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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1990-1991
CORRESPONDENCE
To the editor:
BCR-ABL transcripts may be detected in essential
thrombocythemia but lack clinical significance
We read with interest the letter of Emilia et al1
concerning the absence of BCR-ABL rearrangement in essential
thrombocythemia (ET). They studied 112 patients with ET with nested
reverse transcriptase-polymerase chain reaction (RT-PCR) and found
only one BCR-ABL+ patient who progressed to myelofibrosis
and blast crisis 12 years after diagnosis. Based on their findings, the
authors conclude that the presence of BCR-ABL rearrangement in ET
identifies a subset of patients at risk for progression to acute
leukemia and suggest that these patients probably represent chronic
myelogenous leukemia (CML) of thrombocythemic onset. We do not
share their opinion on the basis of our own experience. We used single and nested RT-PCR and interphase fluorescence in situ
hybridization (FISH) to prospectively evaluate 47 patients with ET who
fulfilled the criteria of the Polycythemia Vera Study Group (32 women;
median age 49 years, range 14-80 years). Ten patients were
untreated, 31 were treated with anagrelide, and 6 were treated with
hydroxyurea. Median platelet count was 1300 × 109/L
(range 608-3742 × 109/L), 20 patients had mild
leukocytosis, none had basophilia, 3 had a borderline low leukocyte
alkaline phosphatase (LAP) score. Twenty patients had mild
splenomegaly and 15 had focal reticulin fibrosis. None of the 40 cytogenetic studies performed revealed the Ph chromosome. One-step and nested RT-PCR for BCR-ABL transcripts (b3a2 and b2a2
subtypes) were performed on peripheral blood samples using methodology
described by Kawasaki et al2 and Cross et
al,3 respectively, with slight modifications, with a
sensitivity of 10 4 and 106 determined by
K562 cell dilution. Assays were carried out with appropriate controls
and 20 healthy individuals were BCR-ABL. FISH
analysis was performed on peripheral blood smears as
described.4 In 5000 bone marrow cells from 25 controls the
BCR-ABL extra signal (ES) probe (Vysis, Downers Grove, IL)
demonstrated 1 yellow (fusion) signal, 1 green signal, and 2 red
signals (BCR-ABL fusion positive pattern) in 0.14% (0.3% [3
SD = 0.9%]), with a sensitivity of 98.5%. For each
patient, 200 nuclei were scored. Three Ph chromosome-negative patients were found to harbor b3a2
BCR-ABL fusion transcripts by RT-PCR (6.4 %). Both one-step and nested
PCR results were positive in 1 patient; only nested PCR
yielded positive results in the other 2 patients. BCR-ABL transcripts
were detected in the first patient at diagnosis and several times
during follow-up while on treatment with anagrelide. The other 2 BCR-ABL+ patients were first evaluated during treatment
with anagrelide. Repeated samples remained positive in the second
patient while negative PCR results were obtained on sequential
analysis in the third patient. Interphase FISH results on these
patients showed lack of fusion signal. Follow-up was 73, 68, and 116 months, respectively. Clinical and laboratory features in patients with
positive results did not differ from the BCR-ABL
group and they followed an uneventful course. Median follow-up in the
BCR-ABL group was 60 months (range 8-169 months); one of
these patients developed myelofibrosis with myeloid metaplasia 7 years
after diagnosis. Studies on BCR-ABL expression in ET have yielded discordant results.
While Blickstein et al5 and Singer et al6
reported high frequency (48% and 63%, respectively) of BCR-ABL
signals, Hackwell et al7 and Emilia et al1
were unable to corroborate these findings. Our results confirm the
presence of BCR-ABL positivity by PCR in some patients with ET, albeit
at a lower frequency than that reported by Blickstein et al. We
analyzed peripheral blood samples, but higher frequencies have been
reported in bone marrow. Although the presence of the Ph chromosome in
ET carries a poor prognosis,8 the clinical significance of
BCR-ABL positivity in Ph-negative ET at various levels of sensitivity
remains unclear. The finding of this molecular abnormality by PCR in
our patients doesn't seem to imply a diagnosis of CML, as suggested by
the absence of clinical features of CML, their long-term uneventful follow-up, and the spontaneous disappearance of BCR-ABL transcripts in
one of them. Interphase FISH in peripheral blood samples was negative
in our 3 patients with positive PCR tests, thus excluding the existence
of a masked t(9;22) in the background of a hidden CML. The presence of
the BCR-ABL rearrangement detected by means of PCR in these patients
doesn't seem to exclude the diagnosis of ET nor to influence the
course of the disease. In our opinion, therapeutic decisions should not
be based on PCR results.
Paula Heller, Laura I. Kornblihtt, Maria T. Cuello, Irene Larripa, Vesna Najfeld, and Felisa C. Molinas
Correspondence: Felisa C. Molinas, Hematología
Investigación, IDIM Alfredo Lanari, Combatientes de Malvinas
3150,1427 Buenos Aires, Argentina; e-mail:
fmolinas{at}mail.retina.ar
References
1.
Emilia G, Marasca R, Zucchini P, et al.
BCR-ABL rearrangement is not detectable in essential thrombocythemia [letter].
Blood.
2001;97:2187-2189[Free Full Text].
2.
Kawasaki ES, Clark SS, Coyne M, et al.
Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro.
Proc Natl Acad Sci USA.
1988;85:5698-5702[Abstract/Free Full Text].
3.
Cross NCP, Hughes TP, Feng L, et al.
Minimal residual disease after allogenic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: correlations with acute graft-versus-host disease and relapse.
Br J Haematol.
1993;84:67-74[Medline]
[Order article via Infotrieve].
4.
Lampert CL, Kafko M, Scalise A, Najfeld V.
The value of interphase fluorescence in situ hibridization in the study of patients with lymphoproliferative disorders: further evidence for a higher sensitivity for detecting chromosome 7 and 8 aneuploidy.
Cancer Genet Cytogenet.
1998;105:193-197[CrossRef][Medline]
[Order article via Infotrieve].
5.
Blickstein D, Aviram A, Luboshitz J, et al.
Bcr-abl transcripts in bone marrow aspirates of Philadelphia negative essential thrombocythemia patients: clinical presentation.
Blood.
1997;90:2768-2771[Abstract/Free Full Text].
6.
Singer IO, Sproul A, Tait RC, Soutar R, Gibson B.
BCR-ABL transcripts detectable in all myeloproliferative states [abstract].
Blood.
1998;92:427a.
7.
Hackwell S, Ross F, Cullis JO.
Patients with Essential Thrombocythemia do not express bcr-abl transcripts [letter].
Blood.
1999;93:2420[Free Full Text].
8.
Stoll DB, Peterson P, Exten R, et al.
Clinical presentation and natural history of patients with essential thrombocythemia and the Philadelphia chromosome.
Am J Hematol.
1988;27:77-83[Medline]
[Order article via Infotrieve].
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