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CLINICAL TRIALS AND OBSERVATIONS

Brief report
Monosomal karyotype in primary myelofibrosis is detrimental to both overall and
leukemia-free survival
Rakhee Vaidya,1 Domenica Caramazza,2 Kebede H. Begna,2 Naseema Gangat,1 Daniel L. Van Dyke,3 Curtis A. Hanson,4
Animesh Pardanani,1 and Ayalew Tefferi1
1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN; 2Cattedra ed Unita di Ematologia, Policlinico Universitario di Palermo, Palermo,
Italy; 3Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN; and 4Division of Hematopathology, Department of Laboratory
Medicine, Mayo Clinic, Rochester, MN

Survival in cytogenetically high-risk pa-
tients with acute myeloid leukemia or
myelodysplastic syndromes is signifi-
cantly worse in the presence of a mono-
somal karyotype (MK). The objective of
the present study was to determine
whether the same held true for primary
myelofibrosis. Among 793 primary myelo-
fibrosis patients seen at our institution,
62 displayed an unfavorable karyotype by
way of complex karyotype (n ⴝ 41) or
sole trisomy 8 (n ⴝ 21). Seventeen (41%)
of the 41 patients with complex karyotype
were classified as having an MK. Median
survival was 6, 24, and 20 months in
patients with MK, complex karyotype with-
out monosomies, and sole trisomy 8,
respectively (P < .0001). The correspond-
ing 2-year leukemic transformation rates
were 29.4%, 8.3%, and 0 (P < .0001); haz-
ard ratios (95% confidence intervals) were
6.9 (1.3-37.3) and 14.8 (1.7-130.8). The
prognostic relevance of MK was not ac-
counted for by the Dynamic International
Prognostic Scoring System. We con-
clude that MK in primary myelofibrosis is
associated with extremely poor overall
and leukemia-free survival. (Blood. 2011;
117(21):5612-5615)

Introduction
Prognosis in primary myelofibrosis (PMF) is assessed by the
International Prognostic Scoring System (IPSS)1 or the dynamic
IPSS (DIPSS),2 both of which use the following adverse risk
factors: age ⬎ 65 years, hemoglobin ⬍ 10 g/dL, leukocyte count
⬎ 25 ⫻ 109/L, circulating blasts ⱖ 1%, and constitutional symp-
toms. IPSS is applicable at the time of diagnosis, and DIPSS is
applicable at any point during the disease course. Independent of
IPSS, complex karyotype and sole trisomy 8 adversely affect both
overall and leukemia-free survival in PMF.3,4
Two recent studies in acute myeloid leukemia (AML) have sug-
gested that a monosomal karyotype (MK), which is defined as 2 or more
autosomal monosomies or a single autosomal monosomy associated
with at least 1 structural abnormality, identifies a subset of patients with
unfavorable karyotype who are short-lived5,6; 4-year survival rates were
3%-4% in the presence of MK versus 13%-26% in its absence.6 We
have recently shown that MK was equally detrimental in the setting of
myelodysplastic syndromes (MDS)7; overall and leukemia-free
survival rates in patients with the complex karyotype were
negatively affected by the presence of MK (2-year survival rates
were 6% and 23% in the presence or absence of MK, respectively).
The objective of the present study was to determine whether MK
has a similar adverse prognostic effect in PMF.
Methods
After receiving approval from the Mayo Clinic Institutional Review Board,
we reviewed medical records of patients with PMF referred to the Mayo
Clinic during 1970-2009. The study considered only those patients with
available bone marrow and cytogenetic information at the time of their first
referral to the Mayo Clinic. The diagnoses of PMF and leukemic
transformation were according to World Health Organization criteria.8
Cytogenetic results were interpreted and reported according to the Interna-
tional System for Human Cytogenetic Nomenclature.9 The presence of
fewer than 20 evaluable metaphases did not disqualify patients from study
inclusion as long as ⱖ 10 metaphases were examined in those patients with
“normal” reports; patients with an insufficient number of metaphases were
excluded. A complex karyotype was defined by the presence of 3 or more
distinct numeric or structural cytogenetic abnormalities. MK was defined
by the presence of 2 or more distinct autosomal monosomies or a single
autosomal monosomy associated with at least 1 structural abnormality.5 An
abnormality was considered clonal when at least 2 metaphases had the same
aberration in case of a structural abnormality or an extra chromosome. For
classification as a monosomy, the monosomy had to be present in at least
3 metaphases.
All statistical analyses considered parameters at time of first referral to
the Mayo Clinic. Differences in the distribution of continuous variables
between categories were analyzed by either Mann-Whitney (for compari-
son of 2 groups) or Kruskal-Wallis (comparison of 3 or more groups) test.
Patient groups with nominal variables were compared by ␹2 test. Overall
survival analysis was considered from the date of first referral to our
institution to date of death or last contact. Leukemia-free survival was
calculated from the date of first referral to our institution to date of leukemic
transformation or last contact/date of death. Overall and leukemia-free
survival curves were prepared by the Kaplan-Meier method and compared
by the log-rank test. Cox proportional hazard regression model was used for
multivariable analysis. P values ⬍ .05 were considered significant. The Stat
View (SAS Institute) statistical package was used for all calculations.

