|
|
 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):
[in this window]
[in a new window]
| 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.
|
|
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:
[in this window]
[in a new window]
|
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
|
|
| |
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.
| |
REFERENCES |
1.
Ramsay NK, Kersey JH:
Indications for marrow transplantation in acute lymphoblastic leukemia.
Blood
75:815, 1990[Free Full Text]
2.
Barrett AJ:
Bone marrow transplantation for acute lymphoblastic leukaemia.
Baillieres Clin Haematol
7:377, 1994[Medline]
[Order article via Infotrieve]
3.
Dopfer R, Henze G, Bender-Gotze C, Ebell W, Ehninger G, Friedrich W, Gadner H, Klingebiel T, Peters C, Riehm H:
Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: Results of the German Cooperative Study.
Blood
78:2780, 1991[Abstract/Free Full Text]
4.
Barrett AJ, Horowitz MM, Pollock BH, Zhang MJ, Bortin MM, Buchanan GR, Camitta BM, Ochs J, Graham-Pole J, Rowlings PA:
Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.
N Engl J Med
331:1253, 1994[Abstract/Free Full Text]
5.
Chessells JM, Rogers DW, Leiper AD, Blacklock H, Plowman PN, Richards, Levinsky R, Festenstein H:
Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia.
Lancet
1:1239, 1986[Medline]
[Order article via Infotrieve]
6.
Chessells JM, Bailey C, Wheeler K, Richards SM:
Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X.
Lancet
340:565, 1992[Medline]
[Order article via Infotrieve]
7.
Barrett AJ, Horowitz MM, Gale RP, Biggs JC, Camitta BM, Dicke KA, Gluckman E, Good RA, Herzig RH, Lee MB:
Marrow transplantation for acute lymphoblastic leukemia: Factors affecting relapse and survival.
Blood
74:862, 1989[Abstract/Free Full Text]
8.
Herzig RH, Bortin MM, Barrett AJ, Blume KG, Gluckman E, Horowitz MM, Jacobsen SJ, Marmont A, Masaoka T, Prentice HG:
Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission.
Lancet
1:786, 1987[Medline]
[Order article via Infotrieve]
9.
Butturini A, Rivera GK, Bortin MM, Gale RP:
Which treatment for childhood acute lymphoblastic leukaemia in second remission?
Lancet
1:429, 1987[Medline]
[Order article via Infotrieve]
10.
Weisdorf DJ, Woods WG, Nesbit MEJ, Uckun F, Dusenbery K, Kim T, Haake R, Thomas W, Kersey JH, Ramsay NK:
Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: Risk factors and clinical outcome.
Br J Haematol
86:62, 1994[Medline]
[Order article via Infotrieve]
11.
Frassoni F, Labopin M, Gluckman E, Prentice HG, Vernant JP, Zwaan F, Granena A, Gahrton G, De Witte T, Gratwohl A, Reiffers J, Gorin NC:
Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with timeA report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT).
Bone Marrow Transplant
17:13, 1996[Medline]
[Order article via Infotrieve]
12.
Chao NJ, Forman SJ, Schmidt GM, Snyder DS, Amylon MD, Konrad PN, Nademanee AP, O'Donnell MR, Parker PM, Stein AS:
Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission.
Blood
78:1923, 1991[Abstract/Free Full Text]
13.
Balduzzi A, Gooley T, Anasetti C, Sanders JE, Martin PJ, Petersdorf EW, Appelbaum FR, Buckner CD, Matthews D, Storb R:
Unrelated donor marrow transplantation in children.
Blood
86:3247, 1995[Abstract/Free Full Text]
14.
Oakhill A, Pamphilon DH, Potter MN, Steward CG, Goodman S, Green A, Goulden P, Goulden NJ, Hale G, Waldmann H, Cornish JM:
Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission.
Br J Haematol
94:574, 1996[Medline]
[Order article via Infotrieve]
15.
Wheeler K, Richards S, Bailey C, Chessells J:
Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemiaThe MRC UKALL X experience.
Br J Haematol
101:93, 1998
16.
Giralt SA, Champlin RE:
Leukemia relapse after allogeneic bone marrow transplantation: A review.
Blood
84:3603, 1994[Free Full Text]
17.
Mehta J, Powles R, Horton C, Milan S, Treleaven J, Tait D, Catovsky D:
Bone marrow transplantation for primary refractory acute leukaemia.
Bone Marrow Transplant
14:415, 1994[Medline]
[Order article via Infotrieve]
18.
Giona F, Testi AM, Annino L, Amadori S, Arcese W, Camera A, Di, Montezemolo LC, Ladogana S, Liso V, Meloni G:
Treatment of primary refractory and relapsed acute lymphoblastic leukaemia in children and adults: The GIMEMA/AIEOP experience. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Associazione Italiana Ematologia ed Ocologia Pediatrica.
