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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3861-3862
BRIEF REPORT
Imatinib mesylate (STI571) in the treatment of
relapse of chronic myeloid leukemia after allogeneic stem cell
transplantation
Eduardo Olavarria,
Charles Craddock,
Francesco Dazzi,
David Marin,
Sarah Marktel,
Jane F. Apperley, and
John M. Goldman
From the Haematology Department, Hammersmith Hospital,
London, England.
 |
Abstract |
Donor lymphocyte infusion (DLI) can restore durable molecular
remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell
transplantation, but for patients who do not respond survival is poor.
Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL
tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse
to chronic phase after stem cell transplantation for CML, did not
benefit from treatment with DLI, and then was administered STI571 at a
dose of 400 mg daily. There was a rapid, complete hematologic response,
and complete restoration of donor-type hematopoiesis (100% 46, XX
marrow metaphases) was achieved after 6 months of therapy, though
RT-PCR studies still detected BCR-ABL transcripts in the blood at low
level. This case demonstrates that imatinib mesylate can be highly
effective in the management of patients who have relapses after
allograft for CML.
(Blood. 2002;99:3861-3862)
© 2002 by The American Society of Hematology.
| |
Introduction |
Allogeneic hematopoietic stem cell
transplantation (allo-SCT) is the only approach capable of curing
patients with chronic myeloid leukemia (CML).1 One of the
major causes of treatment failure after allo-SCT is relapse. The
relapse rate is low for patients allografted in chronic phase with
unmanipulated cells, but it is much higher when donor marrow cells are
T-cell depleted.2 Approaches to treat patients with CML in
relapse after allografting include interferon- , chemotherapy, second
SCT, and immunomodulation with donor lymphocyte infusion (DLI).
Although DLI can restore durable molecular remissions in a high
percentage of patients with CML in relapse after
allografting,3,4 a significant proportion of patients do
not benefit from DLI therapy because of disease progression or toxicity
(namely, grant-versus-host disease [GVHD]) associated with the procedure.
The BCR-ABL oncoprotein is a constitutively activated tyrosine
kinase now considered to be the principal cause of the chronic phase of
CML. Imatinib mesylate inhibits the Abl tyrosine kinase and thus blocks
the proliferation of CML cell lines and clonogenic CML progenitor
cells.5,6 Imatinib mesylate (then called STI571) was first
administered to patients with CML in the summer of 1998, and additional
clinical trials recruited patients rapidly. The drug is given orally,
is well tolerated, and has a manageable side-effect profile. Results
from phase 2/3 trials suggest that complete cytogenetic remission (CCR)
can be obtained in all phases of the disease.7
Thus far, only a limited number of patients in relapse after
allo-SCT have been treated with imatinib mesylate.8,9 We have reported the reappearance of transient full donor chimerism in 4 patients who had relapses in blastic phase after allo-SCT treated with
imatinib mesylate.8 Here we report a patient in hematologic relapse in the chronic phase of CML treated with imatinib mesylate after failure to respond to DLI.
| |
Study design |
A 40-year-old man was diagnosed with CML in
December 1993. Interferon- (IFN-) administration failed to elicit
a cytogenetic response. He underwent allogeneic SCT from an HLA-matched
unrelated female donor in October 1997. Conditioning included
cyclophosphamide (120 mg/kg) and total body irradiation (14.4 Gy).
Acute (grade 2) and chronic (limited) GVHD developed, necessitating
immunosuppressive therapy with cyclosporine and prednisolone for 11 months after SCT. Despite full donor chimerism and complete cytogenetic
remission soon after SCT, reverse transcription-polymerase chain
reaction (RT-PCR) for BCR-ABL transcripts remained positive at variable levels after SCT. The patient satisfied our criteria for molecular relapse in January 1998 and was treated with escalating doses of DLI
from September 1998. He progressed to cytogenetic relapse in September
1999 and to hematologic relapse in chronic phase in November 1999. He
received interleukin-2-activated donor lymphocytes in December 1999 with no benefit. In August 2000, he was entered in the Novartis
STI571-0113 study. At study entry, cytogenetic analysis showed 20/20
(100%) XY, t(9;22) metaphases with several other abnormalities,
including del(13q), t(5;12), der(6), der(8), and nonclonal
rearrangements. The patient commenced treatment with imatinib mesylate
at 400 mg daily. No significant side effects were noted. Three months
later his blood counts and marrow histology had normalized.
