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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4072-4079
Minimal Residual Disease Status Before Allogeneic Bone Marrow
Transplantation Is an Important Determinant of Successful Outcome for
Children and Adolescents With Acute Lymphoblastic Leukemia
By
Christopher J.C. Knechtli,
Nicholas J. Goulden,
Jeremy P. Hancock,
Victoria L.G. Grandage,
Emma L. Harris,
Russell J. Garland,
Claire G. Jones,
Anthony W. Rowbottom,
Linda P. Hunt,
Ann F. Green,
Emer Clarke,
Alan W. Lankester,
Jacqueline M. Cornish,
Derwood H. Pamphilon,
Colin G. Steward, and
Anthony Oakhill
From the Department of Pathology and Microbiology, School of Medical
Sciences, University of Bristol; the Department of Paediatric
Haematology, Royal Hospital for Sick Children, Bristol; Institute for
Transplantation Sciences, National Blood Service, Bristol; and the
Division of Child Health, University of Bristol, Royal Hospital for
Sick Children, Bristol, UK.
 |
ABSTRACT |
The efficacy of allografting in acute lymphoblastic leukemia (ALL)
is heavily influenced by remission status at the time of transplant.
Using polymerase chain reaction (PCR)-based minimal residual disease
(MRD) analysis, we have investigated retrospectively the impact of
submicroscopic leukemia on outcome in 64 patients receiving allogeneic
bone marrow transplantation (BMT) for childhood ALL. Remission BM
specimens were taken 6 to 81 days (median, 23) before transplant. All
patients received similar conditioning therapy; 50 received grafts from
unrelated donors and 14 from related donors. Nineteen patients were
transplanted in first complete remission (CR1) and 45 in second or
subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor  or
 rearrangements, electrophoresis, and allele-specific oligoprobing.
Samples were rated high-level positive (clonal band evident after
electrophoresis; sensitivity 10 2 to 103),
low-level positive (MRD detected only after oligoprobing; sensitivity 103 to 105), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all
MRD), MRD was detected at high level in 12 patients, low
level in 11, and was undetectable in 33. Two-year event-free survival
for these groups was 0%, 36%, and 73%, respectively (P < .001). Follow-up in patients remaining in continuing remission is 20 to
96 months (median, 35). These results suggest that MRD analysis could
be used routinely in this setting. This would allow identification of
patients with resistant leukemia (who may benefit from innovative BMT
protocols) and of those with more responsive disease (who may be
candidates for randomized trials of BMT versus modern intensive relapse
chemotherapy).
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
ALLOGENEIC BONE marrow transplantation
(allo-BMT) provides a survival advantage over chemotherapy for patients
with acute lymphoblastic leukemia (ALL) who sustain early BM relapse or
present with poor-risk features at diagnosis.1-6 However, 30% to 40% of transplant recipients will still relapse after the procedure.4,7-15 Although a number of recent therapeutic
interventions could potentially improve this situation, eg,
intensification of conditioning or posttransplant
immunotherapy,16 such measures may increase toxicity and
should ideally only be targeted toward those at highest risk of further
relapse.
As far as allo-BMT is concerned, outcome is poor for patients who enter
transplant with a high leukemia cell burden. This is illustrated by the
results from patients transplanted for resistant disease or in
relapse.13,17-22 By extrapolation, because many patients
transplanted in remission still relapse, it seems likely that presence
of disease persisting at levels just below the remission threshold
might worsen outcome. This has already been shown in patients
undergoing autologous BMT where several groups have shown that the
submicroscopic level of leukemia in the marrow graft, reflecting the
leukemia cell burden in the patient before transplant, has a
significant bearing on outcome.23-26
Submicroscopic disease is otherwise termed minimal residual disease
(MRD) and can be assessed by several techniques in ALL, the most widely
applicable of which involves amplification of Ig heavy chain (IgH) or
T-cell receptor (TCR) gene rearrangements by polymerase chain reaction
(PCR).27-30 Using combinations of IgH, TCR, and TCR
primer pairs, a molecular marker of the leukemic clone can be
identified in more than 95% of B-lineage and more than 90% T-lineage
ALL. This can be used to track MRD with a sensitivity of 0.01% in at
least 90% of patients.31
MRD analysis (using either IgH PCR or bcr-abl reverse
transcriptase [RT]-PCR) to identify early signs of relapse after
allo-BMT has been reported previously.32-35 However,
delaying the tracking of MRD to the post-allo-BMT period inevitably
restricts the therapeutic modalities available for the eradication of
residual leukemia cells detected at this late stage. We decided to
study MRD before allo-BMT to investigate whether useful prognostic
information could be acquired on which to base earlier, more
comprehensive decisions about the use of different conditioning
regimens, T-cell depletion strategies, and post-BMT immunomodulation,
or possibly to delineate patients worthy of comparative trials of
modern intensive chemotherapy versus allo-BMT. Using a method described
previously,31 we assessed pretransplant MRD retrospectively
in a cohort of 64 patients undergoing allo-BMT in remission for
relapsed or high-risk ALL from either sibling or unrelated donors. This
study shows the profound impact of submicroscopic disease load on
event-free survival (EFS).
