The effect of first-line imatinib interim therapy on the outcome... allogeneic stem cell transplantation in adults with newly diagnosed

Transcription

From www.bloodjournal.org by on January 14, 2009. For personal use only.
2005 105: 3449-3457
Prepublished online Jan 18, 2005;
doi:10.1182/blood-2004-09-3785
The effect of first-line imatinib interim therapy on the outcome of
allogeneic stem cell transplantation in adults with newly diagnosed
Philadelphia chromosome–positive acute lymphoblastic leukemia
Seok Lee, Yoo-Jin Kim, Chang-Ki Min, Hee-Je Kim, Ki-Sung Eom, Dong-Wook Kim, Jong-Wook Lee,
Woo-Sung Min and Chun-Choo Kim
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Copyright 2007 by The American Society of Hematology; all rights reserved.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
The effect of first-line imatinib interim therapy on the outcome of allogeneic stem
cell transplantation in adults with newly diagnosed Philadelphia
chromosome–positive acute lymphoblastic leukemia
Seok Lee, Yoo-Jin Kim, Chang-Ki Min, Hee-Je Kim, Ki-Sung Eom, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, and Chun-Choo Kim
Previously, we suggested that imatinib
incorporation into conventional chemotherapy as an alternative (imatinib interim
therapy) might be a useful strategy for
bridging the time to allogeneic stem cell
transplantation (SCT) for newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Phⴙ
ALL). Here, we provide an updated report
on this strategy in 29 patients. At the time
of enrollment, 23 patients (79.3%)
achieved complete remission (CR). After
the first imatinib cycle, the median break-
point cluster region–Abelson oncogene
locus (BCR-ABL)/ABL ratios decreased
by 0.77 log in 25 (86.2%) responders, and
their BCR-ABL/ABL ratios decreased further by 0.34 log after the second imatinib
cycle, which included 7 molecular CR.
One patient (4.3%) relapsed during the
imatinib therapy. The remaining 3 patients were primarily refractory to both
imatinib and chemotherapy. Twenty-five
(86.2%) of the 29 patients received transplants in first CR. With a median follow-up
duration of 25 months after SCT, the 3-year
estimated probabilities of relapse, nonrelapse mortality, disease-free survival, and
overall survival were 3.8%, 18.7%, 78.1%,
and 78.1%, respectively. In comparison to
our historical control data, first-line imatinib interim therapy appears to provide a
good quality of CR and a survival advantage for patients with Phⴙ ALL. Further
long-term follow-up is needed to validate
the results of this study. (Blood. 2005;
105:3449-3457)
© 2005 by The American Society of Hematology
Introduction
The Philadelphia chromosome (Ph) is the most frequent cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL),
with an overall incidence of 20% to 40%.1-4 Most patients with Ph⫹
ALL have an extremely poor prognosis when treated by chemotherapy alone.2,3,5-9 Current chemotherapy regimens induce complete remissions (CRs) in more than 70%, but most patients relapse
within 6 to 11 months of treatment and die of the disease. The
5-year overall survival rates for those treated with intensive
chemotherapy alone is less than 10%. To date, only allogeneic stem
cell transplantation (SCT) performed early during remission has
permitted long-term survival (35%⫺65%).10-15 Outcome for allogeneic SCT in an actively relapsed or a refractory status is poor.
Because the results of allogeneic SCT correlate with the pretransplantation leukemia burden, improved treatment strategies are
clearly needed to ensure CR at the time of SCT for patients
with Ph⫹ ALL.
Imatinib (Glivec, STI571), a selective breakpoint cluster region–
Abelson oncogene locus (BCR-ABL) protein tyrosine kinase
inhibitor, has been demonstrated to induce overall responses (CR ⫹
marrow-CR ⫹ partial marrow response) in 60% to 70% of patients
with relapsed or refractory Ph⫹ ALL, including patients that have
previously undergone transplantation, with limited toxicity.16-18
Unfortunately, the median time to progression is only 2 to 3
months, which reflects the time required to develop resistance to
imatinib. Considering the frequency and kinetics of resistance, it is
felt likely that imatinib monotherapy is not sufficient as a first-line
treatment for Ph⫹ ALL. Reports of additive or synergistic effects
in vitro of imatinib in combination with cytotoxic agents (eg,
anthracyclines, cytarabine, or vincristine) support the use of
clinical trials to test the feasibility of combination therapies.19-21
In this regard, the initiation of imatinib earlier in the disease
course with cytotoxic agents either as alternative or concurrent
schedules may reduce the likelihood of resistance and improve
treatment outcome.
From this point of view, we undertook a prospective phase 2
study to evaluate the effect of imatinib incorporation into conventional chemotherapy as an alternative before allogeneic SCT
(imatinib interim therapy) for newly diagnosed Ph⫹ ALL. Our
previously published preliminary data suggested that first-line
imatinib interim therapy might be a useful strategy for bridging the
time to allogeneic SCT for newly diagnosed Ph⫹ ALL.22 Here, we
report on the updated results of this strategy, which better define the
role of imatinib interim therapy. In addition, we evaluated whether
first-line imatinib interim therapy would improve the outcome of
allogeneic SCT.
From the Catholic Hematopoietic Stem Cell Transplantation Center, College of
Medicine, The Catholic University of Korea, Seoul, Korea.
Reprints: Seok Lee, Department of Hematology, St Mary’s Hospital, The
Catholic University of Korea, 62 Youido-Dong, Youngdeungpo-Ku, Seoul 150713, Korea (South); e-mail: leeseok@catholic.ac.kr.
Submitted October 1, 2004; accepted December 30, 2004. Prepublished online
as Blood First Edition Paper, January 18, 2005; DOI 10.1182/blood-2004-093785.
Patients, materials, and methods
Eligibility
Between September 2000 and August 2003, 37 (28.2%) of the 131 adults
(aged 15 years or older) with ALL were Ph⫹ at the time of diagnosis. Of
Supported by a Korea Research Foundation Grant (KRF-2004-013-E00011).
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.
An Inside Blood analysis of this article appears in the front of this issue.
