1000 (454-3460) 467 (37-1720) 253 (12-2466) ,.0001 ,.0001 ,.0001
Risk stratification,* %
Low 37 25 17
Intermediate 40 32
Intermediate-1 22
Intermediate-2 33
High 23 43 28
Leukocytes, $11 3 109/L, % 33.1 56.5 36.3 ,.0001 .4 ,.0001
Platelets, .1000 3 109/L, % ,.0001 ,.0001
cases, CALR-mutated ET patients displayed younger age, male sex, mutated cases in terms of age and gender distribution and thrombosis
higher platelet count, lower hemoglobin level, lower leukocyte risk but displayed lower hemoglobin level.
count, and lower incidence of thrombosis. Triple-negative ET
patients also displayed younger age, lower hemoglobin level, lower Presenting features: JAK2 vs CALR vs MPL mutated vs
leukocyte count, and lower incidence of thrombosis, compared with triple-negative PMF
JAK2-mutated cases. Comparison of triple-negative and CALR-
mutated ET patients showed the latter to be associated with male sex Table 2 lists the presenting features in the combined Mayo-
and higher platelet count. MPL-mutated cases were similar to JAK2- Italian cohort of patients with PMF (n 5 428). Compared with
Table 2. Presenting features of 1004 patients with ET or PMF, stratified by their mutational status
P
JAK2 mutated (A) CALR mutated (B) Triple negative (C) MPL mutated (D) A vs B A vs C B vs C A vs D
ET, N 5 576
No. of patients 336 134 84 22
Age, median (range), y 58 (16-88) 49 (13-91) 47 (16-81) 57 (22-85) ,.0001 .0004 .8 1.0
Age $60 y, n (%) 157 (47) 36 (27) 29 (34) 8 (36) ,.0001 .04 .2 .3
Females, n (%) 227 (68) 66 (49) 61 (73) 13 (59) .0002 .4 .0007 .4
Hemoglobin, median (range), g/dL 14.3 (9.8-17.9) 13.5 (6.9-16.4) 13.2 (8.4-16.7) 13.8 (9.0-16.0) ,.0001 ,.0001 .7 .02
Leukocytes, median (range), 3109/L 9.6 (3.5-53.4) 8.5 (2.6-32.6) 8.3 (2.8-15.4) 7.4 (4.0-17.7) .0007 .0006 .6 .07
Platelets, median (range), 3109/L 841 (469-3000) 1000 (454-3460) 854 (500-3300) 900 (685-2249) ,.0001 .4 .003 .1
Leukocytes $11 3 109/L, % 31 24 20 26 .1 .04 .5 .6
Platelets .1000 3 109/L, % 29 54 38 41 ,.0001 .1 .02 .2
Thrombosis history, % 37 27 20 45 .04 .004 .3 .4
PMF, N 5 428
No. of patients 258 92 52 26
Age, median (range), y 65 (28-90) 54 (18-83) 67 (14-88) 60 (29-80) ,.0001 .3 ,.0001 .046
Age $60 y, n (%) 173 (67%) 35 (38%) 39 (75%) 15 (58%) ,.0001 .3 ,.0001 .3
Females, n (%) 88 (34%) 39 (42%) 18 (35%) 9 (35%) .1 .9 .4 1.0
Hemoglobin, median (range), g/dL 11.0 (5.4-17.5) 11.3 (8.0-15.5) 9.6 (5.2-13.5) 10.2 (6-14) .3 ,.0001 ,.0001 .08
Leukocytes, median (range), 3109/L 9.9 (0.8-106.1) 8.0 (1.8-40.0) 6.7 (1.4-146.6) 5.8 (2.5-42.0) .003 .1 .7 .03
Platelets, median (range), 3109/L 260 (12-2466) 387 (15-1563) 147 (14-900) 179 (31-925) ,.0001 .001 ,.0001 .06
Leukocytes $11 3 109/L, % 46 23 41 33 .0002 .5 .03 .2
Platelets .1000 3 109/L, % 3 9 0 0 .02 .2 .03 .4
the concept of a disease continuum between JAK2-mutated ET and Abnormalities. The study in Florence was supported by a special
PV and, instead, suggest 2 separate disease entities that are primarily grant from Associazione Italiana per la Ricerca sul Cancro (AIRC 5
distinguished by their morphologic traits. In other words, PV and ET per Mille) to AIRC-Gruppo Italiano Malattie Mieloproliferative
are not distinguished by their genetic profile but by their phenotypic (AGIMM) (#1005; for a description of the AGIMM project and list
characteristics and clinical course. of investigators, see www.progettoagimm.it). This work was also
The respectively favorable and unfavorable prognostic impact supported also by Fondo per gli Investimenti della Ricerca di Base
of CALR-mutated and triple-negative mutational status in PMF is (FIRB; RBAP11CZLK) and Progetti di ricerca di interesse nazionale
therapeutically relevant. Obviously, treatment decisions should also (PRIN; 2010NYKNS7) (A.M.V.).
account for the Dynamic International Prognostic Scoring System–
plus risk stratification21 and additional prognostically detrimental
mutations.10,11,22 The apparently higher incidence of fibrotic trans-
formations in MPL-mutated ET warrants further investigation.
In conclusion, currently known mutations have yet to over- Authorship
shadow the need for morphologic distinction of ET from PV, in
terms of not only diagnostic but also prognostic relevance. In other Contribution: A.T. designed the study, contributed patients,
extracted data, performed statistical analysis, wrote the paper, and
words, determination of JAK2/CALR mutational status alone, without
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