| |
PATIENTS, MATERIALS, AND METHODS |
Patients.
Those eligible for study were children and adolescents with ALL aged
less than 18 years at diagnosis who underwent allogeneic BMT between
January 1, 1990 and August 1, 1996. All patients were in remission and
less than 20 years of age at the time of BMT. Of 145 such patients
identified, 74 were excluded due to a lack of adequate diagnostic
material (39 patients) or suitably archived pre-BMT material (35 patients). This left 71 patients open to study, but MRD was not
evaluable in a further 7 who lacked an amplifiable gene rearrangement.
Of the 64 patients open to study, 40 were male and 24 female. Ages at
diagnosis ranged from 1.3 to 16.9 years (median, 4.4), white blood cell
(WBC) counts at diagnosis from 0.8 to 606 × 109/L
(median, 28) and ages at BMT from 2.0 to 19.8 years (median, 7.2). The
diagnosis of ALL was confirmed by morphological and immunophenotypic
analysis using standard criteria.36,37 Thirty-three patients had common ALL, 14 pre-B ALL, 2 null-B ALL, 1 mature B ALL,
and 14 T-lineage ALL.
Patient cytogenetic results and remission status at BMT are summarized
in Table 1. Nineteen patients were
transplanted in first complete remission (CR1) for high-risk disease
[t(4;11), t(9;22), presentation WBC count >100 × 109/L, high Oxford hazard score38
and/or failing to remit after 4 weeks of remission induction
therapy] and the remainder were transplanted in CR2 or subsequent
remissions. The only patient who had experienced isolated
extramedullary relapse (central nervous system [CNS])
more than 6 months after the end of first-line treatment had already
received radiotherapy to the CNS. All other patients transplanted for
isolated extramedullary relapse had relapsed within 6 months of
completion of conventional therapy. Remission induction and
consolidation therapy was administered according to the Medical
Research Council (MRC) UKALL X or XI protocols for 2.9 to
8.7 months (median, 4.8) in all patients transplanted in CR1. In those
patients who relapsed before BMT, the time from last relapse to BMT
ranged from 2.8 to 12.1 months (median, 5.1) and all had received
intensive remission reinduction and consolidation therapy according to
the MRC UKALL R1 or R2 protocols (40 patients) or the BFM ALL 90 protocol (5 patients). One patient had received an autologous BMT
conditioned with cyclophosphamide and etoposide as consolidation
therapy after remission reinduction for first relapse.
BMT protocol.
All transplants were performed at the Royal Hospital for Sick Children,
Bristol, UK. The approach to HLA typing, BM graft processing, and
supportive care was as described previously.14 Donor
characteristics are given in Table 1. All patients were conditioned
with cyclophosphamide 60 mg/kg for 2 days and total body irradiation
(60 received 14.4 Gy fractionated into 8 doses and 4 under the age of 3 years received 10 Gy as a single fraction at low-dose rate).
Twenty-three patients who had relapsed in an extramedullary site
received additional radiotherapy to the affected area as part of the
conditioning. Intravenous CAMPATH-1G was administered to all recipients
of grafts from unrelated donors and to 6 recipients of grafts from
related donors. T-cell depletion with CAMPATH-1M or -1G was performed
on all grafts from unrelated donors (except 3 patients who received
CellPro [CellPro Inc, Bothell, WA] CD34-selected cells)
and on 3 grafts from related donors, 1 of whom had a T-cell add back
infused at the time of BMT.
For graft-versus-host disease (GVHD) prophylaxis, all patients received
cyclosporin A (CSA) and, in addition, short-course methotrexate (MTX)
was administered to the recipients of non-T-cell-depleted related and
mismatched unrelated grafts. Acute GVHD (aGVHD) was graded 0-IV and
chronic GVHD (cGVHD) as none, limited, or extensive according to
criteria described previously.39,40 Details on the
occurrence of aGVHD are given in Table 1. Two patients in continuing
remission had limited cGVHD and 1 patient died with uncontrolled
extensive GVHD affecting the skin and liver.
Samples.
Samples from 64 children were analyzed for the presence of MRD in
specimens taken at a median of 23 days (range, 6 to 81) before BMT. The
median time from the start of remission induction to sampling was 111 days (range, 70 to 227) for those transplanted in CR1 and from the
start of remission reinduction after the last pre-BMT relapse was 132 days (range, 74 to 296) for those transplanted in CR2 and beyond. All
samples were analyzed morphologically to ensure remission status. Local
ethical approval was obtained for the study.
DNA preparation.
DNA was extracted from BM mononuclear cells (BM MNCs) using QIAmp kits
according to the manufacturer's instructions (Qiagen GmbH, Hilden,
Germany) or by conventional phenol-chloroform extraction and ethanol
precipitation.41 In 26 cases stored presentation mononuclear cells were not available and DNA was obtained from archival
BM aspirate slides as described previously.42 Because of
concerns over the variable quality of DNA obtained from archival slides, these were not used as a source of DNA for the analysis of
pre-BMT samples.
Characterization of clone-specific rearrangements and investigation
of remission specimens.
A more complete description of the methodology can be found
elsewhere.31 In essence, leukemic material from the time of last relapse (or from the time of diagnosis if the patient was transplanted in first remission), was screened for IgH, TCR, or
TCR rearrangements using PCR amplification with FR3-JH,
V2-D3, V1/9-JI/II, and, in two cases of T-ALL, V1-J1
primer pairs. Clonal bands were sequenced either directly or via a
cloning step. Twenty base oligonucleotides were synthesized to map to
the DNJ (IgH), VND (V2-D3), or VNJ (V1/9-JI/II and
V1-J1) junctions.
Having ascertained that the BM MNC DNA from each pre-BMT specimen was
amplifiable by control PCR,31 1 µg was amplified in a
100-µL reaction using the same conditions as above but an outer downstream primer was used for FR3 and V2-D3 PCR as a maneuver against contamination.31 A non-DNA-containing negative
control and two samples each containing 1 µg of normal BM MNC DNA as
well as 10-fold dilutions of leukemia cell DNA in normal BM MNC DNA were amplified in parallel as controls. The resultant PCR products were
size-resolved by 8% polyacrylamide gel electrophoresis (PAGE) and
transferred to a nylon support by semidry electroblotting. The
membranes were then probed with the leukemia-specific oligonucleotide end-labeled with 32P-dATP followed by autoradiography.
High-level MRD was defined as that evident as a clonal band after PAGE
only (ie, before allele-specific oligoprobing; sensitivity
102 to 103) and low-level MRD as
that identified after PAGE and oligoprobing (sensitivity
103 to 105).
Statistical analysis.
An overall  2 test with partition43 was used
to compare relapse rates between the three MRD groups. Actuarial
probabilities of EFS were calculated using the method of Kaplan and
Meier44 where an event was defined as relapse or death.
Univariate and multivariate analysis using the Cox proportional hazards
model was performed to assess the independence of MRD as a risk factor for relapse. The results have been analyzed up to November 1, 1997, which allows a minimum follow-up of 20 months for patients in
continuing complete remission (CCR).
| |
RESULTS |
Clone-specific rearrangements.
Including the 7 patients in whom a clone-specific rearrangement could
not be identified, 121 clonal rearrangements were identified for the 55 patients with B-lineage ALL (73%, 31%, and 44% had at least one
clonal IgH, V2, and TCR rearrangement, respectively) and 18 for
the 16 with T-lineage ALL (75% had at least one TCR rearrangement
and a V1-J1 rearrangement was identified for the 2 patients
negative by TCR PCR).