© 2005 by The American Society of Hematology
BLOOD, 1 MAY 2005 䡠 VOLUME 105, NUMBER 9
3449
3450
LEE et al
these, 29 patients with newly diagnosed Ph⫹ ALL who completed induction
chemotherapy and intended to undergo human leukocyte antigen (HLA)–
matched allogeneic (sibling or unrelated) SCT were enrolled in this study.
Eight patients were excluded because of death during induction (n ⫽ 1),
lack of donors (n ⫽ 3), old age (n ⫽ 2), and refusal (n ⫽ 2) (Figure 1).
Eligibility criteria consisted of (1) karyotypic and/or molecular evidence of
t(9;22) in leukemic cells, (2) an age younger than 60 years, (3) Eastern
Cooperative Oncology Group performance status of 0 to 2, (4) adequate
renal and hepatic functions (serum creatinine ⬍ 152.5 ␮mol/L [⬍ 2 mg/dL]
and bilirubin ⬍ 51.3 ␮mol/L [⬍ 3 mg/dL]), (5) adequate cardiac status
(New York Heart Association class ⱕ II), and (6) a negative pregnancy test.
All patients in the study provided written informed consent, and the study
protocol was approved by the institutional review board of The Catholic
University of Korea.
Therapy
Induction therapy was started with hyperfractionated cyclophosphamide
(300 mg/m2, every 12 hours, days 1 to 3), vincristine (1.4 mg/m2, days 4 and
11), idarubicin (12 mg/m2, days 4 and 11), and dexamethasone (40 mg, days
1 to 4 and days 11 to 14), which was mainly based on the hyper-CVAD
(cyclophosphamide, vincristine, Adriamycin, and dexamethasone) regimen.6 After induction treatment with the recovery of white blood cell
(WBC; ⱖ 3 ⫻ 109/L) and platelet (ⱖ 60 ⫻ 109/L) counts, the first imatinib
cycle (400⫺600 mg/d for 4 weeks) was started. Patients who achieved CR
after induction therapy were randomly assigned to receive 400 mg or 600
mg imatinib daily. Patients not in CR received the imatinib therapy at a
daily dose of 600 mg. Subsequently, patients in CR received consolidation
chemotherapy consisting of high-dose cytarabine (2 g/m2, every 12 hours,
days 1 to 5) and mitoxantrone (12 mg/m2, days 1 to 2) followed by a second
imatinib cycle bridging the time to SCT. Patients not in CR received salvage
chemotherapy, which was cytarabine (2 g/m2, every 12 hours, days 1 to 4),
mitoxantrone (12 mg/m2, days 1 to 4), and etoposide (100 mg/m2, days 5 to
7). Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents (methotrexate, cytarabine, and methylprednisolone) during the induction and consolidation courses (6 times in total).
At the time of diagnosis, CNS leukemia was considered present when there
was neurologic involvement or when cerebrospinal fluid (CSF) studies
showed 5 or more leukemic blasts/␮L CSF fluid, ensuring no sample
contamination by peripheral blood (PB). Patients with CNS disease
received intrathecal therapy twice weekly until the CSF study findings were
negative during the induction course, and then cranial irradiation (2340
cGy) was added.
The preparative regimen consisted of total body irradiation (TBI; 1320
cGy) and cyclophosphamide (120 mg/kg) for patients in first CR and TBI
(1200 cGy), cytarabine (12 g/m2), and melphalan (140 mg/m2) for patients
in more advanced pretransplantation disease status. Some older patients
(older than 50 years) were given a reduced intensity regimen consisting of
fludarabine (180 mg/m2) and melphalan (140 mg/m2). Graft-versus-host
disease (GVHD) prophylaxis was attempted by administering cyclosporine
plus methotrexate. Cyclosporine was administered intravenously at a
dosage of 3 mg/kg as a continuous infusion from day ⫺1. Subsequently,
when patients were able to tolerate oral administration, they received
cyclosporine orally at 6 mg/kg/d in 2 divided doses until day 90. The dose
of cyclosporine was then gradually tapered and in the absence of GVHD
discontinued 6 months after SCT. If residual leukemia was detected during
the follow-up period after SCT, cyclosporine was rapidly discontinued. All
patients also received a short course of methotrexate, 10 mg/m2 on days 1,
3, 6, and 11. Acute GVHD was treated with high-dose steroids, and
extensive chronic GVHD was treated with cyclosporine and steroids.
Minimal residual disease monitoring
For minimal residual disease (MRD) monitoring, 272 bone marrow (BM)
samples were available from all patients receiving imatinib interim therapy
and were analyzed by real-time quantitative polymerase chain reaction
(RQ-PCR). Samples were collected at diagnosis, before and after imatinib
therapy, and then at 3, 6, 9, 12, 18, 24, and 36 months after SCT.
Mononuclear cells were isolated by Histopaque density gradient centrifugation (Sigma, St Louis, MO; density 1.077 g/mL). Total RNA was extracted
using an RNAqueous kit (Ambion, Austin, TX), and reverse transcription
was performed using 1 ␮g RNA. Plasmid standard titrations with the
defined copy numbers for BCR-ABL and for reference ABL were analyzed
simultaneously with the patient’s samples. As previously described,15 we
designed 1 set of primers for each type of BCR-ABL transcript, ABL, and
TaqMan probes. RQ-PCR was performed in triplicate using iCycler
software 2.1 (Bio-Rad, Hercules, CA) with the standard conditions (95°C
for 10 minutes, 50 cycles at 95°C for 15 seconds, and 60°C for 1 minute).
The 50-␮L PCR reaction mix contained 5 ␮L 1 ⫻ PCR buffer (4.5 mM
MgCl2, 0.2 mM dNTP (deoxyribonucleoside triphosphate), 0.2 ␮M primer,
140 nM TaqMan probe, 1.25 U AmpliTaq gold DNA polymerase, and 4 ␮L
target cDNA). The quantity of BCR-ABL transcript was normalized for
ABL expression (sensitivity, 10⫺5). Negative results were confirmed by
nested PCR.15
Definitions and evaluation of response
CR was defined as the reconstitution of normal BM cellularity with less
than 5% leukemic blasts, together with an absolute neutrophil count of
greater than 1.5 ⫻ 109/L and a platelet count greater than 100 ⫻ 109/L.
Molecular CR was defined by a negative PCR in BM aspirates. Relapse was
defined by the reappearance of more than 5% leukemic cells in BM
aspirates or extramedullary leukemia in patients with previously documented CR. Patients were considered refractory if PB blasts or extramedullary disease had not been eliminated, BM blasts had not been reduced below
5%, or both.
Acute GVHD was classified according to previous published criteria.23
The clinical and laboratory parameters collected to assess the grading of
acute GVHD included the percentage of body surface area covered by a
skin rash, volume of diarrhea, and total bilirubin level. Tissue biopsy
samples were obtained to confirm the diagnosis of acute GVHD whenever
clinically feasible. The diagnosis and grading of chronic GVHD were
established with the use of the clinical and pathologic criteria proposed by
Sullivan et al.24 Studies included hematopoietic and chemical parameters,
skin and lip biopsies, Schirmer test, pulmonary function tests, and other
examinations as indicated. Patients with sustained donor engraftment who
survived more than 14 days and more than 3 months after SCT were
assessed with respect to the occurrence and severity of acute and chronic
GVHD, which were graded by a single investigator at our institution.
Statistical analysis
Figure 1. Overall scheme of disease status until the time of allogeneic stem cell
transplantation in patients treated with imatinib interim therapy.
The clinical characteristics and treatment outcomes of patients receiving
imatinib interim therapy (imatinib group) were compared with the historical
control group of 33 consecutive patients with Ph⫹ ALL who completed
induction chemotherapy and proceeded to HLA-matched sibling or unrelated SCT without imatinib interim therapy from 1996 to 2000 (immediately preceded the imatinib interim therapy trial). No autologous or
FIRST-LINE IMATINIB INTERIM THERAPY IN Ph⫹ ALL
HLA-mismatched SCTs were performed in this group. Except for induction
chemotherapy (idarubicin, vincristine, prednisone, and L-asparaginase) and
CNS prophylaxis (methotrexate plus cranial irradiation), these patients
were treated with the same protocols (postinduction chemotherapy, preparative regimen, and GVHD prophylaxis or treatment) that were given for
patients receiving imatinib interim therapy. The outcomes of 23 of these 33
historical patients in first or second CR treated with SCT from HLAmatched sibling donors has been previously reported.15 Here, we analyzed
the results of 33 historical patients, which included 5 patients that
previously underwent SCT from HLA-matched unrelated donors, and 5
with a refractory pretransplantation disease status. The proportions of
patients with a given characteristic were compared by using the chi-square
or Fisher exact tests. Differences in the means of continuous variables were
checked using the Mann-Whitney U test. Survival duration was calculated
from the date of transplantation until death or the date when last known
alive. Nonrelapse mortality (NRM) was defined as death occurring in
relapse-free patients. Death resulting from any cause after relapse was
considered to have been caused by relapse. When calculating disease-free
survival (DFS), both relapses and deaths in CR were counted as adverse
events. The cumulative relapse rate was calculated by using the same type
of analysis used for DFS, except for those who died in CR, who were
censored at the time of death. Survival curves were plotted using the
Kaplan-Meier method and compared by the log-rank test. Statistical
analyses were performed using SPSS 11.5 software (SPSS, Chicago, IL).
Results
Patient characteristics
In the imatinib group, there were 14 men and 15 women with a
median age of 36 years (range, 18-55 years). Karyotype analysis
3451
revealed additional chromosomal changes in 16 (55.2%) of the 29
patients. As to the breakpoint within the BCR gene, 16 patients
(55.2%) had the p190BCR-ABL transcript (e1a2), and the other 13
(44.8%) had p210BCR-ABL (b2a2 or b3a2). Twenty-three (79.3%) of
the 29 patients achieved CR after induction chemotherapy, while
the other 6 patients (20.7%) were refractory. Their main clinical
features were compared with 33 historical patients with Ph⫹ ALL.
Presenting characteristics and CR rates after induction chemotherapy were not significantly different between the 2 groups
(Table 1).
Disease status until the time of SCT
As shown in Figure 1, 22 of the 23 patients who achieved CR after
induction chemotherapy remained in sustained first CR until the
time of transplantation in the imatinib group. Only 1 patient
relapsed after the first imatinib cycle. Furthermore, 3 of the 6
patients who were refractory to chemotherapy achieved CR after
imatinib interim therapy. The clinical and biologic characteristics
of patients who had primary refractoriness to imatinib, chemotherapy, or both are shown in Table 2. Of these, 4 patients who had
the p190BCR-ABL transcript were primarily refractory to imatinib,
and 3 of them had additional chromosomal changes at the time of
diagnosis. The relapse rate in the imatinib group was lower than
that of the historical group before SCT (1 [4.3%] of 23 versus 11
[40.7%] of 27, P ⫽ .003). In addition, the imatinib group had a
higher rate of proceeding to SCT in sustained or newly achieved
first CR than the historical group (25 [86.2%] of 29 versus 17
[51.5%] of 33, P ⫽ .004; Table 3).
Table 1. Clinical and biologic characteristics of patients
No.
Imatinib group (n ⴝ 29)
Median age, y (range)
Historical group (n ⴝ 33)
P
36 (18-55)
35 (15-48)
.160
14 (48.3)
18 (54.5)
Sex
Male (%)
Female (%)
.622
15 (51.7)
15 (45.5)
9.9 (4.9-13.5)
8.5 (3.8-13.7)
.205
Median WBC count, ⫻ 109/L (range)
32.3 (1.8-239.0)
50.3 (1.6-481.0)
.658
Median platelet count, ⫻ 109/L (range)
42.0 (12.0-313.0)
33.0 (9.0-131.0)
.402
Median LDH level, IU/L (range)
1173 (442-6366)
1767 (250-4188)
.494
Median hemoglobin level, g/dL (range)
Extramedullary involvement
.987
Yes (%)
14 (48.3)
16 (48.5)
No (%)
15 (51.7)
17 (51.5)
Yes (%)
1 (3.6)
1 (3.0)
No (%)
28 (96.4)
32 (97.0)
21 (72.4)
23 (69.7)
8 (27.6)
10 (30.3)
Ph alone (%)
13 (44.8)
17 (51.5)
Additional changes (%)
16 (55.2)
16 (48.5)
p210BCR-ABL (%)
13 (44.8)
16 (48.5)
p190BCR-ABL (%)
16 (55.2)
17 (51.5)
23 (79.3)
27 (81.8)
CNS leukemia
.926
Immunophenotype
B-lineage (%)
B ⫹ myeloid antigen (%)
.814
Karyotype
.599
BCR-ABL subtype
.773
Response to induction therapy
CR (%)
Refractory (%)
Median time to SCT*, d (range)
.803
6 (20.7)
138 (56-217)
6 (18.2)
150 (130-234)
.137
WBC indicates white blood cell; LDH, lactate dehydrogenase; CNS, central nervous system; Ph, Philadelphia chromosome; CR, complete remission; SCT, allogeneic stem
cell transplantation.
*Interval from the start of induction chemotherapy to the date of transplantation.
3452
LEE et al
Table 2. Presenting characteristics of patients who had primary refractoriness to imatinib and/or chemotherapy
No.
Age,
y/sex
Hb level,
g/dL
WBC count,
ⴛ 109/L
Platelet count,
ⴛ 109/L
LDH level,
IU/L
10*
27/M
11.6
223.6
22.0
6366
EMI
No
Immunophenotype
Karyotype
BCR-ABL
isoform
B-lineage
46,XY,del(9)(p22),t(9;22)(q34;q11.2),der(19)
p190
t(9;19)(q12;q13)[14]/48,idem, ⫹ 8, ⫺ der
(19)t(9;19), ⫹ der(22)t(9;22)[10]/46,XY[1]
12†
39/M
8.0
179.2
15.0
1880
Yes
B-lineage
46,XY,t(9;22)(q34;q11.2)[16]/46,XY[4]
p210
14‡
44/M
12.0
122.7
58.0
2050
No
B ⫹ My
45,XY, ⫺ 7,t(9;22)(q34;q11.2)[25]
p190
16†
31/M
10.2
4.7
23.0
1159
Yes
B ⫹ My
46,XY,t(9;22)(q34;q11.2)[20]
p190
19†
28/F
7.9
13.4
12.0
4470
No
B ⫹ My
46,XX,t(9;22)(q34;q11.2),del(9)(p22)[3]/47,
p190
idem,⫹der(22)t(9;22)[17]
24‡
44/F
10.2
1.8
33.0
574
Yes
B-lineage
46,XX,t(9;22)(q34;q11.2)[25]
p190
26‡
20/M
10.5
102.5
32.0
1082
Yes
B ⫹ My
45,XY, ⫺ 7,t(9;22)(q34;q11.2)[12]/45,idem,
p190
der(16)t(1;16)(q12;q11.2)[2]/46,XY[11]
M indicates male; F, female; Hb, hemoglobin; EMI, extramedullary involvement; My, myeloid antigen.
*Patient with refractoriness to imatinib therapy.
†Patients with refractoriness to chemotherapy.
‡Patients with refractoriness to both imatinib therapy and chemotherapy.
MRD-based role of imatinib interim therapy before SCT
The kinetics of the BCR-ABL transcript correlated well with the
clinical courses of patients receiving imatinib interim therapy
(Figure 2). At the time of enrollment, the median BCR-ABL/ABL
ratios were 2.96 (0.14-7.90) ⫻ 10⫺3 in 23 patients in CR. In the 6
refractory patients, the median BCR-ABL/ABL ratios were more
than 10⫺2. After the first imatinib cycle, 22 of the 23 patients in CR
remained in sustained CR. In paired samples (before and after the
first imatinib cycle) from these patients, their median BCR-ABL/
ABL ratios showed a decrease of 0.83 (0.20-1.85) log (Figure
2A-B). Meanwhile, 1 patient (patient no. 10) who had achieved CR
before the first imatinib cycle relapsed; the BCR-ABL/ABL ratio
also increased from 2.96 ⫻ 10⫺3 to 2.55 ⫻ 10⫺2 (Figure 2C). In the
remaining 6 patients refractory to induction chemotherapy, 3
(patient nos. 12, 16, 19) achieved CR with a decrease in MRD
(⫺0.89 log, ⫺0.76 log, and ⫺0.60 log, respectively) after the first
imatinib cycle (Figure 2D), while the other 3 patients (patient nos.
14, 24, 26) showed no hematologic or molecular responses (Figure
2C). Overall, the BCR-ABL/ABL ratios were reduced by 0.77
(0.20-1.85) log in 25 (86.2%) and increased by 0.81 (0.54-1.10) log
in 4 (13.8%) patients after the first imatinib cycle.
Twenty-three of the 25 patients in CR received a second
imatinib cycle following consolidation chemotherapy. Median
Table 3. Disease status until the time of allogeneic stem
cell transplantation
Imatinib group
(n ⴝ 29)
Historical group
(n ⴝ 33)
P
After induction therapy
CR1 (%)
Refractory (%)
23 (79.3)
27 (81.8)
6 (20.7)
6 (18.2)
22/23 (95.7)
16/27 (59.3)
1/23 (4.3)
11/27 (40.7)
.803
After consolidation therapy
Sustained CR1 (%)
Relapse (%)
.003
After salvage therapy
CR1 (%)
3/6 (50.0)
1/6 (16.7)
Refractory (%)
3/6 (50.0)
5/6 (83.3)
25 (86.2)†
17 (51.5)
.545
Pretransplantation disease status
CR1 (%)*
CR2 (%)
Refractory (%)
0
4 (13.8)
.004
9 (27.3)
7 (21.2)
CR1 indicates first complete remission; and CR2, second complete remission.
*Sustained CR1 during the consolidation phase plus newly achieved CR1 after
the imatinib or salvage chemotherapy.
†Includes 7 patients with molecular CR.
