Acute Biphenotypic Leukemia Arising in a Patient
with Essential Thrombocythemia
Gee Chuan Wong* and Lai Heng Lee
Department of Hematology, Singapore General Hospital, Singapore
Acute leukemia is an uncommon complication of patients with essential thrombocythemia (ET).
We describe a patient with ET, who transformed to acute biphenotypic leukemia 4 and 1/2 years
after initial ET diagnosis. She had received hydroxyurea, anagrelide, and interferon, in different
combinations and varying doses, before leukemic transformation. Acute biphenotypic leukemia
was confirmed on bone marrow studies and immunophenotyping. Complete remission (CR) was
achieved with induction chemotherapy for acute leukemia. This was followed with consolidation
chemotherapy and the patient has remained in CR 9 months after initial induction chemotherapy.
To our knowledge, this is a rare event of acute biphenotypic leukemic transformation of a patient
with ET. Am. J. Hematol. 81:624–626, 2006.
C 2006 Wiley-Liss, Inc.
Key words: essential thrombocythemia; acute biphenotypic leukemia; transformation;
hydroxyurea; anagrelide; interferon
Essential thrombocythemia (ET) is a chronic mye-
loproliferative disorder in which morbidity and mor-
tality are more frequently related to arterial and
venous thrombosis. Being a clonal disorder, there is
an inherent tendency to evolve into acute myeloid leu-
kemia (AML) [1,2]. Longer disease duration and evo-
lution into myelofibrosis are risk factors for increasing
the risk of leukemic transformation . This risk may
also be affected by certain cytoreductive agents used
in the treatment of ET. We report a patient with ET
whose disease evolved into acute biphenotypic leuke-
mia 4 and 1/2 years after initial diagnosis.
MATERIALS AND METHODS
Reviews were made of the case notes of patients
diagnosed with essential thrombocythemia in the
Department of Hematology, Singapore General
Hospital, between 1975 and 2003. A total of 192
cases of ET were reviewed. Two patients had trans-
formed to acute leukemia. One of them developed
acute biphenotypic leukemia and her case will be
A 60-year-old Chinese female, a known hyperten-
sive, presented with a 6-month history of numbness
of the face and hands in August 2000. There was no
prior history of bleeding or thrombosis. Clinical
examination then was normal; in particular, there
was no organomegaly. Complete blood count re-
vealed a platelet count of 1109 ? 109/L (140–440),
hemoglobin of 11.9 g/dL (12.0–16.0), hematocrit
36.8% (36–46), and white cell count 13.4 ? 109/L
(4.0–10.0). There was no splenomegaly on ultra-
sound examination. Bone marrow aspirate showed
moderately increased megakaryocytes. Bone marrow
trephine biopsy showed hypercellular marrow with
marked increase of mature megakaryocytes, some
showing atypical forms and cluster formations.
There was no reticulin fibrosis. Cytogenetics was 46,
XX, del (20)(q11q13) in 3 of 20 metaphases. There
was no detectable Bcr/Abl transcript. The patient
was hence diagnosed to have ET, based on bone
marrow histopathology and exclusion of secondary
causes of thrombocytosis .
*Correspondence to: Gee Chuan Wong, Department of Hema-
tology, Singapore General Hospital, Block 6, Level 5, Outram
Road, Singapore 169608, Singapore.
Received for publication 23 September 2005; Accepted25 January
Published online in Wiley InterScience (www.interscience.wiley.com).
American Journal of Hematology 81:624–626 (2006)
C 2006 Wiley-Liss, Inc.
