Acute biphenotypic leukemia arising in a patient with essential thrombocythemia.
ABSTRACT 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.
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ABSTRACT: The 2008 edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues recognizes a special category called "leukemias of ambiguous lineage." The vast majority of these rare leukemias are classified as mixed phenotype acute leukemia (MPAL), although acute undifferentiated leukemias and natural killer lymphoblastic leukemias are also included. The major immunophenotypic markers used by the WHO 2008 to determine the lineage for these proliferations are myeloperoxidase, CD19, and cytoplasmic CD3. However, extensive immunophenotyping is necessary to confirm that the cells indeed belong to 2 different lineages or coexpress differentiation antigens of more than 1 lineage. Specific subsets of MPAL are defined by chromosomal anomalies such as the t(9;22) Philadelphia chromosome BCR-ABL1 or involvement of the MLL gene on chromosome 11q23. Other MPAL are divided into B/myeloid NOS, T/myeloid NOS, B/T NOS, and B/T/myeloid NOS. MPAL are usually of dire prognosis, respond variably to chemotherapy of acute lymphoblastic or acute myeloblastic type, and benefit most from rapid allogeneic hematopoietic stem cell transplantation.Seminars in Diagnostic Pathology 02/2012; 29(1):12-8. · 1.80 Impact Factor
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ABSTRACT: Background: Leukaemic transformation (LT) is rare in the natural history of Philadelphia(Ph) chromosome-negative myeloproliferative disorders (MPD), and has a dismal prognosis. Little literature is available on Asian patients.Aims: The aim of this study is to report a single institution experience of Asian patients who developed acute leukaemia after being diagnosed and treated for Ph chromosome-negative MPDs, and to compare the findings of this series with similar studies from the literature.Methods: Patients were recruited from the MPD registry of Singapore General Hospital, Department of Hematology. Clinical data including treatment modalities and duration of use in myeloproliferative phase, latency to LT, characteristics of leukaemia, chemotherapy administered and survival after LT were examined.Results: Over a 29-year period from 1980 to 2009, there were 22 Asian patients with LT of Ph chromosome-negative MPD of which four had polycythaemia vera (PV), nine had essential thrombocythaemia (ET), seven had myelofibrosis (MF) and two had unspecified MPD at diagnosis. Primary treatment modality was Hydroxyurea (HU) during MPD phase. Median latency to LT was 14 years for PV, 10 years for ET and 1 year for MF. Median age at LT diagnosis was 67.5 years. Nine patients had complex cytogenetics, with abnormalities of chromosomes 5 and 7 being common.Overall, median survival was 2 months after LT. Eight patients who received induction chemotherapy had a median survival of 2.5 months. Survival was independent of MPD type and treatment administered. None received stem cell transplantation.Conclusions: LT of Ph chromosome-negative MPD is rare and uniformly fatal. Despite chemotherapy, survival was poor, and patients succumbed to refractory disease and infections. Asian patients did not have a more favourable outcome. It remains to be investigated whether upfront stem cell transplant may be a treatment option.Internal Medicine Journal 05/2012; 42(5):513 - 517. · 1.70 Impact Factor
- Annals of Oncology 09/2009; 20(11):1899-900. · 6.58 Impact Factor
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
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.
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626 Case Report: Wong and Lee
American Journal of Hematology DOI 10.1002/ajh