Br J Haematol
86:55, 1994[Medline]
[Order article via Infotrieve]
19.
Biggs JC, Horowitz MM, Gale RP, Ash RC, Atkinson K, Helbig W, Jacobsen N, Phillips GL, Rimm AA, Ringden O:
Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy.
Blood
80:1090, 1992[Abstract/Free Full Text]
20.
Bortin MM, Horowitz MM, Gale RP, Barrett AJ, Champlin RE, Dicke KA, Gluckman E, Kolb HJ, Marmont AM, Mrsic M:
Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s.
JAMA
268:607, 1992[Abstract/Free Full Text]
21.
Chao NJ, Forman SJ:
Allogeneic bone marrow transplantation for acute lymphoblastic leukemia, in
Forman SJ,
Blume KG,
Thomas ED
(eds):
Bone Marrow Transplantation. Boston, MA, Blackwell Scientific, 1994, p 618.
22.
Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW, Appelbaum FR, Bryant E, Chauncey TR, Sale G, Sanders JE, Storb R, Sullivan KM, Anasetti C:
Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: The effect of leukemic burden, donor HLA-matching, and marrow cell dose.
Blood
89:4226, 1997[Abstract/Free Full Text]
23.
Uckun FM, Kersey JH, Haake R, Weisdorf D, Nesbit ME, Ramsay NK:
Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia.
N Engl J Med
329:1296, 1993[Abstract/Free Full Text]
24.
Seriu T, Yokota S, Nakao M, Misawa S, Takaue Y, Koizumi S, Kawai S, Fujimoto T:
Prospective monitoring of minimal residual disease during the course of chemotherapy in patients with acute lymphoblastic leukemia, and detection of contaminating tumor cells in peripheral blood stem cells for autotransplantation.
Leukemia
9:615, 1995[Medline]
[Order article via Infotrieve]
25.
Steenbergen EJ, Verhagen OJ, van Leeuwen EF, van den Berg H, Behrendt H, Slater RM, von dem Borne AE, van der Schoot CE:
Prolonged persistence of PCR-detectable minimal residual disease after diagnosis or first relapse predicts poor outcome in childhood B-precursor acute lymphoblastic leukemia.
Leukemia
9:1726, 1995[Medline]
[Order article via Infotrieve]
26.
Vervoordeldonk SF, Merle PA, Behrendt H, Steenbergen EJ, van den Berg H, van Wering ER, von dem Borne AE, van der Schoot CE, van Leeuwen EF, Slaper-Cortenbach IC:
PCR-positivity in harvested bone marrow predicts relapse after transplantation with autologous purged bone marrow in children in second remission of precursor B-cell acute leukaemia.
Br J Haematol
96:395, 1997[Medline]
[Order article via Infotrieve]
27.
Campana D, Pui CH:
Detection of minimal residual disease in acute leukemia: Methodologic advances and clinical significance.
Blood
85:1416, 1995[Free Full Text]
28.
Cole-Sinclair MF, Foroni L, Hoffbrand AV:
Genetic changes: Relevance for diagnosis and detection of minimal residual disease in acute lymphoblastic leukaemia.
Baillieres Clin Haematol
7:183, 1994[Medline]
[Order article via Infotrieve]
29.
Knechtli CJC, Goulden NJ, Langlands K, Potter MN:
The study of minimal residual disease in acute lymphoblastic leukaemia.
J Clin Pathol-Mol Pathol
48:M65, 1995
30.
Roberts WM, Estrov Z, Kitchingman GR, Zipf TF:
The clinical significance of residual disease in childhood acute lymphoblastic leukemia as detected by polymerase chain reaction amplification by antigen-receptor gene sequences.
Leuk Lymphoma
20:181, 1996[Medline]
[Order article via Infotrieve]
31.
Goulden NJ, Knechtli CJC, Garland RJ, Langlands K, Hancock JP, Potter MN, Steward CG, Oakhill A:
Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia.
Br J Haematol
100:235, 1998[Medline]
[Order article via Infotrieve]
32.
Miyamura K, Tanimoto M, Morishima Y, Horibe K, Yamamoto K, Akatsuka M, Kodera Y, Kojima S, Matsuyama K, Hirabayashi N, Yazaki M, Imai K, Onozawa Y, Kanamaru A, Mizutani S, Saito H:
Detection of Philadelphia chromosome-positive acute lymphoblastic leukemia by polymerase chain reaction: Possible eradication of minimal residual disease by marrow transplantation.
Blood
79:1366, 1992[Abstract/Free Full Text]
33.