She was started on cytoreductive therapy with
hydroxyurea, in varying doses, to maintain a plate-
let count in the range of 400 ? 109/L to 600 ? 109/
L from August 2000 to August 2001. Subsequently,
anagrelide was started as the patient was becoming
anemic with hydroxyurea. Anagrelide was tried for
4 months, at varying doses (maximum dose 3 mg/
day). However, the patient was intolerant of its side
effects. From December 2001 to September 2002,
hydroxyurea was added, allowing a reduction in
dose of anagrelide, to maintain a platelet count in
the range of 400–600 ? 109/L. Between September
2002 and January 2003, a trial of interferon was ini-
tiated, initially in combination with hydroxyurea
and then in combination with anagrelide. The side
effects of interferon were also not tolerated by the
patient. Finally, in January 2003, she was restarted
on a combination of anagrelide and hydroxyurea,
on which she remained till January 2005, when her
disease was noted to have transformed to acute leu-
kemia. This patient had received aspirin 100 mg
daily since diagnosis.
In January 2005, the patient’s complete blood count
showed a white cell count 6.3 ? 109/L, hemoglobin
10.4 g/dL, platelet count 231 ? 109/L, and peripheral
blasts 12%. She was asymptomatic. Bone marrow as-
pirate showed a hypercellular marrow with 59% blasts.
Immunophenotyping of blasts demonstrated both B-
lymphoid and myeloid expression: CD19þ, CD10?,
CD79aþ, Tdtþ, CD13þ, CD33?, MPOþ, CD117þ,
CD34þ. Bone marrow cytogenetics showed 46, XX,
t(8;21)(q22;q22), der (9)t(1;9)(q12;q34), add (14)(p13),
del (20)(q11.2) in all 20 metaphases.
A diagnosis of acute biphenotypic leukemia was
made based on EGIL score [5,6]. The patient was
started on induction chemotherapy with idarubicin
and cytarabine. Vincristine was also administered.
During induction chemotherapy, she developed neu-
tropenic sepsis and pseudomonas infection of a leg
ulcer. Complete remission (CR) was achieved 34 days
after induction chemotherapy. Consolidation chemo-
therapy with idarubicin and cytarabine was compli-
cated by pneumonia and Pseudomonas aeruginosa bac-
teremia. She remained in CR 6 months after diagnosis
of leukemia. Full blood count showed a white cell
count 7.4 ? 109/L, hemoglobin 13.6 g/dL, and plate-
let count 275 ? 109/L, with a normal differential
count. There was no thrombocytosis throughout her
follow-up. Bone marrow studies showed remission of
leukemia and no features of ET.
ET is a chronic myeloproliferative disorder in
which thrombohemorrhagic complications are more
frequent than a risk of progression to acute leuke-
mia (AL). The risk of developing acute leukemia in
ET is very low [7,8], frequently described as less
than 2% of cases. It is believed that there are risk
factors that predict transformation to acute leuke-
mia, which include cytogenetic abnormalities, mye-
lofibrotic features in the bone marrow, and the use
of cytotoxic agents . Evolution to AML is com-
monly described in the literature, while transforma-
tion to acute lymphocytic leukemia (ALL) is consid-
ered unusual . Transformation to acute bipheno-
typic leukemia is a very rare event in the evolution
of ET. This was described by Martin et al. in 2005
Our patient did not have significant bone marrow
fibrosis at presentation. However, she had the cyto-
genetic abnormality of del(20) at presentation and
she had received cytoreductive agents in the 4 and
1/2 years prior to leukemic transformation to acute
The leukemogenic potential of hydroxyurea re-
mains a topic of debate. Randi et al.  reported
that none of their 188 patients with ET treated with
hydroxyurea alone, some for more than 10 years,
developed AML. Experience in patients with sickle
cell disease who consumed hydroxyurea for long peri-
ods also showed no development of AML. In a recent
publication of the MRC Primary Thrombocythemia 1
Study, Harrison et al.  concluded that hydrox-
yurea plus low-dose aspirin was superior to anagrelide
plus low-dose aspirin for patients with ET at high risk
for vascular events. However, the median follow-up
of the patients was only 39 months. Barbui et al. 
reported a mean time from ET presentation to leuke-
mic transformation of approximately 6.5 years. In
another studythat retrospectively
patients with ET, the rate of transformation to myelo-
dysplastic syndrome (MDS)/AML was 1.3%, 0.7%
for 741 patients treated with hydroxyurea alone and
1.2% for patients treated with interferon only, in
comparison with 4% of patients treated with alkylat-
ing therapy . However, Sterkers et al.  reported
a leukemic risk of approximately 3.5% with hydrox-
yurea alone. We recognize that not all studies in the
literature are sufficiently powered to assess whether
hydroxyurea is truly leukemogenic. Such studies
require large patient numbers as well as long-term fol-
low-up of at least 7 years or more.
Treatment of patients with multiple cytotoxic
agents that have leukemogenic potential has been
repeatedly shown to be associated with high leukemic
risk. It was also postulated that patients requiring
treatment with multiple agents may have biologically
more aggressive disease and are, therefore, inherently
more likely to transform. Murphy et al.  proposed
625Case Report: Acute Biphenotypic Leukemia
American Journal of Hematology DOI 10.1002/ajh
that one drug may potentiate the leukemogenic effect
of a subsequent drug. Anagrelide has not been known
to be leukemogenic thus far. In a large analysis of
1618 patients (934 with ET), with a maximum follow-
up of 7 years, anagrelide did not increase the rate of
conversion to acute leukemia . In another series of
37 consecutive young patients followed for a median
of 10.7 years, no leukemia was reported as well .
Interferon is also not known to be leukemogenic. Bar-
bui noted that in 159 ET patients treated with inter-
feron, only 2 cases of acute leukemia were reported
. Our patient received all threeof these agents, in
varying combination, in the 4.5 years before transfor-
mation to acute leukemia. It will be difficult to evalu-
ate whether hydroxyurea is the main leukemogenic
agent or, perhaps, an interplay of drugs potentiated
another’s leukemogenic potential. The requirement of
multiple agents to control thrombocytosis and del(20)
cytogenetic abnormality at presentation (usually seen
in MDS/AML patients) reflect a biologically more
aggressive disease that is inherently more likely to
transform. The added abnormalities of t(8;21), der(9),
t(1;9), add(14) in all 20 metaphases at transformation
to acute biphenotypic leukemia could possibly be the
result of a combination of an originally more aggres-
sive ET disease and the subsequent use of multiple
cytoreductive agents. In our patient, leukemic transfor-
mation occurred in 4.5 years, earlier than the reported
median leukemic transformation time of 6.5 years.
Essential thrombocythemia is a clonal stem cell
disorder. Transformation of ET to leukemia demon-
strates the pluripotent potential of the neoplastic
hemopoietic stem cell, with the ability to transform
to leukemia not only of the myeloid but also lym-
phoid lineage . In this case report, we demon-
strate a case of transformation to acute bipheno-
typic leukemia (BAL). BAL is believed to arise from
a multipotent progenitor cell and carries a poor
prognosis. The cytogenetic abnormality of del(20)
and the need to use multiple agents to control
thrombocytosis in our patient reflect a more aggres-
sive disease. Hence, it is not surprising to see trans-
formation to BAL. It is also worthwhile to note that
BAL can develop in other myeloproliferative disor-
ders, as described by Kim et al. of a case of BAL
arising in a patient with unclassified myeloprolifera-
tive disorder . BAL transformed from unclassi-
fied MPD also has a grave prognosis and responds
poorly to chemotherapy.
1. Shibata K, Shimamoto Y, Suga K. Essential thrombocythemia
terminating in acute leukemia with minimal myeloid differentia-
tion. A brief review of recent literature. Acta Haematol 1994;
2. Geller SA, Shapiro E. Acute leukemia as a natural sequel to
primary thrombocythemia. Am J Clin Pathol 1982;77:353–356.
3. Emilia G, Sacchi S, Temperani P. Progression of essential
thrombocythemia to blastic crisis via idiopathic myelofibrosis.
Leuk Lymphoma 1993;9:423–426.
4. Michels JJ. Bone marrow histopathology and biological mar-
kers as specific clues to the differential diagnosis of essential
thrombocythemia, polycythemia vera and prefibrotic or fibrotic
agnogenic myeloid metaplasia. Hematol J 2004;5(2):92–102.
5. Bene MC, Castoldi G, Knapp W. Proposals for the immunolog-
ical classification of acute leukemias.European Group for the
Immunological Characterization of Leukemias (EGIL). Leuke-
6. Bene MC, Bernier M, Casasnovas RO. The reliability and spe-
cificity of c-kit for the diagnosis of acute myeloid leukemias and
undifferentiated leukemias.The European Group for the Immu-
nological Classification of Leukemias (EGIL). Blood 1998;92(2):
7. Razzan M, Tamponi G, Schinco P. Thrombosis-free survival
and life expectancy in 187 consecutive patients with essential
thrombocythemia. Ann Hematol 1999;78:539–543.
8. Sterkers Y, Preudhomme C, Lai JL. Acute myeloid leukemia
and myelodysplastic syndromes following essential thrombocy-
themia treated with hydroxyurea: high proportion of cases with
17p deletion. Blood 1998;91:616–622.
9. Finazzi G, Barbui T. Treatment of essential thrombocythemia
with special emphasis on leukemogenic risk. Ann Hematol
10. Radaelli F, Mazza R, Curioni E. Acute megakaryocytic leuke-
mia in essential thrombocythemia: an unusual evolution? Eur
J Haematol 2002;69(2):108–111.
11. Martin SE, DellaValla J. Untreated essential thrombocythemia
evolving to biphenotypic leukemia, Philadelphia chromosome posi-
tive with monosomy 7: response to imatinib and reduced-intensity
allogeneic stem cell transplant. Leukemia 2005;19(6):1095–1096.
12. Randi ML, Fabris F, Girolami A. Leukemia and myelodyspla-
sia effect of multiple cytotoxic therapy in essential thrombocy-
themia. Leuk Lymphoma 2000;37:379–385.
13. Harrison CN, Campbell PJ, Wheatley K. Hydroxyurea com-
pared with anagrelide in high-risk essential thrombocythemia.
N Engl J Med 2005;353:33–45.
14. Barbui T, Barosi G, Grossi A. Practice guidelines for the ther-
apy of essential thrombocythemia. A statement from the Italian
Society of Hematology, the Italian Society of Experimental
Hematology and the Italian Group for Bone Marrow Trans-
plantation. Haematologica 2004;89:215–232.
15. Gugliotta L, Marchiolo R, Fiacchini M. Epidemiological, diag-
nostic, therapeutic and prognostic aspects of essential thrombo-
cythaemia in a retrospective study of the GIMMC group in
two thousand patients. Blood 1997;90:348a, abstract >1523.
16. Murphy S. Therapeutic dilemmas: balancing the risks of bleed-
ing, thrombosis and leukemic transformation in myeloprolifera-
tive disorders (MPD). Thromb Haemost 1997;78:622–626.
17. Fruchtman SM, Petitt RM, Gilbert HS. Anagrelide Study Group:
Anagrelide: Analysis of long term safety and leukemogenic poten-
tial in myeloproliferative diseases. Leuk Res 2005;29:481–491.
18. Storen EC, Tefferi A. long-term use of anagrelide in young
patients with essential thrombocythemia. Blood 2001;97:863–866.
19. Barbui T. The leukemia controversy in myeloproliferative disor-
ders: is it a natural progression of disease, a secondary sequela
of therapy, or a combination of both? Semin Hematol 2004;
20. Kreft A, Burg J, Fischer T. Essential thrombocythemia terminat-
ing in pure erythroleukemia. Am J Hematol 2004;77(2):140–143.
21. Kim J, Park CJ, Seo EJ. A case of biphenotypic blast crisis of unclas-
sified myeloproliferative disorder. Ann Hematol 2002;8(10):603–604.
626 Case Report: Wong and Lee
American Journal of Hematology DOI 10.1002/ajh