BCR-ABL/ABL ratios were observed to further reduce by 0.60
(0.06-1.58) log after consolidation chemotherapy, but no patient
achieved a molecular CR. After the second imatinib cycle, the
median BCR-ABL/ABL ratios decreased by 0.34 (0.07-1.31) log,
compared with levels after consolidation. In addition, the BCRABL transcript was not detected in 7 patients (patient nos. 1, 4, 15,
17, 22, 27, 29) (Figure 2B). Meanwhile, 2 resistant patients (patient
nos. 10, 24) after the first imatinib cycle were also resistant to the
second imatinib cycle with an increase in MRD. The remaining 2
patients in CR (patient nos. 12, 13) and 2 resistant patients (patient
nos. 14, 26) proceeded directly to SCT after the first imatinib cycle.
All patients tolerated the imatinib therapy well.
Transplantation outcome
The overall treatment outcomes of the 29 patients in the imatinib
group are listed in Table 4. Twenty-eight (25 first CR, 3 refractory)
of the 29 patients underwent HLA-matched sibling (n ⫽ 22) and
unrelated (n ⫽ 6) SCT after the completion of first (n ⫽ 4) or
second (n ⫽ 24) imatinib cycles at a median time of 138 days
(range, 56-217 days) from the start of induction therapy. Some
patients received additional imatinib therapy or chemotherapy until
an unrelated donor became available. However, 1 patient (patient
no. 10) who showed resistance against imatinib died of septicemia
before SCT. A conditioning regimen was started 7 days after the
last day of the imatinib cycle. All patients achieved a successful
engraftment. Acute GVHD was observed in 10 patients (35.7%; 7
grade II, 2 grade III, 1 grade IV). Twelve (46.2%) of the 26
evaluable patients had chronic GVHD (9 limited, 3 extensive).
With a median follow-up duration of 25 months (range, 12⫹ to
45⫹ months) for surviving patients after SCT, 24 patients are alive
with a leukemia-free status, and 4 patients have died (early or late
transplant-related complications in 3 [1 hemorrhagic cystitis, 1
grade IV acute GVHD, and 1 extensive chronic GVHD] and
relapse mortality in 1). The 3-year estimated probabilities of
relapse, NRM, DFS, and overall survival were 3.8% ⫾ 3.8%,
18.7% ⫾ 11.7%, 78.1% ⫾ 11.6%, and 78.1% ⫾ 11.6%, respectively (Figures 3-4).
In the historical group, 31 (17 first CR, 9 second CR, 5
refractory) of the 33 patients underwent HLA-matched sibling
(n ⫽ 26) and unrelated (n ⫽ 5) SCT. Median time to SCT was 150
days (range, 130-234 days). Two patients died of disease progression before SCT. Because of the higher incidence of advanced (⬎
first CR) pretransplantation disease status, patients in the historical
group received a more intensive preparative regimen (TBI ⫹
3453
Figure 2. Kinetics of the BCR-ABL transcript and its clinical correlation in 29 patients with Phⴙ ALL treated with imatinib interim therapy. (A) Plot showing quantitative
MRD levels for 15 patients with hematologic CR after imatinib interim therapy. (B) Plot showing quantitative MRD levels for 7 patients with molecular CR after imatinib interim
therapy. Their median BCR-ABL/ABL ratios decreased by 0.83 log after the first imatinib cycle and 0.34 log after the second imatinib cycle, respectively. (C) Plot showing
quantitative MRD levels for 4 patients with a primary refractoriness to imatinib therapy. One patient (patient no. 10) died of septicemia before transplantation. (D) Plot showing
quantitative MRD levels for 3 refractory patients after induction chemotherapy. These patients achieved CR with a decrease in MRD after imatinib therapy. Twenty-five patients
underwent allogeneic SCT with a first CR (A ⫹ B ⫹ D), while the remaining 3 patients had resistant leukemia at the time of SCT (C). Of these, 7 patients (patient nos. 3, 6, 12,
16, 19, 24, 26) still had residual leukemia at 3 or 6 months after SCT. However, with the exception of 2 cases (patient nos. 16, 19), their BCR-ABL/ABL ratios rapidly decreased
to an undetectable level after the development of acute (patient no. 24) or chronic (patient nos. 3, 6, 12, 26) GVHD induced by the rapid withdrawal of cyclosporine. Of 2 patients
without GVHD, 1 (patient no. 16) showed an increase in MRD at 6 months (1.35 ⫻ 10⫺5 3 6.78 ⫻ 10⫺5) and subsequently died of overt hematologic relapse following a further
increase in MRD (8.12 ⫻ 10⫺2) at 12 months after SCT. The overall treatment outcomes of the patients receiving imatinib interim therapy are listed in Table 4. Dx indicates
diagnosis; p, post (ie, after); Ind, induction; C, consolidation; IM, imatinib; S, salvage chemotherapy; M, months; aGVHD, acute GVHD; cGVHD, chronic GVHD.
cytarabine ⫹ melphalan). Acute GVHD was observed in 17
(54.8%) patients (7 grade II, 8 grade III, 2 grade IV). Sixteen
(66.7%) of the 24 evaluable patients had chronic GVHD (7 limited,
9 extensive). The median follow-up of surviving patients in the
historical group was 51 months (range, 40⫹ to 72⫹ months) after
SCT. To date, 19 of the 31 patients that received SCT have died, 11
because of the relapse and progression of leukemia and 8 because
of the transplant-related complications. The 5-year estimated
probabilities of relapse, NRM, DFS, and overall survival were
45.7% ⫾ 10.3%, 27.0% ⫾ 8.2%, 38.7% ⫾ 8.8%, and 38.7% ⫾ 8.8%,
respectively. The imatinib group showed better transplantation outcomes in terms of the probabilities of relapse (P ⬍ .001), DFS (P ⬍ .001),
and overall survival (P ⬍ .001) than the historical group (Figures 3-4).
MRD monitoring after SCT in the imatinib group
All but 2 (patient nos. 7, 14) of the patients who received a
transplant in the imatinib group were monitored for MRD level
after SCT as scheduled (Figure 2). Nineteen patients showed a
sustained molecular CR, while the remaining 7 (patient nos. 3, 6,
12, 16, 19, 24, 26) had residual leukemia 3 or 6 months after SCT.
However, with the exception of 2 patients (patient nos. 16, 19),
their BCR-ABL/ABL ratios rapidly reduced to an undetectable
level after the development of acute (patient no. 24) or chronic
(patient nos. 3, 6, 12, 26) GVHD induced by the rapid withdrawal
of cyclosporine. Of 2 patients without evidence of GVHD, 1
(patient no. 16) showed an increase in MRD at 6 months
(1.35 ⫻ 10⫺5 3 6.78 ⫻ 10⫺5) and subsequently died of overt
hematologic relapse following a further increase in MRD
(8.12 ⫻ 10⫺2) at 12 months after SCT.
Discussion
Despite considerable improvements in the management of Ph⫹
ALL, a substantial proportion of patients continue to die as a result
of disease progression. Consequently, patients at highest risk of
relapse or resistance are likely to benefit from the identification of
new criteria that enable patient outcome to be predicted. The
37/M
52/F
28
29
p210
p210
p210
p190
p190
p190
p210
p190
p190
p210
p190
p210
p210
p190
p190
p190
p190
p210
p190
p190
p210
p190
p210
p210
p190
p190
p210
p210
p190
BCR-ABL
isoform
Ph alone
Additional
Ph alone
Additional
Ph alone
Ph alone
Ph alone
Additional
Additional
Ph alone
Additional
Ph alone
Ph alone
Ph alone
Additional
Additional
Additional
Ph alone
Additional
Additional
Ph alone
Ph alone
Additional
Additional
Ph alone
Additional
Additional
Additional
Additional
Karyotype
CR
CR
CR
Refractory
CR
Refractory
CR
CR
CR
CR
Refractory
CR
CR
Refractory
CR
Refractory
CR
Refractory
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
Status
before
imatinib
400
400
600
600
400
600
600
400
400
400
600
600
600
600
400
600
400
600
400
600
400
600
600
600
400
400
600
400
600
Imatinib
dose,
mg/d
CR (⫺1.26)
CR (⫺0.70)
CR (⫺1.23)
Refractory (⫹0.67)
CR (⫺0.89)
CR (⫺0.89)
CR (⫺0.39)
CR (⫺0.44)
CR (⫺1.13)
CR (⫺0.60)
CR (⫺0.48)
CR (⫺0.77)
CR (⫺0.76)
CR (⫺0.48)
CR (⫺1.48)
CR (⫺0.89)
CR (⫺0.20)
Relapse (⫹0.93)
CR (⫺0.93)
CR (⫺0.50)
CR (⫺1.85)
CR (⫺0.97)
CR (⫺1.22)
CR (⫺0.35)
CR (⫺0.40)
CR (⫺0.89)
CR (⫺0.20)
After first imatinib
Mol CR (UD)
CR (⫺0.62)
Mol CR (UD)
NA
CR (⫺0.37)
CR (⫺0.31)
Mol CR (UD)
CR (⫺0.16)
CR (⫺0.56)
CR (⫺1.02)
CR (⫺0.81)
Mol CR (UD)
CR (⫺1.31)
Mol CR (UD)
NA
NA
NA
CR (⫺0.07)
Relapse (⫹1.63)
CR (⫺0.11)
CR (⫺1.09)
CR (⫺0.09)
CR (⫺0.08)
CR (⫺0.31)
Mol CR (UD)
CR (⫺0.79)
CR (⫺0.27)
Mol CR (UD)
After second imatinib
Response to imatinib*
Mol CR
CR
Mol CR
Refractory
CR
Refractory
CR
Mol CR
CR
CR
CR
CR
Mol CR
CR
Mol CR
Refractory
CR
CR
CR
Relapse
CR
CR
CR
CR
CR
Mol CR
CR
CR
Mol CR
Pre-SCT
status
MSD/PB
MUD/BM
MUD/BM
MSD/PB
MSD/BM
MUD/PB
MSD/BM
MSD/BM
MUD/BM
MUD/BM
MSD/BM
MSD/BM
MSD/BM
MUD/BM
MSD/BM
MSD/PB
MSD/BM
MSD/BM
MSD/BM
NA
MSD/BM
MSD/BM
MSD/BM
MSD/BM
MSD/BM
MSD/BM
MSD/BM
MSD/BM
MSD/BM
Graft
source
129
181
176
101
135
171
215
162
176
217
151
141
126
191
151
137
56
126
141
NA
120
126
139
158
134
127
132
136
128
Time to
SCT, d
⫺
⫹ (L)
⫺
⫺
⫺
⫹ (L)
⫺
⫹ (L)
⫹ (L)
⫺
⫺
⫹ (III)
⫺
⫺
⫹ (II)
⫹ (II)
⫺
⫹ (II)
⫺
⫹ (II)
⫺
⫹ (L)
⫺
⫺
⫺
⫺
⫹ (II)
⫹ (E)
⫺
⫺
NA
⫺
⫺
⫹ (IV)
⫹ (L)
⫺
⫺
NA
⫹ (III)
⫺
⫹ (L)
⫺
⫹ (L)
⫺
⫺
⫹ (E)
⫺
⫺
⫺
⫹ (L)
⫺
⫹ (II)
⫺
⫺
NA
⫹ (E)
⫹ (II)
NA
Chronic
Acute
GVHD (grade)
Alive 12 ⫹ mo
Alive 14 ⫹ mo
Alive 15 ⫹ mo
Alive 16 ⫹ mo
Alive 17 ⫹ mo
Alive 18 ⫹ mo
Alive 18 ⫹ mo
Alive 19 ⫹ mo
Alive 19 ⫹ mo
Alive 20 ⫹ mo
Alive 22 ⫹ mo
Alive 24 ⫹ mo
Alive 25 ⫹ mo
Died 9 mo; relapse
Alive 26 ⫹ mo
Died 4 mo; NRM
Alive 27 ⫹ mo
Alive 28 ⫹ mo
Alive 29 ⫹ mo
Died before SCT
Alive 32 ⫹ mo
Alive 34 ⫹ mo
Died 3 mo; NRM
Alive 37 ⫹ mo
Alive 39 ⫹ mo
Alive 42 ⫹ mo
Alive 43 ⫹ mo
Alive 45 ⫹ mo
Died 32 mo; NRM
Current DFS status;
cause of death
LEE et al
GVHD indicates graft-versus-host disease; DFS, disease-free survival; Mol CR, molecular complete remission; UD, undetectable; NA, not available; MSD, matched sibling donor; MUD, matched unrelated donor; BM, bone marrow; PB,
peripheral blood; E, extensive; L, limited; mo, months; and NRM, nonrelapse mortality.
*Values in parentheses indicate the changes of BCR-ABL/ABL ratio between each paired sample (before and after imatinib level).
28/M
27
17
20/M
55/F
16
26
31/M
15
35/F
18/M
14
44/F
44/M
13
25
30/M
12
24
39/M
11
48/F
38/F
10
23
27/M
9
40/F
31/M
8
23/F
40/F
7
22
43/F
6
21
20/M
5
36/F
26/M
4
20
39/F
3
21/F
40/M
2
28/F
29/M
1
18
39/F
No.
19
Age,
y/sex
Table 4. Overall treatment outcome of patients treated with first-line imatinib interim therapy (n ⴝ 29)
3454
Figure 3. Probabilities of relapse and nonrelapse mortality in the imatinib group
versus the historical group. Solid line indicates imatinib group; dotted line,
historical group.
quantification of BCR-ABL transcripts in Ph⫹ ALL has been used
to assess treatment response and to detect residual leukemia prior to
overt hematologic relapse.15,25-28 Radich et al25 studied 36 adults
with Ph⫹ ALL and found that patients who were PCR positive after
SCT have a significantly higher probability of relapse than
PCR-negative patients. Recently, Scheuring et al29 reported on the
usefulness of MRD analysis, using RQ-PCR in patients with
relapsed or refractory Ph⫹ ALL treated with imatinib monotherapy
as a salvage treatment. They found that 40 (71%) of the 56 patients
achieved a good response with a significant decrease in MRD (1.37
logs in BM, 2.64 logs in PB), and that the BCR-ABL levels in BM
and PB after 2 weeks of imatinib treatment and in BM after 4 weeks
had a predictive relevance to response and progression-free survival.
On the basis of these results, we investigated the MRD-based
role of imatinib as a first-line interim therapy in newly diagnosed
Ph⫹ ALL. Using RQ-PCR, we found that median BCR-ABL/ABL
ratios reduced by 0.77 log in 25 responders (86.2%) after the first
imatinib cycle, compared with levels after induction. After the
second imatinib cycle, median BCR-ABL/ABL ratios decreased by
0.34 log, compared with levels after consolidation. Furthermore,
imatinib interim therapy possibly induced molecular CR in 7
patients. Indeed, 28 of the 29 enrolled patients underwent allogeneic SCT as scheduled after the completion of imatinib interim
therapy. Of these, which included 7 patients with molecular CR, 25
were in first CR at the time of SCT. Patients receiving imatinib
interim therapy showed a lower incidence of relapse during the
consolidation phase and a higher rate of proceeding to SCT in first
CR than the historical patients. A possibility of effect of different
induction regimen or CNS prophylaxis on the pretransplantation
disease status may be excluded in this study because CR rates after
induction chemotherapy and incidence of CNS leukemia were
similar between the 2 groups (Table 1). Several potential factors
could account for the increased success of performing allogeneic
SCT in first CR, including increased availability of HLA-matched
unrelated donors and development of supportive care. Nevertheless, considering the similar presenting features and the same
postinduction chemotherapy protocol, it is unlikely that these
results were caused merely by selection biases. Rather, these results
likely reflect an effect of imatinib on improving the quality of
response and further reducing leukemia burden before SCT.
Shimoni et al30 also reported on the substantial activity of
pretransplantation imatinib monotherapy for patients with chronic
myeloid leukemia in blastic crisis (n ⫽ 10) and Ph⫹ ALL (n ⫽ 5).
In their study, 11 of the 15 patients received transplants in the
chronic phase or in CR. Therefore, first-line imatinib interim
therapy allowed SCT to be conducted in a more favorable status in
association with a low MRD level in patients with Ph⫹ ALL.
3455
A variety of potential mechanisms of resistance against imatinib
have already been reported, including point mutations in the
adenosine triphosphate binding domain or activation loop of the
BCR-ABL oncoprotein, genomic amplification of the BCR-ABL
fusion gene, up-regulation of BCR-ABL transcription, enhanced
imatinib efflux mediated by the up-regulation of multidrug resistance proteins, or the decreased cellular bioavailability of imatinib.31-35 In our study, 4 (13.8%) of the 29 patients were primarily
refractory to imatinib. These 4 patients had the p190BCR-ABL
transcript, and 3 of them had additional chromosomal changes at
the time of diagnosis. However, we did not identify any parameters
predictive of response to imatinib. Hofmann et al36 suggested that
gene expression profiling of Ph⫹ ALL blasts by microarray analysis
could discriminate between imatinib-sensitive and imatinibrefractory leukemias, and that genes related to apoptosis pathways
and cell cycle control were differently expressed in sensitive and
resistant cells. Recently, Wassmann et al37 suggested that day 14
BM with a cutoff at 5% blasts and some presenting variables,
including BCR-ABL amplification, a high WBC count, and circulating PB blasts, were important clinical parameters for predicting
response to imatinib in 68 patients with Ph⫹ ALL receiving
imatinib salvage therapy. If this analysis has the potential to
identify patients at risk of relapse or resistance, tailored therapeutic
interventions should be undertaken.
No data are available regarding the influence of imatinib on the
outcome of SCT, and the optimal timing of imatinib discontinuation has not been defined. In the present study, the conditioning
regimen was started 7 days from the last day of the imatinib cycle.
We did not observe any detrimental effects of imatinib on
engraftment, GVHD, or transplant-related organ toxicity, compared with the historical data. With a median follow-up of 25
months after SCT, 24 of the 28 patients who received transplants in
the imatinib group are currently alive without evidence of leukemia
and have yet to reach median survival. Outcome in the imatinib
group was better than in the historical group with respect to the
probabilities of relapse, DFS, and overall survival. However, this
observation must be interpreted with caution because there were
some limitations to the study design. The controls were a historical
cohort of patients, making this a retrospective comparison. Although all patients who received transplants in the 2 groups were
treated with the same protocols for conditioning and GVHD
prophylaxis or treatment, it is difficult to compare treatment
outcomes of historical approaches initiated many years ago with
the therapeutic approaches of today. In addition, it is important to
note that the follow-up time of the imatinib group was relatively
short, so patients in the imatinib group remain at risk of developing
further late events, such as disease relapse. Despite the limitations
of our study, our results are supported by 2 other reports. Recently,
Figure 4. Probabilities of disease-free survival and overall survival in the
imatinib group versus the historical group. Solid line indicates imatinib group;
dotted line, historical group.
3456
LEE et al
Thomas et al38 reported an encouraging result of concurrent
imatinib plus chemotherapy for 20 patients with Ph⫹ ALL. In their
study, 15 (75.0%) of their 20 patients remained alive without
evidence of leukemia after a median follow-up of 20 months from
the start of induction therapy. Of their 20 patients, 10 (50.0%)
received allogeneic SCT in first CR, and, at a median follow-up of
12 months after SCT, all but 1 of those patients remained alive
without disease. Of the 10 patients who had not undergone
allogeneic SCT, 5 patients remained alive in sustained CR (4⫹ to
24⫹ months). The investigators suggested that outcome for
concurrent imatinib plus chemotherapy was better than with prior
regimes (historical data) in terms of CR rates (P ⬍ .01), DFS
(P ⬍ .001), and overall survival rates (P ⫽ .001). According to
data from the International Bone Marrow Transplant Registry
(n ⫽ 6991),39 patients with acute leukemia who were free of their
leukemia 24 months after allogeneic SCT showed the high
probability of living for 5 or more years (95% confidence interval,
88%-90%). Taken together, our results suggest that the imatinib
interim therapy might provide a survival advantage for patients
with Ph⫹ ALL.
The role of allogeneic SCT remains to be determined, as durable
remissions were observed in some patients with Ph⫹ ALL who
received concurrent imatinib plus chemotherapy alone.38 We also
observed a phenomenon maintaining durable CR in the absence of
allogeneic SCT. In the present study, 3 patients who had sustained
CR (including 1 molecular CR) until the completion of 3 courses of
imatinib interim therapy were excluded because of a lack of
HLA-matched donors. For those patients, maintenance therapy was
planned with 6-mercaptopurine (50 mg/m2/d), methotrexate (15
mg/m2/wk), and imatinib (400 mg/d) for 2 years. Of them, 1 patient
who achieved molecular CR remains alive with a leukemia-free
status after a follow-up of 26 months from the date of initiation of
therapy. Conversely, the remaining 2 patients died of their disease
progression at 11 and 15 months, respectively (data not shown).
Previously, we reported a phenomenon involving increased
MRD followed by a rapid return to a PCR-negative status after
the development of chronic GVHD in some historical patients.15
The current follow-up of the historical group showed that the
probability of relapse was significantly lower in patients with
chronic GVHD than that in patients without chronic GVHD
(22.1% ⫾ 11.3% versus 75.0% ⫾ 15.3%, P ⫽ .009). In the present
study, we were able to repeatedly observe the relationship between
GVHD and antileukemic activity by serially monitoring MRD
level in the imatinib group. Seven of the 28 patients who received
transplants had residual leukemia at 3 or 6 months after SCT. Of
them, 5 patients showed a decrease in MRD to an undetectable
level after the development of acute (n ⫽ 1) or chronic GVHD
(n ⫽ 4), induced by the rapid withdrawal of cyclosporine. However, the remaining 2 patients showed no evidence of GVHD after
cyclosporine withdrawal, and 1 of them showed a pattern of MRD
increase at 6 months after SCT. At this time, we recommended
preemptive imatinib therapy and donor lymphocyte infusion (DLI),
but the patient refused. Unfortunately, the patient died of overt
hematologic relapse with a high MRD level 12 months after SCT.
Regarding the role of GVHD in ALL, the Seattle group first
described an inverse relationship between relapse and GVHD,
especially chronic GVHD.40 According to data from the International Bone Marrow Transplant Registry,41 acute GVHD had a
stronger antileukemic activity in patients with ALL, whereas
chronic GVHD was more important at reducing the probability of
relapse in patients with early-phase myeloid leukemia. Conversely,
other investigators have confirmed the importance of chronic
GVHD in reducing relapse in ALL.42-44 These conflicting results
may be due to either the different prophylactic methods used for
GVHD or to heterogeneities of patient populations. However, the
clinical significance of GVHD in Ph⫹ ALL has not been widely
discussed in the literature. Cornelissen et al14 suggested that Ph⫹
ALL does illustrate the graft-versus-leukemia effect, because they
found significantly fewer relapses and better DFS in adults with
Ph⫹ ALL undergoing HLA-matched unrelated transplantation as
compared with ALL patients with other karyotypes. According to
data from the Seattle group,28 patients with chronic GVHD showed
a significantly lower risk of relapse (relative risk ⫽ .33, P ⫽ .038)
in Ph⫹ ALL. Regarding the treatment options for relapsed patients
with acute and chronic leukemias, DLI has been widely used.
However, the efficacy of DLI was uniformly dismal in patients with
ALL who experience overt hematologic relapse, probably because
of the rapid pace of the disease and the delayed antileukemic effect
of DLI.45 Furthermore, results with imatinib monotherapy were
disappointing for most patients with Ph⫹ ALL with hematologic
relapse after allogeneic SCT.18 Therefore, we suggest that MRDbased postgrafting immunomodulation (eg, immunosuppressant
discontinuation, dose-escalating DLI, etc) in combination with
imatinib at the earliest level of disease recurrence may have a
potential role in the long-term control of residual leukemia
in Ph⫹ ALL.
In summary, this study suggests that first-line imatinib interim
therapy may be a feasible treatment strategy in terms of providing a
good quality of CR and securing a survival advantage for patients
with Ph⫹ ALL. In addition, MRD monitoring makes evaluating the
role of imatinib and postgrafting immunomodulation in individual
patients with Ph⫹ ALL possible. Further long-term follow-up is
needed to validate the results of this study.
Acknowledgments
We thank the dedicated nurses of our stem cell transplantation
program, our fellows and house-staff, and the medical technicians
for their excellent assistance.
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