Blood, 1 February 2003, Vol. 101, No. 3, pp. 1200-1200
CORRESPONDENCE
To the editor:
Molecular response to imatinib mesylate following relapse after
allogeneic SCT for CML
We read with interest the article by Kantarjian et
al.1 With the advent of allogeneic matched sibling stem
cell transplantation (allo-SCT), it is clear that long-term
disease-free survival can be achieved in patients with chronic phase
(CP) chronic myelogenous leukemia (CML).2 Measurement of
BCR/ABL transcript numbers has enhanced the accuracy of
assessment of posttransplantation disease
activity.3 Failure to detect transcripts or detection of
low numbers is associated with prolonged disease-free survival, and
this has become the "gold standard" following allo-SCT. In spite of
the success of allo-SCT relapse will occur in a small but steadily
increasing number of patients over time.4 The use of donor
lymphocyte transfusions (DLTs) induces a remission in a
substantial number of patients but has been associated with fatal
aplasia and severe graft-versus-host disease (GvHD) and relies upon the
availability of the original donor.5,6
Kantarjian et al have demonstrated a complete cytogenetic response to
imatinib mesylate in patients relapsing after allograft and failing
DLTs.1 But a cytogenetic responder may still harbor significant levels of BCR-ABL transcripts. We describe 3 patients who had a molecular response to imatinib mesylate after
relapse of CML following allograft, in first CP. One patient relapsed, with clonal evolution, 10 years following matched sibling bone marrow
transplantation (BMT; his donor had died from a myocardial infarct 5 years after the transplantion). He had a complete
cytogenetic response to imatinib mesylate, 600 mg/d after 3 months, and
was a complete donor chimera by polymerase chain reaction (PCR) of short tandem repeats (STRs; sensitivity
10
4).7 He remains in complete cytogenetic
remission one year later on imatinib mesylate (400 mg/d). The second
patient had a cytogenetic relapse, t(9:22), 5 years following a sibling
allograft uncomplicated by GvHD. He had a complete cytogenetic response
to imatinib mesylate (400 mg/d) at 3 months and was a donor chimera. He
remains in complete cytogenetic remission at 21 months. The third
patient had a sibling allograft in July 1998. He had a cytogenetic
t(9;22) relapse 6 months later and was a mixed chimera. He received
DLTs from the original donor in March and June 2000 without
response. He received a nonmyeloablative SCT in February 2001 from the
original donor, which was followed by a transient response. He had a
complete cytogenetic response at 6 months to imatinib mesylate (400 mg/d). No patient had granulocytopenia or GvHD.
BCR/ABL transcripts were measured in a serial fashion in all patients
using real-time quantitative PCR (RQ-PCR) using TaqMan probes
(sensitivity 106). Standard curves were generated
following application of a dilution series of the bcr-abl-expressing
plasmids pNC210 (a gift of Nick Cross, University of Southampton) for
the b3a2 assay and pb2a2 (generated in house) for the b2a2 assay.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also
tested in serial samples to allow quantitative assessment of
BCR-ABL/GAPDH ratios.
The results are shown in Figure 1. Imatinib mesylate was associated with a molecular remission in 2 patients who were treated for relapsed CML 10 and 5 years following BMT
for CP CML, and in 1 patient, who failed allografting, DLTs,
and a nonmyeloablative SCT, Bcr/Abl transcripts were almost
undetectable. There was no evidence of toxicity in this small group of
patients. O'Dwyer et al8 have demonstrated that clonal
evolution per se does not impair the response to imatinib mesylate,
which concurs with our experience with our first patient. Serial
monitoring using both chimerism analysis and RQ-PCR provides evidence
that imatinib mesylate can induce molecular remissions in patients who
relapse following allo-SCT for CML.
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| Figure 1.
BCR-ABL/GAPDH ratios in serial analysis of
imatinib-treated relapsed CML transplantation patients.
The BCR-ABL/GAPDH ratio is expressed as a percentage following RQ-PCR
analysis of reverse transcribed cDNA samples. Both patients 1 and 3 were 100% Ph-positive at time 0, whereas patient 2 exhibited 40%
Ph-positivity. Both patients 1 and 2 achieved complete BCR-ABL
negativity, whereas patient 3 exhibited extremely low BCR-ABL/GAPDH
ratio (1 × 105) at 14 months.
|
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Shaun R. McCann, Kathy Gately, Eibhlin Conneally, and Mark Lawler
Correspondence: Shaun McCann, Department of
Hematology and Institute for Molecular Medicine St James's Hospital
and University of Dublin, Trinity College, Dublin,
Ireland; e-mail: smccann{at}stjames.ie
Acknowledgments
Funded by the Health Research Board of Ireland and the Higher
Education Authority Program for Research in Third Level Institutions 2
References
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