Submitted November 17, 2010; accepted March 16, 2011. Prepublished online The publication costs of this article were defrayed in part by page charge
as Blood First Edition paper, March 30, 2011; DOI 10.1182/blood-2010-11-320002. 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. © 2011 by The American Society of Hematology

5612 BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21

 From www.bloodjournal.org by guest on March 20, 2018. For personal use only.

BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21 MONOSOMAL KARYOTYPE IN MYELOFIBROSIS 5613

Table 1. Comparison of clinical characteristics of patients with PMF stratified by the presence of MK, complex karyotype without
monosomies, and sole trisomy 8
Complex karyotype without Sole trisomy 8
Variables MK (n ⴝ 17) monosomies (n ⴝ 24) (n ⴝ 21) P

Median age, y (range) 62 (30–83) 60 (42–73) 66 (28–85) .2

Age ⬎ 65 y; n (%) 7 (47) 6 (26) 11 (52) .2
Males, n (%) 9 (53) 14 (58) 11 (52) .9
Median hemoglobin, g/dL (range) 9 (6–11) 10 (5–16) 10 (7–13) .3
Median leukocyte count ⫻ 109/L (range) 6 (2–46) 10 (2–157) 12 (2–142) .8
Median platelet count ⫻ 109/L (range) 50 (6–522) 97 (8–981) 133 (16–684) .2
DIPSS risk group, n (%)
Low 0 1 (5) 0 .7
Intermediate-1 6 (35) 5 (21) 8 (38)
Intermediate-2 8 (47) 15 (62) 10 (48)
High 3 (18) 3 (12) 3 (14)
Constitutional symptoms, n (%) 7 (41) 10 (42) 7 (33) .8
Circulating blasts ⱖ 1%, n (%) 13 (76) 20 (87) 15 (71) .4
Hemoglobin ⬍ 10 g/dL, n (%) 11 (65) 14 (58) 12 (57) .9
Leucocytes ⬎ 25 ⫻ 109/L, n (%) 3 (18) 6 (25) 3 (14) .6
Platelets ⬍ 100 ⫻ 109/L, n (%) 12 (71) 13 (54) 9 (43) .2
Leucocytes ⬍ 4 ⫻ 109/L, n (%) 5 (29) 5 (21) 6 (29) .8
Palpable spleen ⬎ 10 cm, n (%) 1 (33) 9 (56) 3 (23) .2
Splenectomy, n (%) 3 (19) 7 (30) 4 (19) .6
JAK2V617F status, number tested (% positive) 4 (100) 6 (60) 4 (67) .3
Transplanted, n (%) 1 (6) 0 1 (5) .5
Deaths, n (%) 14 (82) 21 (88) 17 (81) .8
Leukemic transformations, n (%) 5 (29) 2 (8) 1 (5) .05

DIPSS indicates Dynamic International Prognostic Scoring System.2

interval] 2.3 [1.1-4.8] and 2.4 [1.2-5.1], respectively). On multivariable

Results and discussion
The present study population of 793 patients with PMF was
selected from a total of 923 consecutive patients with PMF seen at
the Mayo Clinic between January 1970 and December 2009
and who had undergone bone marrow examination. A total of
130 patients were excluded because cytogenetic studies either were
not performed (n ⫽ 65), resulted in insufficient mitotic figures
(n ⫽ 40), or constituted normal karyotype with ⬍ 10 metaphases
analyzed (n ⫽ 19). Six more patients were excluded because of
inaccurate diagnosis. Among the 793 study patients, 341 (43%)
displayed an abnormal karyotype, including 41 (12%) with com-
plex karyotype and 21 (6%) with sole trisomy 8. Among the
41 patients with complex karyotype, 17 (41%) were classified as
MK and 24 (59%) as “complex karyotype without monosomies.”
To determine whether the presence of MK conferred additional
prognostic significance, we compared the patient groups with MK,
complex karyotype without monosomies, or sole trisomy 8. No
significant differences were noted among the 3 groups with regard
to age, hemoglobin level, leukocyte count, platelet count, periph-
eral blast count, DIPSS score, constitutional symptoms, spleen size, or
JAK2V617F mutational status (Table 1). Among the 62 patients with
MK, complex karyotype without monosomies, or sole trisomy 8,
32 (52%) were evaluated within 1 year of their initial diagnosis, and the
median time from initial diagnosis in the remaining 30 patients was
approximately 4 years (range 1.5-8 years). There was no difference in
the interval between initial diagnosis and first bone marrow assessment
at the Mayo Clinic between patients with MK and those with sole
trisomy 8 (P ⫽ .7), whereas this interval was significantly longer in
patients with complex karyotype without monosomies (P ⫽ .01).
Overall survival was significantly worse for patients with MK
than for those with either complex karyotype without monosomies or
sole trisomy 8 (Figure 1). The corresponding median survival times
were 6, 24, and 20 months (P ⬍ .0001; hazard ratio [95% confidence
analysis that included staging according to DIPSS, the independent
prognostic significance of MK was sustained (supplemental Table,
available on the Blood Web site; see the Supplemental Materials link
at the top of the online article). The 2-year survival rates in the
presence of complex karyotype without monosomies, sole trisomy
8, and MK were 51%, 45%, and 17%, respectively. Patients with
MK also displayed significantly inferior leukemia-free survival
(supplemental Figure). At 2 years, blast-phase PMF developed in
5 (29.4%) of 17 patients with MK compared with 2 (8.3%) of
24 with complex karyotype without monosomies and 0 of 21 with
sole trisomy 8 (P ⬍ .0001). The respective hazard ratios (95%
confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8).
Considering the previous categorization of certain cytogenetic
abnormalities as being prognostically “unfavorable” in PMF,4,10 we
re-ran the survival analysis comparing MK (n ⫽ 17) with unfavor-
able karyotype other than complex karyotype or sole trisomy 8
(n ⫽ 57). The corresponding median survivals were 6 and 11 months
(P ⫽ .06), and leukemia-free survival was again inferior in patients
with MK (P ⫽ .0002).
The results of the present study signify the across-the-board
prognostic relevance of MK in myeloid malignancies. In an earlier
study by Breems et al,5 MK⫹ AML was associated with a
significantly shorter 4-year overall survival (4%) than MK⫺ but
cytogenetically high-risk AML (26%). Similar results were re-
ported by another study in which patients with MK, compared with
those with unfavorable cytogenetic findings without MK, displayed
a significantly shorter 4-year survival (3% vs 13%).6 In this
particular study, the inferior survival in MK⫹ patients was attrib-
uted in part to their lower complete remission rates (18% vs 34%),
which was the case in all age groups above age 30 years.
Furthermore, the negative prognostic impact of MK was less
evident in patients with monosomy 7, inv(3)/t(3;3), del(5q), and
t(9;22), as opposed to those with del(7q) or complex karyotype.6 In
a more recent study,11 MK performed better than other “high-risk”
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5614 VAIDYA et al BLOOD, 26 MAY 2011 䡠 VOLUME 117, NUMBER 21

Figure 1. Overall survival of 62 patients with PMF and unfavorable cytogenetic findings further stratified into 3 groups by the presence of MK, complex karyotype
without monosomies, or sole trisomy 8. For purposes of reference, the survival curve of 452 patients with PMF and normal karyotype is included. The latter group of patients
was recruited from the same database used to identify the present study population.

cytogenetic categorization in predicting relapse incidence after
allogeneic stem cell transplantation for AML.
We have recently demonstrated the adverse prognostic effect of
MK in MDS.7 In that particular study,7 among 127 MDS patients
with complex karyotype, the incidence of MK was 83%, which was
substantially higher than the 42% seen in the present study. MK⫹
MDS patients’ lives were significantly shorter than those with
complex karyotype without MK, and the prognostic impact of MK
was not accounted for by advanced age, bone marrow blast
percentage, or the presence or absence of monosomy 7 or
monosomy 5.7 We now show in the present study that MK is
equally as bad in PMF in terms of both overall and leukemia-free
survival. The presence of MK in PMF signified worse survival than
that associated with either the complex karyotype without mono-
somies or sole trisomy 8, both of which were identified previously
as being unfavorable cytogenetic findings in PMF.4 However,
although statistical significance was demonstrated, the number of
patients for each unfavorable cytogenetic category was too small to
be certain about the difference in prognostic impact between MK
and other unfavorable karyotype in PMF in terms of both survival
and risk of leukemic transformation, and the present observations
need to be validated in a larger group of informative patients. From
a practical standpoint, these findings further underscore the impor-
tance of paying attention to cytogenetic findings in PMF and the
prudence of early intervention with investigational drug therapy or
allogeneic stem cell transplantation in MK⫹ PMF, although the
value of such a treatment strategy in this particular patient
population remains to be proven.
Authorship
Contribution: R.V. collected data and participated in data analysis
and the writing of the paper; D.C., K.H.B., and N.G. participated in
data collection; D.L.V.D. reviewed cytogenetic information; C.H.
reviewed histopathology; A.P. contributed patients and participated
in data analysis; and A.T. designed the study, contributed patients,
collected data, performed the statistical analysis, and wrote the
paper. All authors approved the final draft of the paper.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
Correspondence: Ayalew Tefferi, MD, Mayo Clinic, 200 First St
SW, Rochester, MN 55905; e-mail: tefferi.ayalew@mayo.edu.

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2011 117: 5612-5615

doi:10.1182/blood-2010-11-320002 originally published
online March 30, 2011

Monosomal karyotype in primary myelofibrosis is detrimental to both

overall and leukemia-free survival
Rakhee Vaidya, Domenica Caramazza, Kebede H. Begna, Naseema Gangat, Daniel L. Van Dyke,
Curtis A. Hanson, Animesh Pardanani and Ayalew Tefferi

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