Cytogenetics demonstrated 29/30 (97%) Philadelphia chromosome-negative metaphases of female origin and 1/30 (3%) Philadelphia chromosome positivity, with no additional chromosomal abnormalities. In February 2001, his bone marrow was 100% female (donor) by fluorescence in situ hybridization analysis and 100% 46,XX
by conventional metaphase cytogenetics. Quantitative real-time PCR
detected 650 BCR-ABL transcripts per 2.5 µL cDNA with a BCR-ABL/ABL ratio of 1%. This was repeated 9 and 12 months after treatment with
imatinib mesylate started and showed BCR-ABL/ABL ratios of 0.3% and
0.2%, respectively (Table 1). The
patient remains in good health and has had no recurrence of
GVHD.
| |
Results and discussion |
This case illustrates the value of imatinib
mesylate as treatment of relapsed CML after allo-SCT. Our patient did
not respond to DLI. However, he responded rapidly to imatinib mesylate
with normalization of the peripheral blood and bone marrow.
Furthermore, after 3 months of treatment, there was evidence of a
significant cytogenetic response that was complete by 6 months, with
the total disappearance of Philadelphia chromosome-positive
metaphases. PCR studies, however, still detected residual BCR-ABL
transcripts at low levels. We believe that this is the first report of
the efficacy of imatinib mesylate in patients who have relapses in chronic phase after allogeneic SCT.
Donor lymphocyte infusions have become the treatment of choice
for patients in relapse after allogeneic SCT.4,10 Results in patients who have relapses in the advanced phase are poor, but
durable, complete remissions can be achieved in most patients in
chronic-phase or cytogenetic relapse.3,4 GVHD and marrow aplasia remain the 2 most important complications of DLI, but when an
escalating dose schedule is used, these problems are greatly reduced.3 In a recent European Group for Blood and Marrow
Transplantation (EBMT) study, survival after relapse was related to 5 factors: time from diagnosis to transplantation, disease phase at
transplantation, disease phase at relapse, time from transplantation to
relapse, and donor type.10 The effects of individual
adverse risk factors were cumulative so that patients with 2 or more
adverse features had significantly reduced survival rates (35% vs 65%
at 5 years). Furthermore, DLI was less effective in patients in whom
GVHD developed after SCT. According to these data, our patient was not
in the group likely to survive long-term, despite remaining in chronic phase at relapse.
Imatinib mesylate binds to the adenosine triphosphate-binding
site of the ABL and BCR-ABL tyrosine kinases and maintains them in an
inactive conformation.11 It is also capable of inhibiting at least 2 other tyrosine kinases, c-kit and
platelet-derived growth factor receptor.5,11,12
Although in vitro studies have demonstrated selective killing of CML
hematopoietic cells, presumably resulting from BCR-ABL kinase
inhibition, its precise mechanism of action in vivo is still unclear.
However, clinical trials have shown remarkable, though preliminary
results. In an ascending-dose phase 1 study, imatinib mesylate induced
substantial and durable hematologic responses with minimal toxicity in
nearly all patients with chronic-phase CML.13,14 In phase
2 trials, it has produced major cytogenetic remissions in nearly 50%
of patients in chronic-phase disease resistant to
interferon.7 In one third of patients, the cytogenetic
response has been complete. Follow-up remains relatively short, but
responses seem durable. In virtually all patients in CCR, residual
BCR-ABL transcripts are detected by RT-PCR at variable levels. In our
institution, a review of 31 patients in CCR revealed a median
BCR-ABL/ABL ratio of 0.052% (range, 0-0.7%). One patient had a single
negative determination, and in 4 more patients the BCR-ABL/ABL ratio
was more than 0.001% (data not published). The RT-PCR tests in the
patient reported here showed ratios of 0.3% and 0.2%, consistent with
our findings.
Our patient did not respond to DLI. Survival for patients
resistant to DLI is poor.4,15 In the EBMT report, up to
one third of patients had 2 or more adverse prognostic factors for response to DLI.10 Despite recent progress in the
treatment of relapse of CML after allo-SCT, there is still a need for
alternative therapies for a significant proportion of patients. Our
findings suggest that there could be a role for imatinib mesylate in
the management of these patients. It is also possible that the
combination of imatinib mesylate and DLI will prove beneficial in some
cases, thus reducing the need for higher doses of DLI and reducing the risk for complications. Finally, a new strategy may emerge from these
observations the use of imatinib mesylate immediately after SCT may
prevent relapse and increase the efficacy of reduced-intensity conditioning allo-SCT in the future.
| |
Footnotes |
Submitted October 29, 2001; accepted January 15, 2002.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Eduardo Olavarria, Haematology
Department, Hammersmith Hospital, ICSM, Du Cane Rd, London W12 0NN,
England; e-mail: e.olavarria{at}ic.ac.uk.
| |
References |
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Abstract
Introduction