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Blood, 15 January 2003, Vol. 101, No. 2, pp. 781-781
CORRESPONDENCE
To the editor:
Myelodysplastic subclones in chronic myeloid leukemia:
implications for imatinib mesylate therapy
Short-term results with imatinib mesylate (Gleevec; Novartis
Pharmaceuticals, Hanover, NJ) for chronic-phase chronic myelogenous leukemia (CML) are extremely encouraging, with greater than 95% hematologic and 83% major cytogenetic responses in previously untreated patients.1 Long-term experience with
interferon- therapy suggests that only those patients
achieving major cytogenetic responses experience significant survival
benefits.2 Therefore, serial cytogenetic monitoring of
imatinib mesylate-treated patients is imperative so that
individuals not attaining major cytogenetic responses may be referred
for potentially curative allogeneic marrow transplantation or
investigative therapies before progressing to accelerated or blastic
phases. Although repetitive bone marrow aspirations for cytogenetics
are an effective technique to evaluate response, this method is time
consuming, costly, and unpleasant for patients. Several investigators
have reported that peripheral blood fluorescence in situ hybridization
(FISH) for the BCR-ABL translocation, with its ease
of procurement, sensitivity, and quantifiable nature may be a more
convenient, yet accurate, method of serial monitoring.3,4
The specificity of peripheral blood FISH, however, results in its major
limitation; an inability to detect acquisition of additional
cytogenetic abnormalities. We report a case where FISH could have led
to false reassurances of successful imatinib mesylate treatment. A 55-year-old man presented with leukocytosis and a hypercellular
marrow without dysplasia or blast forms. Peripheral blood karyotype
analysis revealed 46, XY,-5, del(6)(q23), t(9;22)(q34;q11.2), +mar and FISH for the BCR-ABL translocation was positive.
Interferon therapy for one year yielded only a partial hematologic
response. Imatinib mesylate resulted in a rapid complete hematologic
response. Marrow FISH at 6 and 10 months demonstrated no evidence of
the BCR-ABL translocation in 500 examined cells each time,
suggesting a complete cytogenetic response. In contrast, marrow
karyotyping yielded 46, XY, der(5)ins(5;5)(p15;q22q12)del(5)(q31q35),
del(6)(q23) in 2 of 21 metaphases (6 months) and 7 of 20 metaphases (10 months), with the remaining cells normal. No
Philadelphia chromosome-positive (Ph+) clones
were identified. Braziel et al5 recently reported a 14-month experience
with imatinib mesylate therapy among interferon refractory/intolerant CML patients. Eighteen of 19 patients achieved a complete hematologic remission and 6 patients achieved a complete cytogenetic response. Two
patients showed evidence of clonal evolution in clones possessing the
Ph+, and 2 developed trisomy 8 independent of the
Ph+ clone. The authors commented that they had observed
trisomy 8 as the sole abnormality, independent of the Ph+
clone, in 3 other patients enrolled on phase 1 trials with
imatinib mesylate. Additional cases of cytogenetic abnormalities
distinct from the Ph+ clone have rarely been reported
following hydroxyurea6 and interferon7,8 therapies. The acquisition of these
cytogenetic abnormalities may represent the changing natural history of
CML, treatment-related effects (although doubtful since imatinib
mesylate would not be expected to be leukemogenic), or a manifestation of an underlying stem-cell defect which produces both Ph+
and Ph clones. These observations of clonal cytogenetic evolution and cytogenetic
polyclonality (ie, a separate non-Ph+ clone) have important
implications for monitoring responses to imatinib mesylate therapy. It
is possible that myelodysplastic subclones may be masked by a more
dominant Ph+ clone and that selective inhibition of the
Ph+ clone by imatinib mesylate may permit polyclonal
emergence. Because peripheral blood FISH analysis is specific for the
BCR-ABL translocation, these cases would go undetected if
FISH alone were used to monitor long-term response. Thus, false
reassurances of successful imatinib mesylate treatment might be drawn
and patients not referred for alternate therapies. These cases support
a role for monitoring algorithms that include periodic bone-marrow
karyotyping of CML patients responding to imatinib mesylate therapy to
exclude unrecognized coexisting myelodysplastic clones and/or clonal
evolution in the absence of Ph+ cells.
Stuart L. Goldberg, Ravi A. Madan, Scott D. Rowley, Andrew L. Pecora, Jack W. Hsu, and Ramana Tantravahi
Correspondence: Stuart L. Goldberg, The Cancer Center at
Hackensack University Medical Center, 20 Prospect Ave, Suite 400, Hackensack, NJ 07601; e-mail: sgoldberg{at}humed.com
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Blood 2002 100: 435-441.
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