Clone-specific probes.
Eighty-five oligonucleotide (41 IgH, 9 V2-D3, 33 V1/9-JI/II, and 2 V1-J1) probes were used in the study. One
probe only was used to investigate the 27 patients with only one
rearrangement and 22 of the patients with more than one rearrangement
available for study. Eleven patients were studied with 2 probes, 2 with 3 probes, and 2 with 4 probes: in 10 of these cases probes were designed to rearrangements at different loci. Discrepant results from
probes for different loci in the same patient were found in 3 cases: 2 patients were negative with 1 probe and low-level positive with the
other, and the other patient was negative with 2 probes and low-level
positive with the third. These cases were deemed low-level positive for
the purpose of analysis.
The sensitivity of 7 probes was not evaluable because of the poor
quality or small amount of diagnostic material available. A sensitivity
equivalent to the detection of one leukemic cell in at least 10,000 normal cells was shown in 71 (92%) of the remaining 77 probes as
assessed by 10-fold dilutions of leukemic DNA in normal BM MNC DNA.
Patients.
Thirty-four (53%) patients remain in CCR with a median follow-up of 35 months (range, 20 to 96) from BMT. Twenty-five (39%) patients have
relapsed after BMT with a median time to relapse of 5 months (range,
2.5 to 19). Twenty-two patients relapsed in the marrow only and 3 suffered a combined medullary and extramedullary relapse. Five (8%)
patients, all with unrelated donors, died of complications unrelated to
relapse (aGVHD and respiratory syncytial virus pneumonitis; adenovirus
pneumonitis; hemolytic uremic syndrome and transfusion-associated GVHD;
thrombotic thrombocytopenic purpura and cardiac failure; and
pneumonitis of unknown cause). These figures compare with a CCR rate of
48%, relapse rate of 36%, and transplant-related mortality rate of
16% in the overall group of 145 patients available for study.
Six patients failed to engraft. Stored autologous marrow, obtained
immediately before BMT conditioning, was returned to 4 patients between
days 28 and 35 post-BMT. One patient developed autologous
reconstitution. The remaining patient was reconditioned with in vivo
CAMPATH 1G and cyclophosphamide 60 mg/kg for 2 days with CSA and
MTX for GVHD prophylaxis before being administered peripheral blood progenitor cells from the original donor 91 days after
the first BMT.
Patterns of MRD.
Results of MRD analysis from pre-BMT samples for each patient subgroup,
not including those from patients dying of transplant-related causes,
are given in Table 1. All 8 patients transplanted in CR2 for isolated
extramedullary relapse were found to be MRD (1 relapsed and 1 died from transplant-related mortality [TRM]) and have
been excluded from the following statistical analyses (see Discussion).
A statistically significant difference in relapse rate was found
between the patients tested as high-level MRD+, low-level
MRD+, or MRD (overall 2 = 21.25, P < .001). The incidence of relapse was also
statistically significant when comparing patients with high-level MRD
and those with low-level or negative MRD (partitioned 2 = 18.20, P < .001) but not on comparison of patients with
low-level positive MRD and negative MRD (partitioned 2 = 3.05, P = .081). Relapse rates, including patients dying of TRM, were 74% for patients found to be MRD+ (100% for
high-level MRD+ and 45% for low-level MRD+)
and 20% for patients MRD (see also Table
1).
Kaplan-Meier plots of EFS, inclusive of patients dying from TRM (n = 4)
but exclusive of patients relapsing before allo-BMT in an isolated
extramedullary site (n = 8), are shown in
Fig 1. The 2-year EFS for patients who were
MRD+ was 17% compared with 73% for the group that was
MRD. Subdivision of the MRD+ group gave
the following results for 2-year EFS: high-level MRD+, 0%;
low-level MRD+, 36%; low-level MRD+ or
MRD, 64%.
View larger version (21K):
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| Fig 1.
Kaplan-Meier plots comparing event-free survival of
patients with positive MRD (n = 23), divided into high level (n = 12) and low level (n = 11), and negative MRD (n = 33), but
excluding those who had relapsed in an isolated extramedullary site
before BMT. Two-year EFS is given for each MRD category at the end of
each curve.
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Only MRD was significantly related to EFS (P < .001) out of
all the prognostic variables examined by univariate analysis
(Table 2A). Limited multivariate analysis
confirmed the significance of MRD (P < .001) after separate
adjustment for pre-BMT CR status, presence of Philadelphia chromosome,
type of donor (related v unrelated), and for all of these
factors (Table 2A). The other variables remained nonsignificant in all
of these models. Similar analysis was performed on the subgroup of
patients transplanted in CR2 after medullary relapse (Table 2B).
Pre-BMT MRD and whether pre-BMT relapse occurred on first-line
chemotherapy were significantly related to EFS (P < .001 in
both cases) on univariate analysis. The effect of MRD remained
significant after adjustment for Philadelphia chromosome positivity
(P < .001) and was of borderline significance when adjustment
was made for pre-BMT relapse occurring on treatment (effect of MRD
P = .055). MRD remained of borderline significance after
adjustment for both of these variables (P = .058) where the
effect of pre-BMT relapse occurring on treatment was significant (P = .031) and that of Philadelphia chromosome positivity was not significant.
View this table:
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Table 2.
Cox Proportional Hazards Analysis for All Patients
(n = 56) (A) and Patients Transplanted in CR2 (n = 31) (B) but
Excluding Patients Relapsing Before BMT in an Isolated Extramedullary
Site
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DISCUSSION |
Chemosensitivity of the leukemia clone is an important prerequisite for
successful outcome after allo-BMT for ALL. This is well illustrated by
the poor outcome in patients with disease refractory to conventional
chemotherapy17,19 or with advanced disease.10,45,46 After remission induction (or reinduction) and consolidation, MRD acts as a surrogate marker of remaining chemoresistance and we reasoned that MRD analysis before allo-BMT might
provide useful prognostic information.
The first notable observation is that MRD was not detected in pre-BMT
marrow in any of the 8 patients transplanted in CR2 for isolated
extramedullary relapse, whether this had occurred during or after
conventional therapy. Because MRD is usually present in the marrow at
the time of "isolated" extramedullary relapse of
ALL,47,48 this implies that postrelapse chemotherapy had cleared disease to below the threshold of detection (even in the single
patient from this group who relapsed after transplant). Taken together
with the fact that tracking marrow MRD in patients undergoing
first-line treatment for ALL is an unreliable method for predicting
extramedullary relapse,31 we conclude that pretransplant MRD assessment is likely to have little value for the prediction of
outcome after BMT in this minor subgroup of patients.
The remainder of this discussion will therefore concentrate on the 52 evaluable patients treated in CR1 for high-risk disease or in higher
remission states after BM relapse, either in isolation or combined with
extramedullary relapse. In these patients, we have shown a strong
correlation between the persistence of MRD before BMT and risk of
post-BMT relapse. All 12 patients with high-level MRD went on to
relapse compared with only 12 of the 40 (30%) who were
MRD or found to have MRD detectable only after
allele-specific probing (P < .001). The patients with
high-level MRD made up half of those who relapsed in this study and are
readily detectable by a clonality test that could be performed in any
routine molecular biology laboratory.
To some extent, the poor outcome of some of the 12 patients with
high-level MRD could have been predicted from first principles. Eight
had relapsed whilst still receiving (7 cases) or within 6 months of
finishing (1 case) first-line chemotherapy, and 3 had Philadelphia
chromosome-positive ALL (Ph1-ALL) transplanted in CR1.
Such patients are already known to be at high risk.7,15,49
However, statistical analysis suggested that pre-BMT MRD level was a
risk factor independent of on-treatment pre-BMT relapse and
cytogenetics by multivariate analysis (Table 2B) and did yield
potentially important prognostic information the remaining patient
with high level MRD had relapsed 12 months off treatment and would
otherwise have been viewed as having a lower risk of relapse. In
patients with Ph1-ALL as a whole, all 4 of those found to
have high-level MRD relapsed whereas 4 out of the 5 patients with
undetectable or low-level MRD remain free of disease.50
Most notably, of the patients relapsing during conventional first-line
chemotherapy, the only one to have cleared MRD continues in remission
28 months after BMT.
Four of the 9 patients with low-level MRD before BMT remain in
remission, suggesting that conditioning therapy or a
graft-versus-leukemia effect successfully eliminated their residual
disease. Two of these patients were transplanted for
Ph1-ALL in CR1 and survive in CCR 24 and 64 months
post-BMT. However, only 1 of the 4 patients with low-level MRD
transplanted in CR2 remains in remission, suggesting that the finding
of MRD in this setting highlights those needing more innovative
therapy. Conversely, 7 of the 31 patients who were
MRD went on to relapse. This "false-negative"
prediction may reflect inadequate sensitivity of the
assay30,51 or sampling error due to heterogeneous
distribution of MRD throughout the marrow.52-54
Despite obvious limitations, including the use of retrospective
analysis, the bias toward T-depleted unrelated donor (UD) BMT, and slight under-representation of patients suffering
transplant-related mortality, this study constitutes the first major
examination of the effect of leukemia cell burden on outcome in
patients receiving allo-BMT for ALL. It is interesting to consider the
impact that the straightforward detection of clonal bands after a
single round of PCR might have had on clinical decision making. Twelve
patients with high-level MRD could have been offered alternative
treatment (eg, further cytoreduction before conditioning, intensified
conditioning, T-replete grafts, and/or post-BMT immunotherapy),
which might have improved upon their universally poor outcome. By
contrast, allo-BMT resulted in a 2-year EFS of 64% in the remaining 40 patients who were either low-level MRD+ or
MRD and transplanted in CR1 or after medullary
relapse. Allo-BMT was more successful in the subgroup of patients who
were MRD (2-year EFS: 73% overall and 67% for
patients transplanted in CR2 after medullary relapse). An important
question remains as to how modern intensive chemotherapy would compare
with allo-BMT in this latter group of patients whose marrow disease has
been cleared to undetectable levels by the chemotherapy administered either as remission induction and consolidation or after relapse.
| |
ACKNOWLEDGMENT |
We are particularly appreciative of the support for C.J.C.K. from the
Ben Drewer Research Fund, and that for N.J.G. from the Leukaemia
Research Fund, the COGENT Trust for providing laboratory facilities,
and PG. We also thank Dr M.N. Potter for supervising C.J.C.K. during the early part of this project, and all colleagues involved in sample collection and patient care at the Royal Hospital for Sick Children, Bristol, in particular Dr H. Kershaw and the nursing
staff of Oncology Day Care Unit. We also thank Prof S. Haidas (St
Sophia Hospital, Athens, Greece), Dr J. Kingston (St Bartholomew's Hospital, London, UK), Dr S. Dempsey (Royal Hospital for
Sick Children, Belfast, UK), Dr M. Stevens (Hospital for Sick Children,
Birmingham, UK), Drs R. Marcus, D. Williams, and V. Broadbent
(Addenbrooke's Hospital, Cambridge, UK), Dr D. Webb (Llandough
Hospital, Cardiff, UK), Dr L. Evan-Wong (Queen Margaret Hospital,
Dunfermline, UK), Prof O. Eden and Dr H. Wallace (Royal Hospital for
Sick Children, Edinburgh, UK), Dr S. Kelly (Wycombe General Hospital,
High Wycombe, UK), Prof J. Chessells and Dr F. Katz (Hospital for Sick
Children, Great Ormond Street, London, UK), Prof R. Pinkerton (Royal
Marsden Hospital, London, UK), Drs D. Walker and M. Hewitt (Queen's
Medical Centre, Nottingham, UK), Prof J. Lilleyman (Children's
Hospital, Sheffield, UK), Drs J. Kohler and M. Radford (General
Hospital, Southampton, UK), and Dr C. Hatton (Wexham Park Hospital,
Slough, UK) for the patient referrals and their help with providing
bone marrow material and clinical information on some of the patients
in the study. We are obliged to R. Thorne for the Kaplan-Meier plots
and to Drs P. Virgo and A. McDermott (Southmead Hospital, Bristol, UK)
for immunophenotyping and cytogenetic data, respectively.
| |
FOOTNOTES |
Submitted March 31, 1998;
accepted July 30, 1998.
Supported by the Ben Drewer Research Fund, the COGENT Trust, the
Leukaemia Research Fund, and PG.
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 Colin G. Steward, MA, PhD, c/o
Oncology Day Care Unit, Royal Hospital for Sick Children, St Michael's
Hill, Bristol BS2 8BJ, UK.
| |
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Abstract
Introduction