Essential Thrombocythemia Terminating
in Pure Erythroleukemia
Andreas Kreft,1*Ju ¨rgen Burg,1Thomas Fischer,2and Charles James Kirkpatrick1
1Institut fu ¨r Pathologie, Klinikum Johannes Gutenberg Universita ¨t Mainz, Mainz, Germany
2Abteilung fu ¨r Ha ¨matologie, Klinikum Johannes Gutenberg Universita ¨t Mainz, Mainz, Germany
Transformation into acute leukemia is a rare event in essential thrombocythemia (ET). The
blasts are usually of myeloid, rarely of megakaryoblastic differentiation. We present the
case of a patient with pure erythroleukemia after a nearly 10-year course of ET, which was
treated with hydroxyurea. The patient, a 58-year-old male, presented with an elevated
thrombocyte count (926,000/mL) and normal values of hemoglobin and leukocytes. After
10 years of therapy with hydroxyurea, the patient developed acute leukemia of solely
erythroid differentiation. Chemotherapy with cytarabine and daunorubicin resulted in
incomplete remission. The patient died 2 months after diagnosis of acute erythroleukemia.
Transformation of ET into erythroleukemia may demonstrate the pluripotent potential of
the neoplastic hemopoietic stem cell, with the ability to cause acute leukemia not only of
myeloid or megakaryoblastic but also of erythroid lineage. Am. J. Hematol. 77:140–143,
ª 2004 Wiley-Liss, Inc.
Key words: essential thrombocythemia; erythroleukemia; secondary acute leukemia
Essential thrombocythemia (ET) is considered to
be a clonal disorder of the pluripotent hematopoie-
tic stem cell , like the other diseases in the group
of chronic myeloproliferative disorders (CMPDs).
Transformation of CMPDs into acute leukemia is
due to clonal evolution of the neoplastic stem cell,
documented in chronic myeloid leukemia (CML) as
CMPDs, with the blasts showing cytogenetic aberra-
tions already established in the chronic phases besides
newly acquired aberrations [2–4]. Blastic transforma-
tion is rather frequent in the course of some CMPDs,
i.e., CML  and chronic idiopathic myelofibrosis ,
but rare in ET, occurring only in about 5% of the
patients after chemotherapy, with a lower incidence in
patients not treated with myelosuppressive agents
[1,7–9]. The neoplastic clones in CMPDs are able to
differentiate into the cell lines that predominate the
chronic phase but also into other lineages in the
blastic phases of disease. Thus, in ET, in which the
megakaryocytes and platelet production dominate the
chronic phase, most secondary leukemias were of
myeloid differentiation [7,8,10,11]. In only a few
ª 2004 Wiley-Liss, Inc.
patients, ET evolved into megakaryoblastic leukemia
[8,11,12]. We present the exceptional case of transfor-
mation of ET into pure erythroleukemia.
The 58-year-old male patient presented in Decem-
ber 1993 with a 2-month history of circulatory dis-
turbances of the left arm and foot. The peripheral
blood count revealed an elevated thrombocyte count
of 926,000/mL with otherwise normal values (hema-
tocrit 44.5%, hemoglobin 15.6 g/dL, erythrocytes
4.97/pL, mean corpuscular volume 90 fL, mean cor-
puscular hemoglobin 31.4 pg, mean corpuscular
hemoglobin concentration 35.4 g/dL, leukocytes
*Correspondence to: Dr. Andreas Kreft, Institut fu ¨ r Pathologie,
Klinikum Johannes Gutenberg Universita ¨ t, Langenbeckstr. 1,
D 55101 Mainz, Germany.
Received for publication 18 November 2003; Accepted 17 April
American Journal of Hematology 77:140–143 (2004)
4,970/mL, 75% neutrophils, 2% band forms, 2% eosi-
nophils, 7% monocytes, 14% lymphocytes). Physical
examination was unremarkable. By sonography, the
spleen was of normal size (8 ? 6 cm). Bone marrow
biopsy revealed normal cellularity of the hematopoi-
esis with increased and enlarged atypical megakar-
yocytes, distributed as single cells or in loose
arrangements, no dense clusters occurred (Fig. 1).
Storage iron was found in the histiocytes. Cytogenetic
analysis showed a normal male karyotype. The diag-
nosis of ET was made, and therapy with hydroxyurea
(HU) was started. The dosage was adjusted to 500 mg
for 6 days/week and 1,000 mg for 1 day/week. The
circulation disturbances disappeared.
The first follow-up investigation after 6 months
revealed a normal thrombocyte count of 252,000/mL.
However, subsequent yearly follow-up investigations
showed an increase of 660,000, up to 851,000 throm-
bocytes/mL. No other disease-related symptoms were
noticed. Additional medication with acetylsalicylic
acid was administered. The highest leukocyte count
registered was 11,000/mL, and the maximal hemo-
globin value was 16 g/dL, associated with a macro-
cytosis of 102 fL.
In June 2003, nearly 10 years after the diagnosis of
ET, the patient presented with normocytic anemia
(hemoglobin 8.4 g/dL, mean corpuscular volume 84
fL), normal thrombocyte (186,000/mL), and leukocyte
count (5,600/mL: 63% neutrophils, 8% band forms,
5% metamyelocytes, 2% myelocytes, 8% monocytes,
14% lymphocytes). The bone marrow biopsy dis-
closed increased cellularity with a predominance of
macrocytic immature precursors of erythropoiesis
(Fig. 2), immunohistochemically positive for CD 34
(Fig. 3a), hemoglobin (Fig. 3b) and PAS but negative
for myeloperoxidase, CD61, and lysozyme. Granulo-
poiesis revealed an almost undisturbed maturation
and the megakaryocytes revealed few enlarged cells.
A reticulin and collagen fibrosis was found. Flow
cytometric analyses of the bone marrow showed
12% glycophorin A and CD36-positive cells. No
increase of immature myeloid or megakaryocytic
cells was seen. Sonographic examination revealed an
enlargedmegakaryocytes,distributed as singlecells, partly in
loose arrangements. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
Bone marrow biopsy at presentation: increased andFig. 2.
sentation: predominance of atypical, partly macrocytic pre-
cursors of erythropoiesis, and maturation of granulopoiesis.
[Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
Secondary acute leukemia, 10 years after pre-
staining for CD34; (b) immunohistochemical staining for
hemoglobin. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
Erythroleukemia in ET 141
enlarged spleen (16 ? 7.6 cm). Cytogenetically, an
aberrant karyotype was found (46, XY, ?3, ?5,
der(10), der(12), ?13, +mC, +mE, +3mG). The
diagnosis of secondary acute leukemia of pure ery-
throid differentiation was established.
The patient received standard chemotherapy with
cytarabine and daunorubicin. Partial remission of the
acute leukemia was induced. Within the bone marrow
enlarged megakaryocytes of the ET reappeared and
the platelet count rose again to 969,000/mL. There-
fore, therapy with anagrelide was administrated.
Further evolution of the aberrant karyotype was
observed (46, XY, ?3, ?4, del(4)(p), ?5, add(9)(p),
der(10), der(12), ?13, ?14, add(14)(p), der(17),
XY). The patient died after recurrent febrile
attacks 2 months after the diagnosis of acute leuke-
mia. An autopsy was not performed.
Like all other CMPDs, ET is regarded as a clonal
disorder of the hematopoietic stem cell . However,
in ET the clonality of the granulopoiesis could not be
established in all patients otherwise fulfilling the diag-
nostic criteria. Nevertheless, in most instances a high
percentage of clonal thrombopoiesis was found,
higher than the percentage of clonality in the granu-
lopoiesis [13–15], indicating a predominant megakar-
yocytic, rather than granulocytic, differentiation of
the neoplastic cell clone. This reflects the presentation
of ET since thrombocytosis is the principal clinical
feature, while proliferation of the neoplastic megakar-
yocytes is the morphological hallmark [1,16]. In con-
trast, most secondary acute leukemias in ET are of
myeloid differentiation [7,10,11], and only few cases
of megakaryoblastic differentiation are described,
mostly admixed with myeloblastic differentiation
[11,12], thus indicating an ‘‘aberrant’’ differentiation
of the neoplastic cell clone in the blastic phase.
The authors are aware of only one previously pub-
lished case of erythroid differentiation in secondary
leukemia after ET, following a therapy with busul-
phan and melphalan . This case was listed among
other secondary acute leukemias in ET, but not
further specified. Since the mixed differentiation is
far more common than the pure erythroid differentia-
tion [17–19], the case we present may be the first
description of pure erythroleukemia in the course of
ET. This leukemia was also termed erythremic mye-
losis or AML-M6b according to the modified FAB
classification . However, erythroid and megakar-
yocytic cells derive from a common bipotential pro-
genitor  and in cases in which the erythropoiesis in
ET was investigated, it was found to be clonal . In
addition, erythrocytosis appears to be a rare event in
the course of otherwise typical ET . Thus a clonal
relation of the erythroid blasts and the ET is prob-
able, although it could not been proved, since no
cytogenetic abnormalities were found at diagnosis
which could be followed. Thus, the neoplastic stem
cell in ET may be able to differentiate not only into
cells of the megakaryopoietic and granulopoietic line,
but also along erythroid differentiation. Its clonal
evolution may result in acute leukemia of any of
these cell lines.
The case under discussion had the typical histo-
morphology of ET, consistent with the clinical pre-
sentation [1,16]. However, the diagnosis of ET is one
of exclusion of other causes of an elevated platelet
count, which are other neoplastic hematological dis-
orders or reactive conditions: CML could be excluded
because no Philadelphia chromosome and no leuko-
cytosis were present . An elevated hemoglobin
value was never observed, providing no evidence of
polycythemia vera . The pre-fibrotic stage of
chronic idiopathic myelofibrosis could not be diag-
nosed as no dense clustering of the megakaryocytes,
no ‘‘cloudy’’ nuclei and no increased granulopoiesis or
fibrosis of the marrow spaces was found . There
were also no dysplastic cytological features of the
hematopoietic cells or cytopenia at the time of diag-
nosis as well as no evidence of an underlying other
neoplasm or inflammatory disease. Thus the diagno-
sis of ET could be established .
A fibre increase or an enlarged spleen was not
found at the time of diagnosis but developed as the
secondary leukemia has occupied the marrow spaces.
Because marrow fibrosis was found in some patients
with acute erythroleukemia , myelofibrosis may
be attributed to the secondary acute leukemia, and
not necessarily to ET. The fibrosis of the marrow
spaces may have hampered the aspiration, explaining
the low yield of erythroid precursors in the aspiration
cytology, compared to the biopsy.
As for most patients with secondary leukemia
in Philadelphia chromosome negative CMPD, the
patient presented here received chemotherapy, i.e.,
HU. The drug has been advocated as a therapy for
the reduction of thromboembolic complications in ET
patients of high risk [9,25]. It is a non-alkylating mye-
losuppressive agent, inhibiting the ribonucleotide
diphosphate reductase and thereby the synthesis of
DNA. It also prevents DNA repair . Therefore,
of the neoplastic cell clone toward acute leukemia in
ET. This may explain the higher percentage of ET
patients with secondary acute leukemia having received
HU [7,8,10,27,28]. However, the actual leukemogenic
potential of HU is still a matter of discussion since no
142Kreft et al.
prospective randomized long-term evaluations are
available . Some evidence may suggest that other
risk factors such as combination with other myelosup-
pressive drugs or old age are also important to the
leukemic transformation [29,30]. Furthermore, blastic
transformation in ET patients could be observed with-
out previous myelosuppressive treatment. However,
only a few reports of leukemic transformation of ET
withoutprevious chemotherapy exist [11,31], indicating
that HU has a leukemogenic potential, which may in
fact be rather low compared to other drugs. Thus the
treatment has apparently promoted the blastic trans-
formation in the presented patient.
1. Imbert M, Pierre R, Thiele J, Vardiman JW, Brunning RD,
Flandrin G. Essential thrombocythaemia. In: Jaffe ES, Harris NL,
Stein H, Vardiman JW, editors. World Health Organization
Classification of tumors: pathology and genetics of tumours of
the haematopoetic and lymphoid tissues. Lyon: IARC Press;
2001. p 39–41.
2. Anastasi J, Feng J, Le Beau MM, Larson RA, Rowley JD,
Vardiman JW. The relationship between secondary chromosomal
abnormalities and blast transformation in chronic myelogenous
leukemia. Leukemia 1995;9:628–633.
3. Ahuja H, Bar-Eli M, Arlin Z, et al. The spectrum of molecular
alterations in the evolution of chronic myelocytic leukemia. J Clin
4. Groupe Franc ¸ ais de Cytoge ´ ne ´ tique He ´ matologique. Cytogenetics
of acutely transformed chronic myeloproliferative syndromes
without a Philadelphia chromosome. A multicenter study with 55
patients. Cancer Genet Cytogenet 1988;32:157–168.
5. Vardiman JW, Pierre R, Thiele J, Imbert M, Brunning RD,
Flandrin G. Chronic myelogenous leukaemia. In: Jaffe ES,
Harris NL, Stein H, Vardiman JW, editors. World Health
Organization Classification of tumors: pathology and genetics of
tumours of the haematopoetic and lymphoid tissues. Lyon: IARC
Press; 2001. p 20–26.
6. Thiele J, Pierre R, Imbert M, Vardimann JW, Brunning RD,
Flandrin G. Chronic idiopathic myelofibrosis. In: Jaffe ES, Harris
NL, Stein H, Vardiman JW, editors. World Health Organization
Classification of tumors: pathology and genetics of tumours of the
haematopoetic and lymphoid tissues. Lyon: IARC Press; 2001.
7. Sterkers Y, Preudhomme C, Lai JL, et al. Acute myeloid leukemia
and myelodysplastic syndromes following essential thrombocythe-
mia treated with hydroxyurea: high proportion of cases with 17p
deletion. Blood 1998;91:616–622.
8. Bernasconi P, Boni M, Cavigliano S, et al. Acute myeloid leuke-
mia (AML) having evolved from essential thrombocythemia (ET):
distinctive chromosome abnormalities in patients treated with
pipobroman or hydroxyurea. Leukemia 2002;16:2078–2083.
9. Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative
disorders. Hematology 2003;200–224.
10. Liozon E, Brigaudeau C, Trimoreau F, et al. Is treatment with
hydroxyurea leukemogenic in patients with essential thrombo-
cythemia? An analysis of three new cases of leukemic transforma-
tion and review of the literature. Hematol Cell Ther 1997;39:
11. Radaelli F, Mazza R, Curioni E, Chiani A, Pomati M, Naiolo A-T.
Acute megakaryocytic leukemia in essential thrombocythemia:
an unusual evolution? Eur J Haematol 2002;69:108–111.
12. Frei-Lahr D, Barton JC, Hoffman R. Blastic transformation of
essential thrombocythemia: dual expression of myelomonoblastic/
megakaryoblastic phenotypes. Blood 1984;63:866–872.
13. El-Kassar N, Hetet G, Brie ` re J, Grandchamp B. Clonality analysis
in essential thrombocythemia: advantages of studying T lympho-
cytes and platelets. Blood 1997;89:128–134.
14. Yan L, El-Kassar N, Gardin C, Brie ` re J. Clonality assays and
megakaryocyte culture techniques in essential thrombocythemia.
Leuk Lymphoma 1996;22(Suppl 1):31–40.
15. Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion
of patients with diagnosis of essential thrombocythemia do not
have a clonal disorder and may be at lower risk of thrombotic
complications. Blood 1999;93:417–424.
16. Georgii A, Bu ¨ sche G, Kreft A. The histopathology of chronic
myeloproliferative diseases. Baillieres Clin Haematol 1998;11:
17. Park S, Picard F, Azgui Z, et al. Erythroleukemia: a comparison
between the previous FAB approach and the WHO classification.
Leuk Res 2002;26:423–429.
18. Domingo-Claros A, Larriba I, Rozman M, et al. Acute erythroid
neoplastic proliferations: a biological study based on 62 patients.
19. Goldberg SL, Noel P, Klumpp TR, Dewald GW. The erythroid
leukemias: a comparative study of Erythroleukemia (FAB M6)
and Di Gugliemo disease. Am J Clin Pathol 1998;21:42–47.
20. Brunning RD, Matutes E, Flandrin G, Vardiman JW, Bennet J,
Harris NL. Acute myeloid leukaemia not otherwise categorised.
In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World
Health Organization Classification of tumors: pathology and
genetics of tumours of the haematopoetic and lymphoid tissues.
Lyon: IARC Press; 2001. p 55–65.
21. Shividasani RA. Molecular and transcriptional regulation of
megakaryocyte differentiation. Stem Cells 2001;19:397–407.
22. GreggXT, LiuY, PrchalJF, Gartland GL,CooperMD,PrchalJT.
Clonality in myeloproliferative disorders [abstract]. Blood 1996;
23. Jantunen R, Juvonen E, Ikkala E, Okasanen K, Anttila P, Ruutu T.
Development of erythrocytosis in the course of essential throm-
bocythemia. Ann Hematol 1999;78:219–222.
24. Pierre R, Imbert M, Thiele J, Vardiman JW, Brunning RD,
Flandrin G. Polycythaemia vera. In: Jaffe ES, Harris NL, Stein H,
Vardiman JW, editors. World Health Organization Classifica-
tion of tumors: pathology and genetics of tumours of the haema-
topoetic and lymphoid tissues. Lyon: IARC Press; 2001. p 32–34.
25. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for
patients with essential thrombocythemia and high risk of throm-
bosis. N Engl J Med 1995;332:1132–1136.
26. Yarbro JW. Mechanism of action of hydroxyurea. Sem Oncol
27. Murphy S. Therapeutic dilemmas: balancing the risk of bleeding,
thrombosis, and leukemic transformation in myeloproliferative
disorders. Thromb Haemost 1997;78:622–626.
28. Nielsen I, Hasselbalch HC. Acute leukemia and myelodysplasia in
patients with a Philadelphia chromosome negative chronic myelo-
proliferative disorder treated with hydroxyurea alone or with
hydroxyurea after busulphan. Am J Hematol 2003;74:26–31.
29. Liu T-C. Multiple factors in the transformation of essential throm-
bocythemia to acute leukemia or myelodysplastic syndrome. Blood
30. Mesa R, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A.
Population-based incidence and survival figures in essential
thrombocythemia and agnogenic myeloid metaplasia: an Olmsted
county study, 1976–1995. Am J Hematol 1999;61:10–15.
31. Balan ˜ os-Meade J, Lo ´ pez-Arvizu C, Cobos E. Acute myeloid leu-
kaemia arising from a patient with untreated essential thrombo-
cythaemia. Eur J Haematol 2002;68:397–399.
Erythroleukemia in ET143