Mitterbauer G, Fodinger M, Scherrer R, Knobl P, Jager U, Laczika K, Schwarzinger I, Gaiger A, Geissler K, Greinix H, Kalhs P, Linkesch W, Lechner K, Mannhalter C:
PCR-monitoring of minimal residual leukaemia after conventional chemotherapy and bone marrow transplantation in BCR-ABL-positive acute lymphoblastic leukaemia.
Br J Haematol
89:937, 1995[Medline]
[Order article via Infotrieve]
34.
Radich J, Ladne P, Gooley T:
Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT.
Biol Blood Marrow Transplant
1:24, 1995[Medline]
[Order article via Infotrieve]
35.
Radich J, Gehly G, Lee A, Avery R, Bryant E, Edmands S, Gooley T, Kessler P, Kirk J, Ladne P, Thomas ED, Appelbaum FR:
Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation.
Blood
89:2602, 1997[Abstract/Free Full Text]
36.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C:
Proposals for the classification of the acute leukaemias. French-American-British (FAB) Co-operative Group.
Br J Haematol
33:451, 1976[Medline]
[Order article via Infotrieve]
37.
Campana D, Coustan-Smith E, Janossy G:
Immunophenotyping in haematological diagnosis.
Baillieres Clin Haematol
3:889, 1990[Medline]
[Order article via Infotrieve]
38.
Chessells JM, Richards SM, Bailey CC, Lilleyman JS, Eden OB:
Gender and treatment outcome in childhood lymphoblastic leukaemia: Report from the MRC UKALL trials.
Br J Haematol
89:364, 1995[Medline]
[Order article via Infotrieve]
39.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED:
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.
Transplantation
18:295, 1974[Medline]
[Order article via Infotrieve]
40.
Shulman HM, Sullivan KM, Weiden PL, McDonald EB, Striker GE, Sale GE, Hachman R, Tsoi M, Storb R, Thomas ED:
Chronic graft versus host syndrome in man: A long-term clinicopathologic study in 20 Seattle patients.
Am J Med
69:204, 1980[Medline]
[Order article via Infotrieve]
41.
Sambrook J, Fritsch EF, Maniatis T:
Commonly used techniques in molecular cloning, in
Sambrook J,
Fritsch EF,
Maniatis T
(eds):
Molecular Cloning: A Laboratory Manual. New York, NY, Cold Spring Harbor Laboratory, 1989, p E3.
42.
Steward CG, Goulden NJ, Katz F, Baines D, Martin PG, Langlands K, Potter MN, Chessells JM, Oakhill A:
A polymerase chain reaction study of the stability of Ig heavy-chain and T-cell receptor delta gene rearrangements between presentation and relapse of childhood B-lineage acute lymphoblastic leukemia.
Blood
83:1355, 1994[Abstract/Free Full Text]
43.
Everitt BS:
The analysis of contingency tables. London, UK, Chapman and Hall, 1980.
44.
Kaplan EL, Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457, 1958
45.
Wingard JR, Piantadosi S, Santos GW, Saral R, Vriesendorp HM, Yeager AM, Burns WH, Ambinder RF, Braine HG, Elfenbein G, Jones RJ, Kaizer H, May WS, Rowley SD, Sensenbrenner LL, Stuart RK, Tutschka PJ, Vogelsang GB, Wagner JE, Beschorner WE, Brookmeyer R, Farmer ER:
Allogeneic bone marrow transplantation for patients with high-risk acute lymphoblastic leukemia.
J Clin Oncol
8:820, 1990[Abstract]
46.
Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel, Laver J, O'Reilly RJ:
Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia.
N Engl J Med
317:1618, 1987[Abstract]
47.
Goulden N, Langlands K, Steward C, Katz F, Potter M, Chessells J, Oakhill A:
PCR assessment of bone marrow status in `isolated' extramedullary relapse of childhood B-precursor acute lymphoblastic leukaemia.
Br J Haematol
87:282, 1994[Medline]
[Order article via Infotrieve]
48.
O'Reilly J, Meyer B, Baker D, Herrmann R, Cannell P, Davies J:
Correlation of bone marrow minimal residual disease and apparent isolated extramedullary relapse in childhood acute lymphoblastic leukaemia.
Leukemia
9:624, 1995[Medline]
[Order article via Infotrieve]
49.
Barrett AJ, Horowitz MM, Ash RC, Atkinson K, Gale RP, Goldman JM, Henslee-Downey PJ, Herzig RH, Speck B, Zwaan FE:
Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood
79:3067, 1992[Abstract/Free Full Text]
50.
Marks DI, Bird JM, Cornish JM, Goulden NJ, Jones CG, Knechtli CJC, Pamphilon DH, Steward CG, Oakhill A:
Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia.
J Clin Oncol
16:931, 1998[Abstract]
51.
Roberts WM, Estrov Z, Ouspenskaia MV, Johnston DA, McClain KL, Zipf TF:
Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia.
N Engl J Med
336:317, 1997[Abstract/Free Full Text]
52.
Hann IM, Morris Jones PH, Evans DIK:
Discrepancy of bone-marrow aspirations in acute lymphoblastic leukaemia in relapse.
Lancet
1:1215, 1977[Medline]
[Order article via Infotrieve]
53.
Martens ACM, Schulz FW, Hagenbeek A:
Nonhomogeneous distribution of leukemia cells in the bone marrow during minimal residual disease.
Blood
70:1073, 1991[Abstract/Free Full Text]
54.
van Bekkum DW:
Residual reflections on the detection and treatment of leukaemia, in
Lowenberg B,
Hagenbeek A
(eds):
Minimal Residual Disease in Acute Leukaemia. Boston, MA, Martinns Nijhoff, 1984, p 385.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. A. Pulsipher, K. M. Boucher, D. Wall, H. Frangoul, M. Duval, R. K. Goyal, P. J. Shaw, A. E. Haight, M. Grimley, S. A. Grupp, et al.
Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313
Blood,
August 13, 2009;
114(7):
1429 - 1436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Irving, J. Jesson, P. Virgo, M. Case, L. Minto, L. Eyre, N. Noel, U. Johansson, M. Macey, L. Knotts, et al.
Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting;
Haematologica,
June 1, 2009;
94(6):
870 - 874.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al.
Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response
Blood,
January 1, 2009;
113(1):
117 - 126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Raetz, M. J. Borowitz, M. Devidas, S. B. Linda, S. P. Hunger, N. J. Winick, B. M. Camitta, P. S. Gaynon, and W. L. Carroll
Reinduction Platform for Children With First Marrow Relapse of Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
J. Clin. Oncol.,
August 20, 2008;
26(24):
3971 - 3978.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Spinelli, B. Peruta, M. Tosi, V. Guerini, A. Salvi, M. C. Zanotti, E. Oldani, A. Grassi, T. Intermesoli, C. Mico, et al.
Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia
Haematologica,
May 1, 2007;
92(5):
612 - 618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Lee, D.-W. Kim, Y.-J. Kim, N.-G. Chung, Y.-L. Kim, J.-Y. Hwang, and C.-C. Kim
Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia
Blood,
October 15, 2003;
102(8):
3068 - 3070.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-B. Vidriales, J. J. Perez, M. C. Lopez-Berges, N. Gutierrez, J. Ciudad, P. Lucio, L. Vazquez, R. Garcia-Sanz, M. C. del Canizo, J. Fernandez-Calvo, et al.
Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value
Blood,
June 15, 2003;
101(12):
4695 - 4700.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Borgmann, A. von Stackelberg, R. Hartmann, W. Ebell, T. Klingebiel, C. Peters, and G. Henze
Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis
Blood,
May 15, 2003;
101(10):
3835 - 3839.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J Moppett, G A A Burke, C G Steward, A Oakhill, and N J Goulden
The clinical relevance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia
J. Clin. Pathol.,
April 1, 2003;
56(4):
249 - 253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. J. Scheuring, H. Pfeifer, B. Wassmann, P. Bruck, J. Atta, E. K. Petershofen, B. Gehrke, H. Gschaidmeier, D. Hoelzer, and O. G. Ottmann
Early minimal residual disease (MRD) analysis during treatment of Philadelphia chromosome/Bcr-Abl-positive acute lymphoblastic leukemia with the Abl-tyrosine kinase inhibitor imatinib (STI571)
Blood,
January 1, 2003;
101(1):
85 - 90.
[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]
|
|
|
|
|
|
|
M. Uzunel, J. Mattsson, M. Jaksch, M. Remberger, and O. Ringden
The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia
Blood,
September 15, 2001;
98(6):
1982 - 1985.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-S. Chen, E. Coustan-Smith, T. Suzuki, G. A. Neale, K. Mihara, C.-H. Pui, and D. Campana
Identification of novel markers for monitoring minimal residual disease in acute lymphoblastic leukemia
Blood,
April 1, 2001;
97(7):
2115 - 2120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Felix, B. J. Lange, and J. M. Chessells
Pediatric Acute Lymphoblastic Leukemia: Challenges and Controversies in 2000
Hematology,
January 1, 2000;
2000(1):
285 - 302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Green, E. Clarke, L. Hunt, A. Canterbury, A. Lankester, G. Hale, H. Waldmann, S. Goodman, J. M. Cornish, D. I. Marks, et al.
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
Blood,
October 1, 1999;
94(7):
2236 - 2246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction