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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2236-2246
Children With Acute Lymphoblastic Leukemia Who Receive T-Cell-Depleted
HLA Mismatched Marrow Allografts From Unrelated Donors Have an
Increased Incidence of Primary Graft Failure but a Similar Overall
Transplant Outcome
By
Ann Green,
Emer Clarke,
Linda Hunt,
Andrew Canterbury,
Alan Lankester,
Geoff Hale,
Herman Waldmann,
Sally Goodman,
Jacqueline
M. Cornish,
David I. Marks,
Colin G. Steward,
Anthony Oakhill, and
Derwood H. Pamphilon
From the National Blood Service and Institute for Transfusion
Sciences, Bristol; the Division of Child Health, University of Bristol,
Bristol, UK; Sir William Dunn School of Pathology, University of
Oxford, Oxford, UK; and the Royal Hospital for Sick Children,
Bristol, UK.
 |
ABSTRACT |
Disparity for HLA in unrelated donor bone marrow transplantation
(BMT) increases the risk of graft rejection and graft-versus-host disease (GVHD) and may compromise transplant outcome. We have compared
the outcome of matched and mismatched transplants from unrelated donors
in 137 children with acute lymphoblastic leukemia (ALL). Their disease
status was complete remission (CR)-1, 24 patients;
CR-2, 88 patients; CR-3, 18 patients; CR-4, 2 patients; and relapse, 5 patients. CAMPATH monoclonal antibodies were
used for T-cell depletion and cyclosporin A was given to 134 children together with short-course methotrexate in 43, mainly when there was
HLA disparity. Fifty-two donor/recipient pairs were HLA-mismatched, 41 at HLA-A and -B and 11 at HLA-DR and -DQ loci. Overall graft failure
was increased in recipients of marrow mismatched at either HLA-A, -B,
-DR, or -DQ (15.7% v 4.8%; P = .057) mainly
because there was a higher proportion of children with primary graft
failure (11.8% v 1.2%; P = .012). The presence of
an HLA-C locus mismatch did not independently increase the likelihood
of graft failure. There was no significant difference in the
incidence of acute GVHD  grade 2 between the matched and
mismatched groups (P = .849). For patients in CR-2,
the risk of relapse post-BMT was significantly lower if leukemic
relapse occurred off-treatment (P = .005). The
Kaplan-Meier overall and leukemia-free survival (LFS)
estimates for recipients of matched and mismatched BMT, respectively, at 36 months were 49% versus 42% (P = .380) and 45% versus 40% (P = .654).
Although HLA mismatching results in an increased occurrence of primary
graft failure with T-cell-depleted allografts, it allows more donors
to be identified rapidly for children with ALL without
compromising overall transplant outcome.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
CHEMOTHERAPY FOR CHILDREN with acute
lymphoblastic leukemia (ALL) has dramatically improved outcome over the
past 20 years so that, on nationally directed protocols, cure rates of 70% to 80% can be expected.1,2 The main cause of
treatment failure is disease relapse and when this occurs on, or
shortly after, stopping treatment, subsequent cures are unlikely to be achieved with further chemotherapy.3,4 Allogeneic bone
marrow transplantation (BMT) is most frequently performed in children with relapsed ALL, and several reports have indicated that survival is
improved when compared with chemotherapy alone.5-7 A
proportion of children with ALL in first complete remission (CR-1) have
features that suggest they are at increased risk of
relapse.8 These include infant ALL associated with
11q23/MLL rearrangement or Philadelphia-positive ALL, both in
children9,10 and adults,10 and studies have
suggested that allogeneic BMT can improve long-term disease-free
survival in these patients. The majority, however, lack a matched
sibling donor (MSD) and the use of unrelated donor marrow has been
explored.10-13 Data from prospective randomized studies are
lacking and the role of unrelated donor BMT remains controversial.
Moreover, in children with high-risk ALL, it is often not possible to
identify rapidly a molecularly HLA-A, -B, -DR, and -DQ matched donor.
Available reports to date using both matched and mismatched unrelated
donor marrow show that leukemia-free survival (LFS) in the range 23%
to 40% can be achieved.14-16
The outcome of unrelated donor BMT for leukemia depends on the
transplant protocol used. The use of T-replete bone marrow has been
associated with a higher incidence of severe acute graft-versus-host disease (GVHD).11,17 With both T-depleted and
T-replete marrow, an increase in graft failure has been documented when
compared with MSD BMT.11-13 Mismatching for HLA-A, -B, and
-C has been associated with a higher risk of graft
failure.18-20 The incidence and severity of acute GVHD is
also higher in most reported series where HLA-A, -B, -C, or -D
incompatibility is present,17,21-26 although in 1 recent
report of patients with chronic myeloid leukemia, the presence of a
single HLA-A or -B mismatch did not increase the risk.27
Other factors such as the type of posttransplant immunosuppression and
marrow cell dose may also have a significant effect on
outcome.28 We have previously reported our results for
unrelated donor BMT in a group of 52 children with ALL in second
complete remission.29 In this report, we extend our
observations to 137 consecutive first transplants in children less than
18 years of age in CR-1, 2, 3, 4, or relapse receiving bone marrow
either matched (85) or mismatched (52) for HLA-A, -B, -DR, and -DQ
antigens from unrelated donors. Our results show that while primary
graft failure is higher in recipients of mismatched grafts, overall
survival (OS) is similar.
| |
MATERIALS AND METHODS |
Patients.
A total of 147 children with ALL had unrelated donor transplants
between October 1988 and July 1997. Informed consent was obtained
in each case. Most received similar conditioning therapy and grafts
depleted of T cells using CAMPATH antibodies. Ten patients who received
either T-cell-replete marrow (1), CD34+-selected grafts
(4), or were recipients of second transplants (5) were excluded
from analysis. Patients were aged 1 to 17 years (median, 8 years). The
male:female ratio was 87:50. Disease status was as follows: CR-1, 24 cases; CR-2, 88 cases; CR-3, 18 cases; CR-4, 2 cases; and relapse, 5 cases (Table 1). Ninety-four patients relapsed in the bone marrow either alone or additionally in the central
nervous system (CNS) (21 patients) or testes (11 patients) or both (3 patients). Fourteen and 4 children
had isolated CNS and testicular relapses, respectively, and 1 relapsed
in both sites. Children were only transplanted for isolated testicular relapse if this occurred on, or within, 3 months of stopping
chemotherapy. Patients were transplanted in first complete remission
when 1 of the following factors was present: t(4;11) in infancy (n = 4), t(9;22) (n = 7), failure to remit using standard therapy (n = 6),
high Oxford Hazard Score (n = 4),30 or biphenotypic
leukemia (n = 1). In 2 further patients, high presenting leukocyte
counts (> 70 × 109/L and 250 × 109/L) were associated with trisomy 8 and trisomy 2 and 16, respectively.30 For patients in CR-1, the median time from
diagnosis to transplant was 214 days (range, 63 to 598). The median
time from diagnosis to relapse for children in CR-2 was 824 days
(range, 152 to 2,011) and from relapse to BMT, 166 days (range, 60 to
651). These intervals did not differ between matched and mismatched
patients (Table 1). The median follow-up of survivors is 38 months
(range, 6 to 104).
Donor selection.
This was from the British Bone Marrow Registry in 68 cases and the
Anthony Nolan Bone Marrow Trust in 69 cases. Seventy-one donors were
male and 65 were female. In 1 case, information on donor gender was not
available. If HLA-A, -B, -DR, and -DQ matched donors could not be
identified, we aimed to select those matched at HLA-DR and -DQ wherever
possible. The majority of mismatches in this series is, therefore, at
HLA-A and -B. HLA typing was the major selection criterion, then
preference was given to younger, male donors. Cytomegalovirus
(CMV)-seronegative patients preferentially received
marrow from CMV-seronegative donors (Table 1).
Histocompatibility studies.
We initially used serologic testing using 2-stage National Institutes
of Health (NIH) complement-dependent
microlymphocytotoxicity for HLA-A and -B loci and restriction fragment
length polymorphism (RFLP) for HLA-DR and -DQ as
previously described.31 Subsequently, typing using
polymerase chain reaction (PCR) and sequence-specific primers (SSP) was
used and where samples were available, retrospective HLA-C typing by
PCR-SSP was performed.31,32 Overall, for HLA-A and -B, 116 donor/recipient pairs were typed by serology and 21 using PCR-SSP; 82 donor/recipient pairs were HLA-C typed retrospectively using PCR-SSP.
For class II antigens, 40 donor/recipient pairs were typed using RFLP
and 97 using PCR-SSP. The definition of HLA-A and -B was similar using
serological and molecular techniques, as molecular typing was usually
performed at low/medium resolution to determine specificity at the
antigen rather than the allele level. Similarly, HLA-C, -DR, and -DQ
typing was performed at a comparable resolution. For statistical
analysis of HLA typing methodology, patients transplanted before
October 22, 1993 when serology and RFLP typing were used, were compared
with the remainder who were predominantly typed by SSP.
Conditioning regimens.
All children received CAMPATH-1G monoclonal antibody (5 to 20 mg/d
depending on body weight) on day  9 to 5 and
cyclophosphamide 60 mg/kg on days 6, 5 with hydration and
mesna (160% of the cyclophosphamide dose). Total body irradiation
(TBI) of 1,440 cGy was given in 8 fractions on day 3 to 0 at 20 cGy/min, except in 9 children less than 4 years old who received single
fraction TBI (1,000 cGy; 5 to 8 cGy/min) instead on day 1 and 3 children less than 3 years old who were conditioned with
cyclophosphamide and busulphan; the dose of busulphan being 4 to 5 mg/kg/d for 4 days as described previously.29
Engraftment.
Patients were considered evaluable for engraftment if they survived for
at least 28 days posttransplant. Neutrophil engraftment was defined as
absolute neutrophil count (ANC) 0.5 × 109/L on 3 consecutive measurements. Primary graft failure was defined as failure
to reach ANC 0.5 × 109/L at any time and secondary
graft failure sustained loss of neutrophils to <0.1 × 109/L after initial engraftment had occurred.
GVHD prophylaxis and grading.
Bone marrow was harvested and processed as previously
described.29 The total nucleated counts
(TNC) harvested were calculated for each recipient
(Table 1). Donor marrow was depleted of T cells ex vivo using
CAMPATH-1M (116 of 137) and CAMPATH-1G (18 of 137) monoclonal
antibodies together with third-party group AB serum as a source of
complement as previously described.33 In 18 transplants,
CAMPATH-1G was used instead of CAMPATH-1M due to a concern
(subsequently unsubstantiated) regarding in vitro efficiency of T-cell
lysis. CAMPATH-1M was then reintroduced and has been used since. Three
patients received a T-cell addback of 0.1 to 0.5 × 106 cells/kg on day 0 as part of a study investigating the
impact of T-cell addition on graft rejection and GVHD34 and
in 3 transplants, recipients were given CAMPATH-1G monoclonal
antibody (5 to 20 mg/d) from day 5 to day +4 to achieve in
vivo T-cell depletion.
Cyclosporin A (CSA) was given to all patients except 3, transplanted
early in the program when it was not routinely given, who received no
posttransplant immunosuppression. In the remainder, it was given from
day 1 to between 3 to 6 months post bone marrow transplant, and
then tapered over 3 months in the absence of GVHD. Levels were
measured twice weekly and dosage modified to maintain therapeutic
levels. We gave 3 doses of intravenous methotrexate 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6 to
37 patients because of HLA mismatch. In 6 patients who received matched
grafts, methotrexate was given at the physician's discretion. Acute
and chronic GVHD were graded using standard
criteria.35,36 Patients were considered evaluable for
chronic GVHD if they engrafted and survived for 100 days.
Supportive care and follow-up.
This was as previously described.29 Briefly, all patients
were transplanted in high-efficiency particle air filtration rooms. CMV-seronegative blood products were given to all patients until April
1996 after which CMV-seronegative red blood cells and
leukodepleted platelet concentrates were used. This change in policy
has not resulted in any CMV infection or disease
in CMV-seronegative donor/recipient pairs (unpublished data,
1999). For patients at high risk of CMV infection,
prophylaxis with intravenous immunoglobulin (IVIg) 200 mg/kg every 3 weeks from day 1 to day +90 and IV aciclovir 500 mg/m2 every 8 hours was given.
Surveillance cultures of buffy coat and throat swabs were performed
weekly and bronchoalveolar lavage (BAL) at 1, 2, and 3 months. More
recently, PCR screening of blood samples twice weekly
has replaced BAL.37 CMV reactivation was treated with
ganciclovir 5 mg/kg twice a day for 14 days, then daily for 14 more
days, and IVIg was administered if there was evidence of pneumonitis.
Ciprofloxacin, itraconazole, and aciclovir were given prophylactically
to all children; cotrimoxazole was given from day +28 to 6 months and
then lifelong penicillin V was started. Granulocyte
colony-stimulating-factor (G-CSF) was started at day
+10 until the ANC was >1 × 109/L for 3 days. Bone
marrow biopsies were performed at 1, 2, 3, 6, 9, and 12 months
posttransplant and every 6 months thereafter or when indicated.
Statistics.
Primary outcome measures of engraftment and GVHD were analyzed using
continuity corrected  2 tests or, where frequencies were
small, 2-tailed Fisher's Exact tests. Between subgroup comparisons of
patient ages, T-cell counts, and TNC subgroups were made using
Mann-Whitney U-tests.
A limited series of multivariable analyses were performed as
appropriate and with consideration given to the number of events per
variable.38 Logistic regression was used for binary outcome (graft failure and acute GVHD). For time to engraftment, survival, and
event-free survival, univariable analyses were performed by constructing Kaplan-Meier curves for subsets of patients and comparing them using logrank tests. Multivariable analysis was performed using
the Cox Proportional Hazards model.
| |
RESULTS |
HLA typing.
HLA-C typing was performed retrospectively in 82 donor/recipient pairs where sufficient archival material was
available. Transplants are referred to as matched where there was
HLA-A, -B, -DR, and -DQ identity. The additional impact of HLA-C
mismatching in both matched and mismatched groups was then evaluated.
Eighty-five donor/recipient pairs were matched and 52 mismatched. There
were 17 mismatched at HLA-A, 16 at -B, 7 at -A+B, 5 at -DR, 5 at -DQ, 1 at +DR+DQ, and 1 at -B+DQ. Sixteen (30.2%) of 53 matched
donor/recipient pairs were mismatched at HLA-C compared with 22 (75.9%) of 29 in the mismatched group. Of the 17 HLA-A mismatches 12 of 17 were at the specificity level as defined by World Health
Organization (WHO) nomenclature39; 9 of 12 were serologically defined and 3 of 12 were defined by PCR-SSP. Five of
12 were mismatches between antigens, which were within the same
cross-reactive epitope groups. Of the 16 HLA-B mismatched pairs, there
were 18 mismatches (2 pairs were mismatched for both HLA-B
specificities). Only 2 of these mismatches were within the same
cross-reactive epitope groups. Of 7 pairs that were HLA mismatched for
both HLA-A and -B, 4 of 7 were within cross-reactive epitope groups,
and 3 mismatches were serologically unrelated. None of the HLA-A and -B
antigens were typed to the allele level. All HLA-C mismatches were
defined by PCR-SSP and were allelic. Of 12 HLA-DR and/or -DQ mismatched pairs, 1 was an HLA-DR mismatch defined by RFLP and 5 were allelic mismatches of DRB1. Seven of 12 mismatches were of HLA-DQ and were
defined by RFLP.
Engraftment.
One hundred thirty-five patients who survived for a minimum of 28 days
posttransplant were considered evaluable for engraftment. One hundred
twenty-three children engrafted including 80 of 84 (95.2%) in the
matched group and 43 of 51 (84.3%) in the mismatched group;
Table 2. We considered the proportion of
all patients with primary graft failure and then secondary graft
failure, omitting patients with primary graft failure from the
denominator. There was a higher proportion of children with primary
graft failure in the mismatched group (P = .012). The
proportion of patients with any graft failure was also higher in the
mismatched group, largely reflecting the increase in primary graft
failure (P = .057; see above). There was no difference in the
occurrence of secondary graft failure (P = 1.000).
Graft failure occurred in 0 of 17 patients with an HLA-A mismatch
alone, in 4 of 16 children mismatched for HLA-B, 1 of 6 mismatched for
HLA-A plus -B, 1 of 1 mismatched for HLA-B and -DQ, and 2 of 11 mismatched for HLA-DR or -DQ. Using Bonferronis' adjustment of
Fisher's exact test, there was a borderline association between
mismatch for HLA-B and any graft failure (P = .063), but not
for HLA-A or -DR or -DQ when each was compared separately with the
matched group. The difference was more significant when primary graft
failure alone was considered (P = .039) (data not shown).
We examined the effect of HLA-C matching where data were available (80 of 137 cases). In cases matched at -C, 95.2% had durable engraftment;
there was no primary graft failure, and 4.8% had secondary graft
failure. In those mismatched at -C, the respective proportions were
84.2%, 10.5%, and 5.3%. There was a significantly increased chance
of primary graft failure in recipients of an HLA-C mismatched graft
(P = .047; Table 2). No differences were seen for secondary
(P = 1.000) and any (P = .141) graft failure. We also subdivided both the -A, -B, -DR, and -DQ matched and mismatched groups of children into those who were either matched, mismatched, or
not tested for HLA-C. There was no significant effect of HLA-C matching
with either group (Table 2), but numbers of patients were small.
Multivariable analysis was not possible. Use of methotrexate was
associated with an incidence of primary (P = .030), but not secondary (P = .320) or any (P = .515) graft failure.
However, methotrexate was given mostly to recipients of mismatched
grafts (Table 1). A logistic regression analyis was possible with
overall graft failure and showed that mismatching was significantly
associated with any graft failure (adjusted odds ratio, 5.2; 95%
confidence interval, 1.1 to 24.0; P = .036), whereas
methotrexate administration was not significantly associated
(P = .471). We also analyzed whether disease status,
donor/recipient CMV status, donor gender, HLA methodology, patient age,
TNC dose, and postgraft immunosuppression influenced engraftment.
Patients with primary graft failure had a higher TNC in univariable
analysis (P = .069), but any effect of cell dose was not
significant when adjusted for the HLA matching in a logistic regression
analysis (P = .290).
Of 4 children in the matched group who rejected their grafts, 3 were
rescued with autologous marrow, while 1 relapsed shortly after day 28. In the mismatched group, 7 children with graft rejection had autologous
marrow rescue and 1 relapsed shortly after day 28. Only 1 of these 12 children survives; of the remainder, 8 died either due to relapse after
first BMT and 3 due to treatment-related toxicity or relapse after a
second unrelated donor BMT.
The median time to engraftment was 15 days. We constructed Kaplan-Meier
curves to compare the kinetics of engraftment between recipients of
matched versus mismatched grafts and in children who received
methotrexate versus those who did not. There was no difference in time
to engraftment between recipients of matched and mismatched grafts
(P = .461), but there was a suggestion of slower engraftment
for patients who received methotrexate in both groups. Overall,
patients who received methotrexate engrafted more slowly, median, 16 days (95% confidence interval, 15 to 18 days) versus 15 days (95%
confidence interval, 15 to 16 days) (P = .037;
Fig 1). Seventy-five percent of patients
who received methotrexate engrafted by day 22 (95% confidence
interval, 18 to 27 days) compared with day 18 for those who did not
receive methotrexate (95% confidence interval, 17 to 20 days). These
variables were also considered in a multivariable Cox Proportional
Hazard model. This confirmed that methotrexate significantly delayed engraftment (P = .046), whereas HLA mismatching did not
(P = .425).
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| Fig 1.
Kaplan-Meier plots of the rate of engraftment in patients
receiving methotrexate (MTX+) versus those who did not
(MTX ). The difference is significant (P = .037).
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GVHD.
One hundred twenty-three children were evaluable for acute GVHD; 80 in
the matched and 43 in the mismatched group. No significant effect of
HLA-A, -B, -DR, and -DQ or HLA-C matching was seen
(Table 3). A multivariable analysis using
HLA-A, -B, -DR, and -DQ matching and HLA-C matching as variables was
performed and neither were significant (data not shown). Use of
methotrexate did not affect the probability of grade 2-4 acute GVHD
(Table 3) and when matching and methotrexate administration were
analyzed together in a logistic regression, neither were significant
(data not shown). The incidence of acute GVHD was not significantly
influenced by remission status, donor/recipient CMV status, donor
gender, or HLA-typing methodology (Table 3). TNC and patient age did
not differ between children with grade 0-1 versus those with grade 2-4 acute GVHD (TNC 5.01 [1.90 to 14.99] v 4.97 [2.64 to
14.86], respectively, P = .928; patient age 8 [1 to 17]
v 8.5 [1 to 16] years, respectively, P = .747;
figures given as median [range]). A series of logistic regression
analyses were performed to look at the effect of HLA matching with
adjustments for the other variables listed in Table 3, and none were
found to be significant. The incidence of grade 3-4 acute GVHD for the
matched and mismatched groups was 2.5% versus 7.0%, respectively
(P = .342).
Thirteen of 113 (12%) evaluable patients developed chronic GVHD. In 6 (5%), it was extensive (3 survive) and in 7, it was of limited extent
(3 survive). Of the 6 survivors with chronic GVHD, all are in full-time
employment or education. An additional patient developed fatal acute
transfusion-associated GVHD after day 100.
LFS.
LFS for the whole group is shown in Fig 2A.
Relapse was the main cause of death (50 of 74 patients; 67.6%,
Table 4). Thirty patients in the matched
group (35.3%) and 20 in the mismatched group (38.5%) relapsed
posttransplant (Fig 2B). In 11 cases, this occurred after primary (6)
or secondary (5) nonengraftment (vide supra). In univariable
Kaplan-Meier analysis, LFS was not significantly influenced by matching
for HLA-A, -B, -DR, -DQ (Fig 2B) or HLA-C (Table 5). These results were confirmed
when both variables were analyzed together in a Cox Proportional
Hazards model. Administration of methotrexate did not influence LFS in
either the matched or mismatched groups. Methotrexate and HLA-matching
were tested in a multivariable Cox Regression model and neither were
significantly associated. None of the other parameters previously
described were significantly associated with LFS (Table 5). There was a nonsignificant trend towards poorer outcome for recipients of grafts
from male donors and patients transplanted in CR3/4/relapse (Fig 2C). A
multivariable analysis using just matching, disease status, CMV (any
positive), donor sex, and age failed to show significant determinants
(P > .100 for all), however there was a suggestion that LFS
was slightly better with grafts from female donors (Hazard rate ratio
0.67; 95% confidence interval, 0.42 to 1.06; P = .085).
Further, relapse was not correlated with the interval from diagnosis to
BMT in CR-1 patients and from diagnosis to relapse, or relapse to BMT
in CR-2 patients (data not shown). Sixty-two percent of CR-2 patients
in the matched group relapsed on therapy compared with 61% in the
mismatched group.
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| Fig 2.
Kaplan-Meier plots of LFS for (A) the whole group, (B)
matched (M) versus mismatched (MM) transplants, and (C) LFS according
to remission status. No statistically significant differences were
seen. Tick marks indicate censoring.
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|
We also conducted an investigation of the factors influencing LFS in
just the group of 88 patients transplanted in CR-2. An initial
univariable analysis showed that only duration of CR-1 ( 730, and
>730 days) and donor gender were significant (P = .005 and
.041, respectively, Fig
3). Other factors analyzed, including HLA-matching,
CMV status, patient age, or TNC did not reach statistical significance.
Matching, CR-1 duration, and donor gender were entered into a Cox
Proportional Hazards regression model. Length of CR-1 was the only
variable that significantly affected LFS (P = .007, Table 6). Again recipients of a graft from
a female donor had a survival advantage, but this did not reach
statistical significance (P = .067; Table 6).
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| Fig 3.
Kaplan-Meier plots of LFS in CR-2 patients who relapsed
on (730 days) or off (>730 days) therapy. The
difference is significant (P = .005). Tick marks indicate
censoring.
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|
In the matched group, 1 patient had a second unrelated donor transplant
29 months after the first following chemotherapy to induce a further
remission and died of transplant-related toxicity. Two patients in the
mismatched group also had second transplants at 6 and 17 months post
first BMT after further chemotherapy. Neither was successful, with
death from transplant toxicity in 1 and a further relapse in the other.
One child who relapsed after a mismatched graft received chemotherapy
followed by donor lymphocyte infusions, but did not enter a further remission.
Overall outcome and cause of death.
Relapse was the principal cause of treatment failure (50 patients;
36.5%) followed by viral infections in 9 children (6.6%) and GVHD
with associated sepsis in 4 (2.9%) (Table 4). Overall survival was
analyzed in exactly the same manner as LFS with the same parameters
tested in both univariable and multivariable analysis. The results are
shown in Fig 4. In univariable analysis, OS
was not influenced by any parameter except that, as for LFS, there was
a nonsignificant trend toward a poorer overall outcome in older
children and in recipients of grafts from male donors. Multivariable analysis using just matching, disease status, CMV (any positive), donor
sex, and age again failed to show significant determinants, although
there was a trend towards better outcome for children receiving
transplants from female donors (Hazard rate ratio, 0.66; 95%
confidence interval, 0.41 to 1.06, P = .087) and a slight trend
toward poorer survival with increased age (P = .080).
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| Fig 4.
Kaplan-Meier plots of OS for (A) the whole group, (B)
matched (M) versus mismatched (MM) transplants, and (C) OS according to
remission status. No statistically significant differences were seen.
Tick marks indicate censoring.
|
|
At the time of analysis, 60 patients were alive and more than 6 months
post-BMT. Forty-seven patients were at school full-time, 6 were at
university full-time, and 3 are in full-time employment. Of the
remaining 4 patients, 2 had relapsed disease, 1 was having a second
BMT, and 1 was preschool age.
| |
DISCUSSION |
The principal finding of this study was an increased incidence of
primary graft failure in children receiving HLA mismatched grafts
(11.8% v 1.2%; P = .012, Table 2). There was no
difference in the incidence of secondary graft failure, and the only
parameter in our patients that predicted for a significant increase in
graft failure was HLA mismatch. Most mismatches were at HLA-A and -B loci. Other reports have shown that graft failure is more common in
recipients of unrelated donor bone marrow mismatched at HLA-A, -B, or
-C loci.19-21 Our data suggest a trend toward an increased incidence of any graft failure in recipients of HLA-B mismatched marrow
when compared with recipients of matched grafts (P = .063). This seems to result mainly from more primary graft failure (P = .039). While an HLA-C mismatch did increase the chance of graft failure, the presence of additional HLA-C mismatches in the HLA-A, -B,
-DR, and -DQ mismatched children did not independently predict for this
outcome as far as we are able to ascertain. Because most children who
received mismatched marrow were given methotrexate in addition to
cyclosporin as postgraft immunosuppression, we analyzed these variables
together. The number of children with sustained engraftment was still
lower in mismatched donor/recipient pairs irrespective of methotrexate
administration. Methotrexate did result, however, in slower overall engraftment.
Three other centers have reported series of 25 or more unrelated donor
marrow allografts for children with ALL.14-16 In these, sustained engraftment was observed in 93%, 100%, and 100% compared with 91% in our patients. Graft failure is a serious complication of
unrelated donor BMT; only 1 of 7 patients who had cryopreserved back-up
bone marrow infused is currently alive, and 3 further patients died
after a second unrelated donor allogeneic BMT from either transplant
toxicities or relapse. It is noteworthy that 2 patients (1 in the
matched and 1 in the mismatched group) had, by definition, primary
graft failure (ie, neutrophils <0.5 × 109/L at day
28), but relapsed before day 35. It is possible that either rapid
leukemic relapse inhibited engraftment or that failure to engraft donor
cells permitted the reemergence of leukemic cells. Analysis of
engraftment excluding these patients would not alter our findings. It
is now recognized that long-term survivors of unrelated donor
allografts for acute leukemia who are in sustained hematologic
remission may revert to predominantly recipient type hemopoiesis
without noticeable changes in the peripheral blood count.40
It is possible that a proportion of our patients are not full donor
chimeras even though they are in continued hematologic remission.
Further molecular analysis, not routinely available for our patients,
would be required to confirm this and compare the incidence in
recipients of matched and mismatched grafts.
We observed a low incidence of acute GVHD grades 2-4 in recipients of
both matched and mismatched grafts (20.0% v 23.3%,
respectively). The incidence of grade 3-4 acute GVHD was 2.5% versus
7.0%. These incidences do not significantly differ between the 2 groups. Similarly, there was a low incidence of chronic GVHD resulting
in 7 deaths overall (5.1%). The low incidence of acute and chronic
GVHD in recipients of mismatched grafts did not result from the use of posttransplant methotrexate in these patients and probably reflects, in
part, the efficacy of T-cell depletion with CAMPATH antibodies. These
were used as conditioning therapy in all and for marrow manipulation in
134 patients. Although immunofluorescent measurements indicate
approximately 3 logs of ex vivo T-cell depletion, more than 99%
residual cells are still coated with antibody (unpublished observations, 1987) and continued T-cell destruction
is likely in vivo. In 2 previous reports of T-cell-depleted unrelated
donor BMT in children with acute leukemia, the incidence of acute GVHD, grade 2-4, was 22% and 33%.16,41 In 1 report where 45 of
50 patients received T-cell-replete grafts, the incidence of acute GVHD was 49% and 67% for matched versus mismatched grafts,
respectively,15 and in a further report 89%.14
The actuarial LFS for the 137 children in this series is 43% at 36 months posttransplant. These results compare favorably with other
reports of unrelated BMT in childhood ALL where LFS was 23% at 3 years
in 43 patients (although 28 of 43 patients were in third remission or
relapse),14 30% at 2 years in 35 patients,15
and 40% at 4 years in 25 patients.16 These differences may, in part, reflect our T-cell-depletion strategy using
CAMPATH-1 antibodies (vide supra). It has been reported that
in patients with ALL who receive CAMPATH-1 purged grafts, the risk of
relapse is similar to that in recipients of T-cell-replete
marrow.42 One surprising finding in this study was that
recipients of marrow from female donors had a marginally better
survival. An increase in acute GVHD is reported after bone marrow
transplantation from parous female donors. It is possible that our
results are explained by effective T-cell depletion and a low
consequent rate of acute GVHD in both the matched and mismatched groups.
We analyzed whether patients in the mismatched group were at equivalent
risk of relapse to those recipients of matched grafts by comparing the
intervals from diagnosis to transplant for patients transplanted in
CR-1 and from diagnosis to relapse and relapse to transplant in
children transplanted in CR-2. We found no differences; moreover, the
proportion of patients relapsing on treatment in the matched and
mismatched group was 62% versus 61%, respectively. When patients in
CR-2 were considered separately, we found that children relapsing
on-therapy (CR-1 duration 730 days) had a significantly higher
probability of posttransplant relapse. This correlates well with our
previous observation that minimal residual disease (MRD) is still
detectable at commencement of BMT in most patients who relapse on
therapy, but only in a small minority of those who relapse after
completion of first line treatment.43
In summary, we believe that our results using T-cell-depleted
transplants are sufficiently encouraging to justify further studies
that investigate the role of unrelated BMT in the management of
childhood ALL. We have shown that selecting mismatched donors increases
the incidence of primary graft failure, but does not significantly
affect overall outcome. The ability to use mismatched donors clearly
increases the number of children who can have unrelated donor BMT and
may reduce the time from relapse to transplant. The other striking
finding of our report is the low incidence of acute and chronic GVHD
and the excellent functional status of long-term survivors. Further
studies are needed to better define which groups of children with ALL
benefit most from unrelated donor BMT (compared with alternative
treatments) and which poor-outcome groups require different strategies
such as intensified conditioning or posttransplant immune modulation.
| |
ACKNOWLEDGMENT |
We thank the nursing and medical staff of the transplant unit for
patient care. Drs Mike Potter and Nick Goulden contributed greatly to
the care of patients during this study. We are grateful to Bob Thorne
and Heather Hawkins for help with data collection and to Bridget Hunt
for preparing the manuscript.
| |
FOOTNOTES |
Submitted January 13, 1999; accepted June 1, 1999.
E.C. was supported by a program research grant from the National Blood Authority.
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.
Address reprint requests to Derwood H. Pamphilon, MD,
Consultant Haematologist, Royal Hospital for Sick Children, St
Michael's Hill, Bristol BS2 8BJ, UK; e-mail:
derwood.pamphilon{at}nbs.nhs.uk.
| |
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ABSTRACT
INTRODUCTION