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Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3503-3508
Low Transplant Mortality in Allogeneic Bone Marrow Transplantation
for Acute Myeloid Leukemia: A Randomized Study of Low-Dose Cyclosporin
Versus Low-Dose Cyclosporin and Low-Dose Methotrexate
By
P. Zikos,
M.T. Van Lint,
F. Frassoni,
T. Lamparelli,
F. Gualandi,
D. Occhini,
N. Mordini,
G. Berisso,
S. Bregante,
F. De Stefano,
M. Soracco,
V. Vitale, and
A. Bacigalupo
From the Divisione Ematologia II Ospedale San Martino, Istituto
Medicina Legale, Universitá, Servizio Radioterapia Istituto
Tumori, Genova, Italy.
 |
ABSTRACT |
Sixty patients undergoing allogeneic bone marrow transplant for
acute myeloid leukemia (AML) in first remission (CR1; n = 49) or
more advanced phase (n = 11) were entered in a prospective trial of
graft-versus-host disease (GvHD) prophylaxis: low-dose cyclosporin A
(IdCSA; 1 mg/kg/d from day  1 to +20 day; n = 28) or IdCSA plus
low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for days +3, +6, and +11; n = 32). Primary
end points were acute GvHD (aGvHD) and transplant-related mortality
(TRM); secondary end points were relapse and survival. The conditioning
regimen consisted of cyclophosphamide (120 mg/kg) and fractionated
total body irradiation (3.3 Gy/d for 3 consecutive days). The actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34%
for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at
1 year was 11% versus 13%, respectively, and older patients ( 29
years) had higher TRM than younger patients (22% v 5%,
P = .01). The age effect was significant in the IdCSA group
(P = .04) but not in the IdCSA + IdMTX group
(P = .1). The median follow-up is 4.4 years, with an
overall actuarial survival of 78% for CR1 patients and 36% for
patients with advanced disease. For patients in CR1 the outcome of the
two regimens was as follows: survival 77% versus 80%
(P = .6), relapse 20% versus 9% (P = .1), and
TRM 13% versus 17% (P = .6). This study suggests that TRM
can be reduced in AML patients undergoing allogeneic marrow transplants
with a mild conditioning regimen and low-dose immunosuppression, and this translates in a 78% 5-year survival for CR1 patients. Beyond CR1
the major obstacle remains leukemia relapse, which is not prevented by
low-dose in vivo immunosuppression.
| |
INTRODUCTION |
ALLOGENEIC BONE MARROW transplantation
(BMT) is a well-established therapy for patients with acute myeloid
leukemia (AML), and has been proven to be at least as effective or
superior to chemotherapy and autologous transplants in first remission
(CR1) patients.1 The success of allogeneic BMT has been
limited by transplant-related mortality (TRM). Graft-versus-host
disease (GvHD) alone or in combination with infections or interstitial pneumonia accounts for a substantial proportion of failures after allogeneic BMT.2 Between 20% and 50% of patients
administered grafts from HLA identical siblings develop significant
acute GvHD (aGvHD). HLA disparity, older age, donor-recipient sex
mismatch, and posttransplantation immunosuppressive regimen are all
predictors of aGvHD.3 In addition, the intensity of the
conditioning regimen should be taken into account. Protocols including
high-dose chemotherapy4 or high-dose total body irradiation
(TBI)5 are associated with a high incidence of GvHD and
TRM. At a given intensity of pretransplant conditioning, the
combination of cyclosporin (CSA) and methotrexate (MTX) seems to be
superior to either regimen alone in preventing aGvHD.6
We have previously described a fractionated TBI (fTBI) regimen
consisting of three daily fractions of 3.3 Gy each that is associated
with a low risk of interstitial pneumonia.7 We have subsequently shown that small variations within that schedule had a
significant impact on leukemia relapse,8 and we have since
then corrected the dose according to thermoluminescent dosimeter readings to deliver the nominal dose.
With this relatively mild conditioning regimen we then investigated a
possible effect of reducing in vivo immunosuppression. Patients were
randomized to receive high-dose CSA (5 mg/kg/d) or low-dose CSA (IdCSA,
1 mg/kg/d), from day 1 to day +20.9 Although the two
groups differed significantly in CSA dose and CSA serum levels only
between day 0 and day 10, the IdCSA regimen (1 mg/kg) significantly
reduced leukemia relapse and resulted in improved
survival.9 An update of that study with median follow-up of
8.8 years (range, 7 to 10) still shows a survival advantage for IdCSA
in young patients (<35 years, P = .03), but not in older
patients (P = .7) (unpublished data).
In the attempt of reducing GvHD, especially in older patients, we have
therefore compared the best arm of that study (CSA, 1 mg/kg) with the
combination of IdCSA and low-dose methotrexate (ldMTX). We are now
reporting the results of this second randomized trial.
| |
MATERIALS AND METHODS |
Study design.
Patients aged 16 to 50 years with AML were eligible. Patients were
randomized to receive IdCSA (1 mg/kg body weight) administered in
continuous intravenous infusion, from day 1 to day +20, or IdCSA
with IdMTX (10 mg/m2 on day +1, and 8 mg/m2 on
days +3, +6, and +11). The dose of MTX could be further reduced or
omitted by the attending physician in case of severe mucositis or
febrile neutropenia. Patients were stratified at randomization for age
(<30 or 30) and phase of the disease (CR1 or >CR1). On day +21,
after BMT patients were placed on oral CSA (10 mg/kg/d), the dose was
adjusted according to creatinine levels and CSA serum levels. The dose
of CSA was reduced in case of creatinine levels greater than 1.7 mg% and CSA levels greater than 700 ng/mL. CSA was
tapered at 1 year after BMT and discontinued in the absence of chronic
GvHD. If aGvHD developed, patients were treated with 6methylprednisolone in doses ranging between 2 and 10 mg/kg/d.
Aim of the study.
The aim of the study was to test whether the association of MTX with
IdCSA would reduce aGvHD as compared with IdCSA alone. With a baseline
incidence of 61% in our previous study9 and with an
expected reduction of 35%, we expected to enroll 36 patients in each
arm to achieve a significant difference in aGvHD, with a significance
level of 0.05 and a power of 0.80.
End points.
Primary end points were aGvHD and TRM; secondary end points were
relapse and survival.
Patients.
Sixty patients with AML underwent BMT from HLA identical siblings at
our institute between 1990 and 1994 after giving informed consent.
Forty-nine patients were in CR1, eight in first untreated relapse, two
in second remission, and one in second relapse. Clinical details of
patients are outlined in Table 1. The two groups were comparable for
age, sex, French-American-British (FAB) classification, and time
between diagnosis and transplant (Table 1).
Transplantation.
Conditioning regimen was cyclophosphamide (60 mg/kg on days 7 and
6; total, 120 mg/kg), followed by fTBI; (3.3 Gy/d on days 3,
2, and 1 delivered at a dose rate of 12 cGy/min from a linear accelerator with lung shielding to 9.9 Gy). The received dose of TBI
was monitored with thermoluminiscent dosimeters as
described8 and adjusted to deliver the prescribed dose of
3.3 Gy/d. All patients received ciprofloxacine from day 7 until the
onset of fever or resolution of neutropenia, and
trimethoprim-sulfamethoxazole was then administered from day +30 until
day +365 to prevent Pneumocystis carinii infections. High-dose
immunoglobulins (400 mg/kg/wk) were administered until day +100. All
patients received acyclovir (500 mg/m2 intravenously every
8 hours from day 1 to day +30, 800 mg orally every 6 hours from day
+31 to day +100, followed by 800 mg orally every 12 hours from day +101
to day +365). Bone marrow cells were slowly infused
unmanipulated after the last dose of TBI. The day of infusion was
designed as day 0. The median number of infused cells was 4.5 × 108/kg/body weight (range, 1.3 to 11; 3.4 v 4.5 for
the two groups, respectively; P = .09). Bone marrow was
obtained under general anesthesia (20 to 25 mL/kg of donor weight),
aiming at a cell dose greater than 4 × 108/kg.
Cytomegalovirus (CMV) infections were monitored with
antigenemia10 and treated with ganciclovir or
foscarnet,11 and more recently, with combination of the
two.12
Engraftment and chimerism.
Engraftment was defined as the first of 3 consecutive days with
absolute number of neutrophils (PMN) greater than 0.5 × 109/L. Chimerism for DNA polymorphism using microsatellites
(HUMF13A1, chromosome 6; HUMTH01, chromosome 11; HUMvWA31, chromosome
12; HUMFES/FPS, chromosome 15; and D19S253, chromosome 19) was
assessed.13
aGvHD.
aGvHD was scored according to current criteria.14
Statistical analysis.
Kaplan-Meier curves were used for survival, relapse, and TRM incidence
as also the incidence of aGvHD grade II-IV.15 The Mann-Whitney test was used to compare means for continuous variables between groups. Fisher's exact test was used for 2 × 2 tables. Cox regression analysis was used to define predictors on
survival and incidence of chronic GvHD (cGvHD).16
| |
RESULTS |
Patient compliance.
The median administered dose of CSA between day 1 and day +20 was
1.03 mg/kg (range, 0.9 to 2.5) for 28 patients in the IdCSA arm and
1.01 mg/kg (range, 0.9 to 1.4) for 32 patients in the IdCSA + IdMTX
arm. For the latter, the median administered dose of MTX on days +1,
+3, +6, and +11 was 10 mg/m2 (range, 8.77 to 11.43), 7.38 mg/m2 (2.94 to 8.75), 7.14 mg/m2 (5.26 to
8.75), and 6.67 mg/m2 (2.94 to 8.75), respectively. On days
+1, +3, +6, and +11 MTX was administered to 32 patients (100%), 30 (94%), 21 (66%), and 15 (47%), respectively. The median cumulative
dose of MTX was 24 mg/m2 (range, 10 to 35).
Engraftment.
All patients achieved engraftment as proven by sex markers or DNA
polymorphism. Patients administered MTX achieved a neutrophil count of
greater than or equal to 0.5 × 109/L on day 16 as compared with day 12 for CSA alone (P < .0001). There
was also a delay in platelet engraftment of 2 days (14 v 16, P = .08). Median platelet counts on days 0-20, 21-50, 51-100, and greater than 100 were 31 versus 25 × 109/L, 88 versus
82 × 109/L, 100 versus 96 × 109/L, and 189 versus 191 × 109/L for IdCSA versus IdCSA + IdMTX,
respectively (statistically not different).
aGvHD.
No patient developed aGvHD grade IV. aGvHD was scored as grade 0-I in
11 versus 21 patients, and grade II-III in 17 versus 11 patients for
the two groups, respectively (P = .03, Fisher's exact test).
The median day to develop aGvHD was 14 (range, 7 to 40) versus 17 (range, 7 to 57) for two groups (P = .1). The overall
incidence was 47% for the whole group. The actuarial probability of
developing aGvHD grade II-III was 61% versus 34%, respectively (P = .02; Fig 1). Patients
receiving IdCSA alone had a 2.3-fold higher risk to develop aGvHD grade
II-III than those receiving IdCSA + IdMTX, and this was also true for
patients in CR1. In patients 30 years or older, the incidence of aGvHD
grade 0-I, II, and III was 27%, 55%, 18% versus 75%, 25%, and 0%,
respectively, for the IdCSA versus IdCSA + IdMTX group
(P = .03). We could not find a correlation between the dose
of administered MTX and aGvHD.
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| Fig 1.
Actuarial probability of developing aGvHD grade II-IV,
showing a significant difference between the two groups: CSA + MTX, 34% versus CSA alone, 61% (P = .02).
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cGvHD.
cGvHD was scored in 54 of 60 patients (26 v 28 from each group,
respectively) alive 100 days posttransplant. This was scored as absent
or limited in 15 versus 19 patients and as extensive in 11 versus 9 patients for the two groups, respectively (P = .1).
Relapse rate.
At the time of analysis 12 patients had relapsed and 9 of them (6 v 3 for the two groups, respectively) had died. The overall probability of relapse was 22% for all patients and 14% for CR1 patients. Among 28 patients in the IdCSA group, 8 relapsed at a median
interval of 266 days (range, 64 to 1,175) versus 4 of 32 patients in
the IdCSA + IdMTX group, who relapsed at a median interval of 115 days
(range, 80 to 954; P = .6). The actuarial relapse rate is
32% versus 14% for the two groups, respectively (P = .1).
The results were not significantly different when stratified by median
age (29 years, 33% v 19%, P = .07), grade of aGvHD
(grade 0-I, 27% v 11%, P = 0.3; grade II-IV, 35%
v 19%, P = .36), or phase of the disease (CR1, 20%
v 9%, P = .3; Fig 2). In
multivariate analysis CR1 (P = .008) and cGvHD
(P = .01) were favorable predictors of persisting remission.
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| Fig 2.
Actuarial risk of TRM. There was no significant
difference between patients receiving CSA + MTX or CSA alone.
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TRM.
The actuarial TRM at 5 years is 14% for all patients, and 15% for CR1
patients. The probability of TRM is 11% versus 17% in the two groups,
respectively (P = .6), and 13% versus 17% for CR1 patients
(Fig 3). The major nonrelapse causes of
death were GvHD (1 v 1 deaths), infections (1 v 2 deaths), and IP (1 v 0 deaths) for the two groups,
respectively.
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| Fig 3.
Overall outcome for patients in CR1. The actuarial
survival rate for the two groups was 78%, relapse rate was 14%, and
TRM was 15%.
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In multivariate COX analysis on TRM the only predictor was patient's
age (RR 1.2, P = .01), whereas donor age,
gender, disease phase, aGvHD, interval diagnosis-BMT, FAB subtype, and
GvHD prophylaxis had no significant impact. The actuarial TRM of
patients under the age of 29 (median) was 5% versus 22% for older
patients (P = .01).
Survival.
Forty-three of sixty patients are currently alive with a median
follow-up of 4.4 years (range, 0.5 to 7). The 5-year actuarial survival
is 71% for whole group and 78% for patients in CR1 (Fig 3). Nineteen
of twenty-eight patients in the IdCSA group are alive, at a median
interval of 2,119 days (range, 904 to 2,534) versus 24 of 32 patients
in the IdCSA + IdMTX group, at a median interval of 1,728 days (910 to
2,476). The 5-year actuarial survival is 67% versus 74% for the two
groups, respectively (P = .1). There was no difference
between groups when we stratified patients according to recipient age
( 29 or >29, 81% v 73%, P = .5 and 59%
v 68%, P = .5), phase of disease (CR1 or >CR1,
77% v 80%, P = .8 and 20% v 50%,
P = .5), or time between diagnosis to BMT (<180 or 180
days, 92% v 78%, P = .34 and 46% v 69%,
P = .4). In multivariate COX analysis there was no variable
which predicted failure in survival
analysis.
| |
DISCUSSION |
In the present study we have shown that IdCSA combined with IdMTX
reduces the risk of aGvHD when compared with IdCSA alone, although this
does not have a significant impact on survival; for patients in CR1,
TRM was 12%, relapse rate was 14%, and survival rate was 78%; and
for patients with advanced disease, alternative strategies to control
leukemia should be devised.
Concerning the first point, better prevention of aGvHD is one reason
for improved outcome of allogeneic BMT, and in particular, the widely
used combination of CSA and full-dose MTX.6,17 In the
present study, despite a significant reduction of the dose of CSA and
also of MTX, no patient had grade IV and only two patients experienced
grade III GvHD, possibly also a result of a mild conditioning regimen.
There was a reduction of GvHD in patients administered CSA + MTX as
compared with CSA alone, especially in patients over 30 years of age.
Many centers use CSA at the dose of 2.5, 3, or 5 mg/kg, but to our
knowledge there is no trial suggesting this is the best dose, and it
may actually be a high dose in terms of toxicity and
immunosuppression.18 The dose of 1 mg/kg of CSA was derived
from a randomized study which suggested that 1 mg/kg/d in the first 10 days post-BMT produced less multiorgan toxicity, and a lower rate of
relapse when compared with 5 mg/kg.9 The median
administered dose of MTX was 24 mg/m2, approximately 50%
less than the full dose of the original protocol.19 All
patients randomized to the MTX arm received MTX (10 mg/m2) on day +1; some patients did not receive their MTX
on days +3, +6, or +11 because of clinical conditions such as severe
mucositis and or febrile neutropenia. Within the MTX arm we could not
find a correlation between the number of doses of MTX and aGvHD, nor between the total dose of MTX administered in the first 11 days and
aGvHD. Nevertheless, patients in the CSA + MTX arm had a significant reduction of aGvHD as compared with controls receiving CSA alone, suggesting a primary role for the MTX dose on day +1. The encouraging control of aGvHD did not eliminate the effect of patient age: TMR was
5% in younger patients (29 years) versus 22% in older patients,
and this was confirmed in multivariate analysis.
As to the second point, we are reporting an actuarial survival rate of
78% at 7 years for AML in CR1, using a relatively mild conditioning
regimen. Our observation that IdCSA can strongly influence leukemia
relapse9 suggests that the GvHD prophylaxis has a
significant impact on control of leukemia in the context of this
conditioning regimen. It could possibly be more difficult to detect the
impact of GvHD prophylaxis in the setting of high-dose TBI. Our results
seem superior to those reported from international registries17 or recently from the MRC-AML 10 study (56%
survival, 34% relapse).20 Our unit is primarily a referral
center, and we tend to see more and more patients with high-risk
factors such as delayed remissions or chromosomal abnormalities.
Despite this trend in the past 3 years, after this randomized trial was
closed, we have treated 22 consecutive AML patients in CR1 with CSA + MTX and have confirmed a very encouraging actuarial survival rate of
94% (unpublished data). Among the possible reasons for
the extremely low TRM in our center we would like to point out a high number of nucleated bone marrow cells in this trial, 4.5 × 108/kgwhich is achieved by obtaining 20 to 25 mL/kg of
donor body weight in small aliquots,21 and a high number of
nucleated cells has been recently reported to be a strong predictor of
favorable outcome also in the unrelated setting.22 In
addition we have significantly reduced mortality caused by CMV by
treating patients with a high number of CMV-antigen positive cells with
combined ganciclovir plus foscarnet therapy.12 Therefore we
believe that factors such as a total fTBI of less than 10 Gy, low-dose
immunosuppression, high marrow cell dose, and aggressive therapy of CMV
have all contributed to determine the very low mortality.
Regarding patients with disease beyond CR1, the major problem remains
leukemia relapse. Relapse can be reduced by increasing the conditioning
regimen, but this is associated with greater TMR, as shown in one of
the few randomized trials comparing two different TBI regimens:
patients receiving 12 or 15.75 Gy had a relapse rate of 35% versus
12% (P = .06), and a TMR of 12% versus 32%
(P = .04), resulting in equal overall survival
rates.5 In the same study the incidence of moderate-severe
aGvHD was 21% versus 48% (P = .02). The alternative option
is to reduce GVHD prophylaxis, which in our hands was effective in CR1,
and has also been reported to be successful for patients in first
relapse.23 Alternative strategies such as the use of
radiolabelled monoclonal antibodies are being
investigated.24
There is increasing interest in tailoring the therapy on the major
prognostic factors for AML patients. Several reports have suggested
that some FAB subtypes may be cured with high-dose cytosine arabinoside
in the intensification [M2 with t(8;21) and inv
16]25 or with new chemotherapeutic approaches [M3 with
t(15;17)].26 In part it is possible that the brilliant
results obtained by the GIMEMA group26 may
completely change the approach to the latter AML subtype. However, the
recent EBMT analysis has shown that allogeneic BMT is
superior in controlling the disease also in t(8;21) and inv
16 in which chemotherapy alone has a favorable effect.25,27 Therefore, if the TRM could be kept at 20%
for patients above 30 years of age and consistently below 10% for younger individuals, then allogeneic BMT in CR1 will be a therapeutic option for more patients with an HLA identical sibling. For patients over the age of 45, relatively mild conditioning regimens are being
tested with encouraging results.28 However, the problem of
advanced disease remains and requires alternative strategies to control
leukemia relapse.
| |
FOOTNOTES |
Submitted September 22, 1997;
accepted December 16, 1997.
Supported by Associazione Italiana Ricerca contro il Cancro (AIRC)
Milano grant to A.B. and Associazione Ricerca Trapianto Midollo Osseo
(ARITMO) Genova.
Address reprint requests to A. Bacigalupo, MD, Divisione
Ematologia 2 (PAD 5/II), Ospedale San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract