|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1572-1579
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Graft versus host disease prophylaxis with low-dose cyclosporine-A
reduces the risk of relapse in children with acute leukemia given
HLA-identical sibling bone marrow transplantation: results of a
randomized trial
Franco Locatelli,
Marco Zecca,
Roberto Rondelli,
Federico Bonetti,
Giorgio Dini,
Arcangelo Prete,
Chiara Messina,
Cornelio Uderzo,
Mimmo Ripaldi,
Fulvio Porta,
Giovanna Giorgiani,
Eugenia Giraldi, and
Andrea Pession
From the Department of Pediatrics, University of Pavia, IRCCS
Policlinico San Matteo, Pavia; Department of Pediatrics, University of
Bologna, Ospedale Sant'Orsola, Bologna; Department of Pediatric
Hematology and Oncology, Giannina Gaslini Institute, Genova; Department
of Pediatrics, University of Padova; Department of Pediatrics, Ospedale
Nuovo San Gerardo, Monza, University of Milan; BMT Unit, Pausillipon
Hospital, Napoli; Department of Pediatrics, University of Brescia,
Spedali Civili, Brescia, Italy.
 |
Abstract |
Leukemia relapse is a major cause of treatment failure for patients
with acute leukemia given allogeneic bone marrow transplantation (BMT).
This study evaluated whether a reduction of the dosage of
cyclosporine-A (Cs-A) used for graft versus host disease (GVHD) prophylaxis could reduce relapse rate (RR) in children with acute leukemia given BMT. Fifty-nine children who had transplantation from
HLA-identical siblings were randomized to receive Cs-A intravenously at
a dosage of 1 mg/kg/d (Cs-A1) or of 3 mg/kg/d (Cs-A3) until patients
were able to tolerate oral intake. Subsequently, both groups received
Cs-A orally at a dosage of 6 mg/kg/d, with discontinuation 5 months
after BMT. The probability of developing grade II-IV acute GVHD was
57% for the Cs-A1 group versus 38% for the Cs-A3 group
(P = .06); the probability of developing chronic GVHD was 30% for the Cs-A1 group and 26% for the Cs-A3 group
(P = NS). Three patients died of grade IV acute GVHD: 2 were in the Cs-A1 and the third in the Cs-A3 group. The RR was 15% for
the Cs-A1 group and 41% for the Cs-A3 group (P = .034);
1-year transplant-related mortality estimates were 17% and 7%,
respectively (P = NS). With a median observation time of 44 months from BMT, the 5-year event-free survival for children belonging
to Cs-A1 and Cs-A3 groups was 70% and 51%, respectively
(P = .15). Our data demonstrate that the use of low Cs-A
doses is associated with a statistically significant reduction of
leukemia relapse, probably due to an increased graft versus leukemia effect.
(Blood. 2000;95:1572-1579)
© 2000 by The American Society of Hematology.
| |
Introduction |
Allogeneic bone marrow transplantation (BMT) is an
established treatment modality for patients with acute leukemia.
Unfortunately, the success of BMT is offset by the risk of leukemia
relapse and of death for transplant-related causes, mainly
graft versus host disease (GVHD), infectious complications, and
toxicity of the conditioning regimen.
Acute GVHD is a common immunologic complication that occurs in 40% to
50% of allogeneic BMT recipients during the early posttransplant period; chronic GVHD can be observed in 30% to 60% of long-term survivors.1,2 Even though GVHD remains a major contributor to both early and late mortality and morbidity after
BMT,2-5 large retrospective trials have demonstrated lower
relapse rates in patients who developed acute1,6-9 or
chronic GVHD (or both).9-12 In fact, as extensively
demonstrated in animal models, donor immunocompetent cells contribute
to the antileukemic efficacy of BMT through the so-called graft versus
leukemia (GVL) reaction.13,14 Further clinical evidence
supporting the relevance of GVL effect in the eradication of malignant
cells escaping the preparative regimen includes a higher incidence of
leukemia relapse observed after syngeneic or T-cell-depleted
transplants.8
This said, it is not surprising that, to reduce the risk of relapse,
several efforts have been made to identify, in patients with leukemia,
the best strategy of GVHD prevention, able to avoid the occurrence of
severe GVHD, but sparing the GVL reaction.
So far, cyclosporine-A (Cs-A) has been the most commonly used agent for
GVHD prophylaxis after allogeneic BMT and, alone or in combination with
methotrexate, it is included in the GVHD prophylaxis schedule of more
than 70% of transplant recipients.15 The introduction of
Cs-A in the clinical practice has resulted in better prevention of
GVHD, even though a relevant proportion of patients still experience this complication. On the other hand, because of its immunomodulating action on donor T cells, Cs-A could impair the GVL effect.
In this regard, Bacigalupo et al demonstrated in a randomized trial
performed in adults that patients who received Cs-A at a dosage of 1 mg/kg/d had a significant reduction of relapse rate (RR) and, despite
an increased GVHD incidence, a better leukemia-free survival, as
compared to those who received Cs-A at the dose of 5 mg/kg/d.16
On the basis of this experience and considering the reported low GVHD
incidence in childhood,1 we evaluated in a multicenter, randomized, prospective clinical trial whether, in children with acute
leukemia given an allogeneic BMT from an HLA-compatible sibling, the
use of Cs-A at a dose of 1 mg/kg/d could be associated with a lower
risk of leukemia relapse and a better event-free survival (EFS), in
comparison to children treated with Cs-A at a higher dose (3 mg/kg/d).
| |
Patients and methods |
Study design
The study was designed as a prospective, multicenter, centrally
randomized trial aimed at evaluating the impact of 2 different Cs-A
dosages for acute GVHD prophylaxis on the clinical outcome of children
with leukemia given allogeneic BMT from an HLA-identical sibling. The
major end point of the study was to determine whether the use of
low-dose Cs-A (1 mg/kg/d) could reduce RR as compared to standard-dose
Cs-A (3 mg/kg/d). Secondary end points were the occurrence of acute and
chronic GVHD, transplant-related mortality (TRM), and EFS in the 2 groups.
Eligibility criteria for patients to be enrolled in the study were age
between 1 and 18 years, a diagnosis of acute lymphocytic leukemia (ALL)
in first, second, or third complete remission (CR) or of acute
myelogenous (AML) in first or second CR, the availability of an
HLA-genotypically identical sibling, and a written informed consent
from the parents.
To calculate the number of patients to be enrolled in this study a
2-sided sample size evaluation method based on the log-rank test was
used. Considering a study significance level of 0.05 and a study power
of 0.80 and supposing an estimated probability of RR at 18 months of
0.10 for the first arm and 0.40 for the second arm of the study, the
required number of cases resulted in 28 patients per arm with an
accrual time of 24 months and an overall study duration of 48 months.
To monitor the results of the trial, an interim analysis was performed
1 year after study beginning and, subsequently, every year. It was
decided that patient enrollment should be closed when the difference in
RR between the 2 arms reached a P value of .01.
Randomization was centralized at CINECA (North East Inter-University
Italian Computing Center, Bologna, Italy) by one of the investigators
(R.R.), who was not involved in the clinical management of the
patients, and performed using a 1:1 allocation ratio. Patients were
stratified according to diagnosis (ALL or AML) and disease phase (first
CR versus more advanced disease). The analysis was based on the
intention to treat principle. The institutions participating in the
study were not blinded as to Cs-A dose.
Treatment protocol
Pretransplant preparative regimens were assigned according to the
institutional protocols at each clinical site, on the basis of the
underlying disease, and on the age of the recipient. Supportive care
was standardized within each center and uniformly applied to the
patients in both groups. Usually, empirical broad-spectrum antibiotic
therapy was started when children became febrile, and antifungal
therapy was used in the presence of either clinical evidence of fungal
infection or fever persisting after 3 days of antibiotic therapy. As
prophylaxis for Pneumocystis carinii pneumonia, patients
received oral cotrimoxazole, starting from the day of engraftment. To
reduce the risk of infections, children received a commercial
immunoglobulin preparation intravenously at a dosage of 400 mg/kg
every week, starting the week before transplantation and
ending 3 months after the allograft. Cytomegalovirus (CMV) serologic
status was studied before transplantation in all children and
in their donors. Forty of the 59 BMT recipients studied were
seropositive, as well as 35 of the 59 donors. The expression of pp65 human CMV matrix protein was monitored in all patients to
detect CMV reactivation.17 Patients experiencing CMV
reactivation were usually treated with ganciclovir or foscarnet at
conventional doses.
The day of transplantation was designated as day 0. Between day
 7 and 3 before BMT, patients were randomized to receive Cs-A at a dosage of 1 mg/kg/d (Cs-A1 group) or 3 mg/kg/d (Cs-A3 group)
from day 1. The assigned dose of Cs-A was administered intravenously in 2 divided 2-hour infusions. Subsequently, when patients were able to tolerate oral intake, they received Cs-A orally
at a dosage of 6 mg/kg/d in 2 divided doses, with a gradual reduction
until discontinuation, in absence of chronic GVHD, 5 months after BMT.
No other agent was used for GVHD prophylaxis.
Dose modifications of Cs-A were allowed in presence of serum creatinine
levels more than 2 times baseline, whereas Cs-A whole blood levels did
not influence the assigned drug dose. Moreover, physicians were free to
increase the dose of Cs-A for patients experiencing acute GVHD if this
was considered indicated.
At each participating center, the development of acute and chronic GVHD
was monitored throughout the study and graded by a single investigator,
blinded to the randomization arm of the patients. Tissue biopsy samples
were obtained to confirm the diagnosis of GVHD whenever clinically
indicated and feasible. Treatment of acute and chronic GVHD was
administered according to the protocols in use at each institution.
Patient demographics and characteristics
From May 1993 to May 1996, 59 patients (33 males and 26 females)
were centrally randomized and assigned to one of the treatment arms.
Patients were treated in 7 Italian pediatric BMT centers participating
in AIEOP (Italian Association of Pediatric Hematology/Oncology) BMT
group and listed in the appendix. All subjects randomized underwent BMT
from an HLA-identical sibling and were evaluated in the data analysis.
HLA class I and II antigen serologic typing of donors and recipients
was performed by standard National Institutes of Health microlymphocytotoxicity; low-resolution generic oligotyping was used to
confirm the DRB1 identity in 38 donor/recipient pairs.
At time of BMT, patients' median age was 8 years (range 1-18 years).
Forty-seven of the 59 patients enrolled had ALL; 15 children were
transplanted in first CR, 28 in second CR, and the remaining 4 in third
CR. Twelve patients had AML; 9 were given BMT in first CR, and the
remaining 3 in second CR.
Karyotype analysis at diagnosis was available in 48 of the 59 children
(84%). For the purpose of this study, ALL patients with hyperdiploid
karyotype and AML patients with inversion of chromosome 16, translocation 8;21 and 15;17 were classified as having good prognosis
(7 cases). Chromosomal abnormalities classified as poor prognosis
features (7 cases) included ALL with translocation 9;22 and 4;11, as
well as AML with monosomy of chromosomes 5, 7, anomalies of 11q or
translocation 6;9. Patients with normal karyotype, t12;21 or other
cytogenetic abnormalities, as well as those with unavailable
cytogenetic data, were assigned to an intermediate risk category (45 cases, Table 1).
Pretransplant conditioning regimen consisted of: (1) fractionated total
body irradiation (TBI, 1200 cGy in 6 fractions over 3 days), thiotepa
(10 mg/kg in 2 divided doses), and cyclophosphamide (60 mg/kg/d for 2 days) in 29 cases; (2) fractionated TBI, vincristine (1.5 mg/m2 intravenously followed by 2.5 mg/m2
continuous infusion over 5 days), and cyclophosphamide (1800 mg/m2/d for 2 days) in 14 cases; and (3) busulfan (16 mg/kg
in 16 divided doses over 4 days), cyclophosphamide (60 mg/kg/d for 2 days), and melphalan (140 mg/m2 in a single dose) in the
remaining 16 cases. All patients received an unmanipulated marrow inoculum.
Further details on the characteristics of the patients and donors,
pretransplant disease history, and comparison between the 2 arms of the
study are reported in Table 1. The 2 groups were comparable for all the
variables studied.
Definitions
Myeloid and platelet engraftments were defined as the first of 3 consecutive days with neutrophils more than
0.5 × 109/L and unsupported platelets more than
50 × 109/L, respectively. Patients were considered
assessable for engraftment if they survived at least 7 days after the transplant.
Acute and chronic GVHD were classified according to previously
published criteria.18-20 Children with sustained donor
engraftment and surviving more than 14 days and more than 100 days
after the transplant were assessable for occurrence and severity of
acute and chronic GVHD, respectively.
The toxicity related to the transplant procedure was graded according
to the criteria proposed by Bearman and colleagues.21,22 Patients dying of any cause not related to leukemia recurrence were
considered as transplant-related deaths.
Statistical analysis
Data were analyzed as of August 31, 1998. EFS, TRM, RR, GVHD
occurrence, as well as neutrophil and platelet engraftment curves after
transplantation (starting point), were calculated by the Kaplan-Meier
method23 and compared using the log-rank test. In the EFS
analysis, both relapse and death in remission due to any cause were
considered treatment failures, whereas in the RR analysis, only disease
relapse was considered failure. In the TRM analysis, all deaths not due
to leukemia recurrence were considered failures. Results were expressed
as probability (%) and 95% confidence intervals (95% CI). A
multivariate Cox proportional hazard regression model24 was
also used separately for TRM, RR, and EFS, with the following
variables: diagnosis, disease status, donor sex and age, recipient sex
and age, Cs-A dose, and acute GVHD and chronic GVHD occurrence.
Student's t test and Mann-Whitney rank-sum test were used to
compare differences in continuous variables between groups, and
 2 test or Fisher exact test were used to compare
percentages, as appropriate. All P values were 2-sided and a
value less than .05 was considered statistically significant. P
values more than .1 were reported as not significant (NS), whereas
those between .05 and .1 were reported in detail. The SAS package (SAS
Institute, Cary, NC) was used for the analysis of the data.
| |
Results |
The median follow-up for Cs-A1 and Cs-A3 group patients was 44 months (range 21-66) and 43 months (range 23-63) for survivors (P = NS), and 9 months (range 1-20) and 8 months (range 1-40) for deceased patients (P = NS), respectively. Cs-A was
administered intravenously for a median of 17 days (range 6-45 days) to
patients belonging to the Cs-A1 group and for a median of 18 days
(range 11-62 days) to patients of the Cs-A3 group (P = NS).
Engraftment
Marrow engraftment was observed in all patients enrolled in the
study. Neutrophil recovery was achieved within 3 weeks in all children.
The median time for myeloid engraftment was 11 days (range 8-22 days)
and 10 days (range 7-19) for children belonging to the Cs-A1 and Cs-A3
group, respectively (P = NS). Platelet engraftment was
reached in 55 of the 59 patients analyzed, the remaining 4 patients
having died before platelet recovery. Median time for platelet
engraftment was 23 days (range 12-159 days) in the Cs-A1 group and 22 days (range 10-203 days) in the Cs-A3 group, with no significant
difference between the 2 arms.
GVHD
Grade II to IV acute GVHD developed in 28 (47%) of the 59 patients
at a median of 10 days after the transplant (range 7-26 days). This
resulted in a cumulative probability of 48% (35-60%) at 100 days
after BMT. Children randomized to the Cs-A1 group had a greater
cumulative probability of developing grade II to IV acute GVHD in
comparison to those belonging to the Cs-A3 group: 57% (39-74%) versus
38% (20-56%), respectively, P = .06 (Figure 1, top). Grade III to IV acute GVHD was
observed in 12 children (20%), 8 belonging to the Cs-A1 group and 4 to
the Cs-A3 group. The cumulative probability of developing grade III to
IV acute GVHD was 27% (11-43%) for the Cs-A1 group, and 14% (1-26%)
for the Cs-A3 group (P = NS). Median duration of grade II to
IV acute GVHD in surviving patients was 21 days (range 4-56) in the
Cs-A1 group and 26 days (range 5-74) in the Cs-A3 group
(P = NS).
View larger version (18K):
[in this window]
[in a new window]
| Fig 1.
Development of GVHD.
The cumulative probability of developing grade II to IV acute GVHD
(top) and chronic GVHD (bottom) for the Cs-A1 group (continuous line)
and the Cs-A3 group (dotted line) is shown. EV = number of events
occurring in each arm of randomization.
|
|
Table 2 shows the details on organ
involvement by acute GVHD. The Cs-A1 group had a higher incidence of
gastrointestinal (58% vs. 35%) and liver GVHD (42% vs. 17%), as
well as a greater frequency of involvement of at least 2 (65% vs.
39%) or 3 (39% vs. 9%) organs. However, only for the last comparison
(3-organ involvement) was the difference between the 2 arms
statistically significant (P < .05).
Three patients (5%) died due to grade IV acute GVHD on day +39, +40,
and +42, respectively. The first 2 children belonged to the Cs-A1 group
and the third to the Cs-A3 group.
First-line acute GVHD treatment consisted of corticosteroids in all
cases. Median duration of steroid treatment in surviving patients was
30 days (range 9-253) for Cs-A1 patients and 22 days (range 6-270) for
Cs-A3 patients (P = NS). Within the group of patients
experiencing acute GVHD, 59% of children belonging to the Cs-A1 group,
and 55% of those belonging to the Cs-A3 group increased Cs-A dosage.
Second-line treatment with antilymphocyte globulin or monoclonal
antibodies was started in the 3 children who subsequently died of acute
GVHD and in 1 patient belonging to the Cs-A3 group, who recovered from
grade III acute GVHD.
Chronic GVHD developed in 14 of the 53 assessable patients
(26%). In all cases, chronic GVHD followed acute GVHD and no case of
de novo disease was observed. The cumulative probability of developing
chronic GVHD was 28% (15-41%), with a median time from BMT to chronic
GVHD occurrence of 9 months (range 3-18 months). Eleven children, 6 in
the Cs-A1 group and 5 in the Cs-A3 group, had limited skin chronic
GVHD, and 3 children, 2 in the Cs-A1 group and 1 in the Cs-A3 group,
had the extensive form of the disease (Table 2). The Kaplan-Meier
estimate of chronic GVHD occurrence was 30% (13-47%) for the Cs-A1
group and 26% (7-43%) for the Cs-A3 group (P = NS; Figure
1, bottom). Median Karnofsky score of patients with chronic GVHD was
90% (range 50-100%), with no difference between the 2 randomization arms.
The CMV serologic status of the patients and their donors did not have
any influence on GVHD occurrence (data not shown).
Transplant-related morbidity and mortality
Regimen-related toxicity was mild or moderate and mainly limited to
mucosal and gastrointestinal involvement. Details on organ involvement
and severity, as well as comparisons between the 2 arms of the study,
are listed in Table 3. No difference was
observed in incidence and severity of toxicity between the 2 arms of
the study.
On the whole, 8 patients died in remission, as a result of nonleukemic
BMT-related causes, at a median of 2 months after transplantation (range 1-40 months). As mentioned above, acute GVHD was the major cause
of death in 3 children, and fatal infectious complications were
reported in the other 5 children. One child developed fatal P
carinii penumonia, 1 had CMV interstitial pneumonia, and 1 had aspergillus pneumonia. Bacterial infections were the reported cause of
death in the last 2 patients (Table 4).
The 1-year TRM probability was 12% (4-21%) for the entire study
population; it was 17% (3-30%) and 7% (0-16%) for the Cs-A1 and
Cs-A3 groups, respectively (P = NS, Figure
2). Because 1 more patient belonging to the
Cs-A3 group died in remission 40 months after the transplant due to a
bacterial infection, ultimately the 5-year probability of dying in
remission was identical in the 2 groups (17% for the Cs-A1 group and
14% for the Cs-A3 group, respectively, P = NS).
View larger version (23K):
[in this window]
[in a new window]
| Fig 2.
Probability of transplant-related mortality.
The cumulative 1-year probability of TRM is shown for the Cs-A1 group
(continuous line) and the Cs-A3 group (dotted line). EV = number of
events occurring in each arm of randomization.
|
|
Relapse probability
Fifteen of the 59 patients enrolled (25%) presented a
leukemia relapse at a median of 6 months after BMT (range 1.6-31 months), and the overall cumulative RR for the entire cohort of
patients enrolled in the study was 29% (16-41%). Four of the 15 relapsed patients were in the Cs-A1 group and 11 in the Cs-A3 group.
Cumulative RR was 15% (1-29%) for the Cs-A1 group and 41% (22-59%)
for the Cs-A3 group, respectively (P = .034, Figure
3). No difference was observed in the time
from BMT to relapse in the 2 randomization arms.
View larger version (21K):
[in this window]
[in a new window]
| Fig 3.
Probability of relapse.
Relapse probability is shown for the Cs-A1 group (continuous line) and
the Cs-A3 group (dotted line). EV = number of events occurring in
each arm of randomization.
|
|
Fourteen of the 15 relapsed patients died due to disease progression; 1 child is alive with disease present (Table 4).
Survival and EFS
Thirty-seven (63%) of the 59 enrolled patients are surviving after
BMT at a median of 44 months after the transplant (range 21-66 months).
The 5-year Kaplan-Meier estimate of survival is 61% (47-74%) for the
whole cohort of patients studied; it is 70% (54-86%) and 52%
(33-71%), respectively, for the Cs-A1 and the Cs-A3 group
(P = NS).
Thirty-six patients (61%) are alive in complete hematologic remission
at a median observation time of 44 months from BMT (range 21-66 months). The cumulative EFS probability at 5 years for the entire study
population is 59% (46-73%). Twenty-one (70%) of the 30 patients
belonging to the Cs-A1 group are alive and disease-free, whereas in the
Cs-A3 group, 15 (52%) of the 29 patients are alive in remission. The
5-year cumulative EFS probability is 70% (54-86%) for patients
belonging to the Cs-A1 group, and 51% (32-69%) for patients belonging
to Cs-A3 group, respectively (P = NS, Figure 4).
View larger version (22K):
[in this window]
[in a new window]
| Fig 4.
Event-free survival.
The EFS for the Cs-A1 group (continuous line) and the Cs-A3 group
(dotted line) is shown. EV = number of events occurring in each arm
of randomization.
|
|
No significant correlation was observed between sex, age at diagnosis,
age at transplant, leukocyte count at diagnosis, immunophenotype or
interval CR-transplant, and the clinical outcome of the patients, neither in univariate nor in multivariate models (data not shown).
Impact of diagnosis and GVHD
The analysis performed considering ALL patients separately from AML
patients showed results similar to those observed in the whole study
population. In fact, for the 47 patients affected by ALL the relapse
probability was 20% (2-37%) for the Cs-A1 group and 47% (25-68%)
for the Cs-A3 group (P = .06), whereas EFS was 67% (48-86%)
for the Cs-A1 group and 45% (23-66%) for the Cs-A3 group
(P = NS). Considering only the 12 patients affected by AML, the relapse probability was 0% for the Cs-A1 group and 17% (0-46%) for the Cs-A3 group, whereas EFS was 83% (54-100%) for the Cs-A1 group and 67% (29-100%) for the Cs-A3 group (P = NS in both cases).
Analyzing RR and EFS according to grade II to IV acute GVHD occurrence,
irrespective of the arm of randomization, no difference was observed
between patients developing grade II to IV acute GVHD and those without
or with grade I acute GVHD. The 5-year RR was 30% (13-46%) for
patients without or with grade I acute GVHD and 26% (8-44%) for those
with grade II to IV acute GVHD, respectively (P = NS); EFS
was 67% (51-84%) and 51% (31-71%) for subjects without or with
grade I acute GVHD and for those with grade II to IV acute GVHD,
respectively (P = NS).
By contrast, irrespective of the arm of randomization, the
analysis of relapse and disease-free survival according to chronic GVHD
occurrence showed a RR of was 33% (17-48%) for patients without chronic GVHD and 7% (0-21%) for those with chronic GVHD
(P = 0.07). In the same way, EFS was 63% (47-78%) for
patients without chronic GVHD and 83% (60-100%) for those with
chronic GVHD (P = 0.09).
| |
Discussion |
Despite relapse, TRM, and GVHD occurrence, allogeneic BMT from
HLA-identical siblings is curative in 50% to 70% of children with
acute leukemia in first or second CR.22,25-29
New conditioning regimens are under evaluation for the treatment of
acute leukemia. However, it is difficult to achieve a significant
improvement of EFS only by means of more intensive conditioning
regimens. For this reason, there is considerable interest in the
optimal strategy to prevent severe GVHD, but sparing at best the GVL
reaction.13,14
Cyclosporine-A, alone or in combination with methotrexate, is the most
frequently used drug for prophylaxis of acute GVHD. Nevertheless,
little consensus remains on the scheduling, dosage, and blood levels of
the drug. Bacigalupo et al demonstrated in a cohort of adult patients
given Cs-A alone as GVHD prophylaxis that the drug dosage during the
first 10 days after BMT has a critical impact on the clinical outcome
of the transplant procedure.16 In fact, in their
experience, adult patients receiving Cs-A at a dose of 1 mg/kg/d had a
significantly lower risk of relapse, a comparable TRM, and, when
transplanted in first CR, a significantly better probability of EFS as
compared to patients who received Cs-A at the dose of 5 mg/kg/d. An
updated analysis of this study demonstrated that the survival advantage
for the group given the lower Cs-A dose persists in the subgroup of
younger patients.30
This trial compared the standard dosage of Cs-A used in children (3 mg/kg/d) during the first 3 weeks after BMT, with a significantly lower
dose (1 mg/kg/d). Results show that the reduction of Cs-A dosage during
the first 3 weeks after BMT determined a significant decrease (26%) in
the RR for patients treated with 1 mg/kg/d. As expected, the Cs-A1
group patients had lower blood levels of the drug (data not shown), and
they did experience a higher incidence of grade II to IV acute GVHD.
Moreover, these patients had a greater incidence of gut and liver acute
GVHD. However, the TRM directly attributable to acute GVHD was very
limited: only 3 patients, 5% of the whole study population, died from
this complication. The mortality due to infections, which in some
cases could be related to the development of acute or chronic
GVHD or to its treatment, was similar in the 2 groups as well, and the
reduction of Cs-A dosage did not translate either into a longer period
of steroid therapy for GVHD or into a higher incidence of chronic GVHD.
In comparison to patients in the higher Cs-A dose group, the lower RR
of patients belonging to Cs-A1 arm resulted in a 19% advantage in
5-year Kaplan-Meier estimate of EFS. Because children in the lower
Cs-A1 dose group had a greater 1-year TRM, we cannot exclude that, with
a greater number of patients, the advantage offered by the reduced RR
would be offset by an increased number of transplant-related deaths.
To our knowledge, this is the only prospective randomized study
performed on a pediatric population and specifically aimed at comparing
2 different GVHD prophylaxis regimes in children with acute leukemia
undergoing BMT. This consideration is particularly noteworthy also
because, as shown by the retrospective analysis by Ringdén et
al,31 data on GVHD prophylaxis obtained in an adult
population are not directly transferable to children.
It is reasonable to hypothesize that the reduction of RR in our
patients was due to an increased GVL effect, capable of suppressing residual leukemia cells that escaped the cytotoxic effect of
myeloablative therapy. As far as the biologic mechanisms of GVL effect
are concerned, 3 distinct components have been proposed by Horowitz et
al8: (1) an antileukemia effect related to the development
of GVHD and mediated by the action of donor lymphocytes toward
recipient widely distributed tissue antigens; its magnitude correlates
with disease severity, and both acute and chronic GVHD are involved in
the destruction of residual leukemia cells; (2) an allogeneic antileukemia effect, independent of clinically evident GVHD and directed against leukemia-associated or tissue-restricted
antigens; and (3) an antileukemia effect of T cells, independent
of GVHD and impaired by T-cell depletion. In that retrospective
analysis, the greatest antileukemia effect was observed in chronic
myeloid leukemia (CML), an intermediate effect in AML, and the smallest effect in ALL.8 Furthermore, in ALL no evidence was found
for GVL occurring without clinically manifest GVHD.8,32
Cyclospoine-A can interfere with the GVL response. In fact, this agent,
modulating the lymphocyte expansion through inhibition of production of
interleukin-2 and its receptor and increasing production of
transforming-growth factor  , may negatively
influence T-cell function. Further evidence to the negative effect of
Cs-A on GVL effect is provided by the observation that some relapsed patients have been put into a new remission by abrupt Cs-A
discontinuation, often in association with the appearance of signs of
GVHD.20,33
The analysis performed without considering the arm of randomization
showed similar relapse rates in patients with grade 0 to I acute GVHD
and in those with grade II to IV disease. This finding suggests that
the stronger GVL effect observed in patients belonging to the Cs-A1
group could be independent from the development of acute GVHD or,
alternatively, could be ascribable to a subclinical GVHD. Subjects who
did develop chronic GVHD had a lower probability of relapse after the
transplant than those who did not. Nevertheless, chronic GVHD incidence
in the 2 arms of the study was similar, with only a 4.5% higher
probability in the arm receiving the lower Cs-A dosage.
In conclusion, this study indicates that in pediatric patients, who
probably have immunologic advantages for the induction of tolerance in
comparison to adults, the use of Cs-A at 1 mg/kg/d is able to reduce
the risk of leukemia recurrence, likely through an enhanced GVL effect.
Whether this advantage in terms of leukemia control results into a
better EFS remains to be definitively proved.
| |
Footnotes |
Submitted July 7, 1999; accepted November 2, 1999.
Supported in part by grants from AIRC (Associazione Italiana
Ricerca sul Cancro) and IRCCS Policlinico S. Matteo to F.L.
Reprints: Franco Locatelli, Dipartimento di Scienze
Pediatriche, Università di Pavia, IRCCS Policlinico San Matteo, P.le Golgi, 2, I-27100 Pavia, Italy; e-mail:
f.locatelli{at}smatteo.pv.it.
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.
| |
References |
1.
Locatelli F, Uderzo C, Dini G, et al.
Graft-versus-host disease in children: the AIEOP-BMT Group experience with cyclosporin A.
Bone Marrow Transplant.
1993;12:627[Medline]
[Order article via Infotrieve].
2.
Ringdén O, Deeg HJ.
Clinical spectrum of graft-versus-host disease. In:
Ferrara JL,Deeg HJ,Burakoff SJ, eds.
Graft-vs.-Host Disease. New York, NY: Marcel Dekker; 1997:525.
3.
Rowlings PA, Przepiorka D, Klein JP, et al.
IBMTR severity Index for grading acute graft-versus-host disease: a retrospective comparison with Glucksberg grade.
Br J Haematol.
1997;97:855[Medline]
[Order article via Infotrieve].
4.
Martin PJ, Schoch G, Fisher L, et al.
A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment.
Blood.
1990;76:1464[Abstract/Free Full Text].
5.
Martin PJ, Schoch G, Fisher L, et al.
A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment.
Blood.
1991;77:1821[Abstract/Free Full Text].
6.
Doney K, Fisher LD, Appelbaum FR, et al.
Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation: multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival.
Bone Marrow Transplant.
1991;7:453[Medline]
[Order article via Infotrieve].
7.
Sullivan KM, Weiden PL, Storb R, et al.
Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia.
Blood.
1989;73:1720[Abstract/Free Full Text].
8.
Horowitz MM, Gale RP, Sondel PM, et al.
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood.
1990;75:555[Abstract/Free Full Text].
9.
Ringdén O, Labopin M, Gluckman E, et al.
Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis.
Bone Marrow Transplant.
1996;18:921[Medline]
[Order article via Infotrieve].
10.
Zikos P, van Lint MT, Lamparelli T, et al.
Allogeneic hematopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: favorable impact of chronic graft-versus-host disease on survival and relapse.
Haematologica.
1998;83:896[Abstract/Free Full Text].
11.
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED.
Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.
N Engl J Med.
1981;304:1529[Medline]
[Order article via Infotrieve].
12.
Ringdén O, Labopin M, Gluckman E, et al.
Strong antileukemic effect of chronic graft-versus-host disease in allogeneic marrow transplant recipients having acute leukemia treated with methotrexate and cyclosporine: The Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
Transplant Proc.
1997;29:733[Medline]
[Order article via Infotrieve].
13.
Truitt RL, Johnson BD, McCabe CM, Weiler MB.
Graft-versus-leukemia. In:
Ferrara JL,Deeg HJ,Burakoff SJ, eds.
Graft-vs.-Host Disease. New York, NY: Marcel Dekker; 1997:385.
14.
Barrett AJ, Malkovska V.
Graft-versus-leukaemia: understanding and using the alloimmune response to treat haematological malignancies.
Br J Haematol.
1996;93:754[Medline]
[Order article via Infotrieve].
15.
Ruutu T, Niederweiser D, Gratwohl A, Apperley JF.
A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow Transplantation (EBMT).
Bone Marrow Transplant.
1997;19:759[Medline]
[Order article via Infotrieve].
16.
Bacigalupo A, van Lint MT, Occhini D, et al.
Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia.
Blood.
1991;77:1423[Abstract/Free Full Text].
17.
Locatelli F, Percivalle E, Comoli P, et al.
Human cytomegalovirus (HCMV) infection in paediatric patients given allogeneic bone marrow transplantation: role of early antiviral treatment for HCMV antigenaemia on patients' outcome.
Br J Haematol.
1994;88:64[Medline]
[Order article via Infotrieve].
18.
Glucksberg H, Storb R, Fefer A, et al.
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.
Transplantation.
1974;18:295[Medline]
[Order article via Infotrieve].
19.
Shulman HM, Sullivan KM, Weiden PL, et al.
Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients.
Am J Med.
1980;69:204[Medline]
[Order article via Infotrieve].
20.
Aoki Y, Takahashi S, Okamoto S, Asano S.
Graft-versus-leukemia after second allogeneic bone marrow transplantation [letter].
Blood.
1994;84:3983[Free Full Text].
21.
Bearman SI, Appelbaum FR, Buckner CD, et al.
Regimen-related toxicity in patients undergoing bone marrow transplantation.
J Clin Oncol.
1988;6:1562[Abstract/Free Full Text].
22.
Zecca M, Pession A, Messina C, et al.
Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission given bone marrow transplantation from HLA-identical siblings.
J Clin Oncol.
1999;17:1838[Abstract/Free Full Text].
23.
Kaplan EL, Meyer P.
Nonparametral estimation from incomplete observations.
J Am Stat Assoc.
1958;53:457.
24.
Cox DR.
Regression model and life tables (with discussion).
J R Stat Soc B.
1972;34:187.
25.
Pui C-H.
Childhood leukemias.
N Engl J Med.
1995;332:1618[Free Full Text].
26.
Barrett AJ, Horowitz MM, Pollock BH, et al.
Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in second remission.
N Engl J Med.
1994;331:1253[Abstract/Free Full Text].
27.
Dini G, Boni L, Abla O, et al.
Allogeneic bone marrow transplantation in children with acute myelogenous leukemia in first remission: Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO).
Bone Marrow Transplant.
1994;13:771[Medline]
[Order article via Infotrieve].
28.
Uderzo C, Valsecchi MG, Bacigalupo A, et al.
Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.
J Clin Oncol.
1995;13:352[Abstract/Free Full Text].
29.
Uderzo C, Valsecchi MG, Balduzzi A, et al.
Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission.
Br J Haematol.
1997;96:387[Medline]
[Order article via Infotrieve].
30.
Zikos P, van Lint MT, Frassoni F, et al.
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.
Blood.
1998;91:3503[Abstract/Free Full Text].
31.
Ringdén O, Horowitz MM, Sondel P, et al.
Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?
Blood.
1993;81:1094[Abstract/Free Full Text].
32.
Fester A, Bujan W, Moreaux T, Devlack CH, Heimann P, Sariban E.
Complete remission following donor leukocyte infusion in ALL relapsing after haploidentical bone marrow transplantation.
Bone Marrow Transplant.
1994;14:331[Medline]
[Order article via Infotrieve].
33.
Collins RH Jr, Rogers ZR, Bennett M, Kumar V, Nikein A, Fay JW.
Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression.
Bone Marrow Transplant.
1992;10:391[Medline]
[Order article via Infotrieve].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. E. Seif, D. M. Barrett, M. Milone, V. I. Brown, S. A. Grupp, and G. S. D. Reid
Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responses
Blood,
September 17, 2009;
114(12):
2459 - 2466.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Porta, F. Locatelli, and G. R. Burgio
Hematopoietic stem cell transplantation: 40 years of continuous progress and evolution
Haematologica,
November 1, 2008;
93(11):
1607 - 1610.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dominietto, S. Pozzi, M. Miglino, F. Albarracin, G. Piaggio, F. Bertolotti, R. Grasso, S. Zupo, A. M. Raiola, M. Gobbi, et al.
Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia
Blood,
June 1, 2007;
109(11):
5063 - 5064.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bader, H. Kreyenberg, W. Hoelle, G. Dueckers, R. Handgretinger, P. Lang, B. Kremens, D. Dilloo, K.-W. Sykora, M. Schrappe, et al.
Increasing Mixed Chimerism Is an Important Prognostic Factor for Unfavorable Outcome in Children With Acute Lymphoblastic Leukemia After Allogeneic Stem-Cell Transplantation: Possible Role For Pre-Emptive Immunotherapy?
J. Clin. Oncol.,
May 1, 2004;
22(9):
1696 - 1705.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-J. Kolb, C. Schmid, A. J. Barrett, and D. J. Schendel
Graft-versus-leukemia reactions in allogeneic chimeras
Blood,
February 1, 2004;
103(3):
767 - 776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zecca, A. Prete, R. Rondelli, E. Lanino, A. Balduzzi, C. Messina, F. Fagioli, F. Porta, C. Favre, A. Pession, et al.
Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome
Blood,
July 30, 2002;
100(4):
1192 - 1200.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Hoelzer, N. Gokbuget, O. Ottmann, C.-H. Pui, M. V. Relling, F. R. Appelbaum, J. J.M. van Dongen, and T. Szczepanski
Acute Lymphoblastic Leukemia
Hematology,
January 1, 2002;
2002(1):
162 - 192.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bacigalupo, T. Lamparelli, F. Gualandi, S. Bregante, A. Raiola, C. di Grazia, A. Dominietto, C. Romagnani, D. Occhini, F. Frassoni, et al.
Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study
Blood,
November 15, 2001;
98(10):
3174 - 3174.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Storb, R. Champlin, S. R. Riddell, M. Murata, S. Bryant, and E. H. Warren
Non-Myeloablative Transplants for Malignant Disease
Hematology,
January 1, 2001;
2001(1):
375 - 391.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction