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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1209-1217
Prednisone Response Is the Strongest Predictor of Treatment
Outcome in Infant Acute Lymphoblastic Leukemia
By
Michael Dördelmann,
Alfred Reiter,
Arndt Borkhardt,
Wolf-Dieter Ludwig,
Nicolai Götz,
Susanne Viehmann,
Helmut Gadner,
Hansjörg Riehm, and
Martin Schrappe for the ALL-BFM Group
From the Department of Pediatric Hematology and Oncology, Medical
School Hannover, Hannover, Germany; the Oncogenetic Laboratory,
University of Gie en, Gieen, Germany; the Department of
Hematology, Oncology and Tumor Immunology, Robert-Rössle-Clinic,
Charité, Humboldt University Berlin, Berlin, Germany; and St Anna
Kinderspital, Vienna, Austria.
 |
ABSTRACT |
To define prognostic factors in infant acute lymphoblastic leukemia
(ALL), the outcome of 106 infants (age  12 months) during 3 consecutive multicenter trials of the Berlin-Frankfurt-Münster group (ALL-BFM 83, 86, and 90) was retrospectively analyzed according to presenting features and early in vivo response to prednisone. The
prednisone response was defined as the cytoreduction (number of blood
blasts per microliter at day 8) to a 7-day prednisone prephase and 1 intrathecal dose of methotrexate on day 1. Prednisone good responder
(PGR; <1,000 blasts/µL) received conventional therapy and
prednisone poor responder (PPR;  1,000 blasts/µL) received intensified therapy. Infant ALL was characterized by a high incidence of a white blood cell count greater than 100 × 103/µL
(57%), central nervous system leukemia (24%), lack of CD10 expression
(59%), 11q23 rearrangement (49%) including the translocation t(4;11)
(29%), and a comparatively high proportion of PPR (26%), which were
all significantly associated with inferior outcome by univariate
analysis. The estimated probability for an event-free survival at 6 years (pEFS) was by far better for PGR compared with PPR, who had a
dismal prognosis despite intensified treatment (pEFS, 53% ± 6%
v 15% ± 7%, P = .0001). Infant PGR, who were less than 6 months of age (n = 40), lacked CD10 expression (n = 43), and/or had an 11q23 rearrangement (n = 17) fared
significantly better compared with corresponding PPR, as indicated by a
pEFS of 44% ± 8%, 49% ± 8%, and 41% ± 12%, respectively. In
multivariate analysis, PPR was the strongest adverse prognostic factor
(relative risk, 3.3; 95% confidence interval, 1.9 to 5.8; P < .0001). Infants with PGR, comprising a major subgroup (74%) among
infants, might successfully be treated with conventional therapy,
whereas PPR require new therapeutic strategies, including early
treatment intensification or bone marrow transplantation in first remission.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE IDENTIFICATION OF prognostic factors
and evolution of risk-adapted therapy for children with acute
lymphoblastic leukemia (ALL) represents one of the success stories in
modern clinical oncology. However, despite marked advances in therapy of childhood ALL,1 the probability of event-free survival
(pEFS) for infants is approximately 35% only, irrespective of
different treatment protocols.2-10 Early relapse rather
than excessive toxic complications has been identified as the major
factor responsible for the poor outcome in infant ALL. However, the
young age of infants predisposes them to suffering from late effects of
therapy, in particular to the development of neuropsychological
toxicity.9,11,12 Therefore, the current debate centers
around whether and which infants will need intensification of
front-line therapy, including bone marrow transplantation (BMT) or
other innovative treatment strategies.4,5,9,13-17
Because of the rarity of infants among children with ALL, the
definition of independent parameters predicting outcome has been
difficult. Age less than 6 months,2,4 white blood cell count (WBC) 50 × 103/µL,2,5
pro-B-phenotype with lack of CD10 expression,5,15,18 cytogenetic abnormalities of chromosome band 11q23,5 the
translocation t(4;11),7,14,19 and most recently
rearrangement of the mixed-lineage leukemia (MLL) gene at
chromosome band 11q2313-15,20,21 have been related to the
poor prognosis in infant ALL.
In trial ALL-BFM 83, the Berlin-Frankfurt-Münster (BFM) group has
demonstrated the prognostic significance of blast cell reduction in
peripheral blood to a 7-day prednisone prephase and 1 intrathecal dose
of methotrexate on day 1 (prednisone response) as a parameter for early
treatment response. Thus, a new independent risk factor called the
prednisone poor response (PPR) was generated that identifies
approximately 10% of all children with ALL with an pEFS of less than
50%.22 In subsequent ALL-BFM studies,8,23-25 and confirmed by others,26,27 the prednisone response has
emerged as the strongest predictor of outcome in childhood ALL.
To verify whether the prednisone response could be used as a reliable
stratification factor in infant ALL, we retrospectively analyzed the
outcome of 106 infants with ALL according to presenting features and
initial response to prednisone treatment. Our results showed that the
prednisone response was the strongest prognostic factor in infant ALL
and might be used as a stratification factor in risk-adapted treatment
protocols for infant ALL.
| |
PATIENTS AND METHODS |
Patient characteristics.
Between October 1, 1983 and March 31, 1995, 3,829 evaluable children
with previously untreated ALL were enrolled onto 3 consecutive multicenter trials (ALL-BFM 83, 86, and 90). One hundred nineteen (3.1%) were infants 12 months of age, of whom 106 were evaluable for
this study. Thirteen infants did not meet the study criteria for
evaluation: acute myeloid leukemia, pre-existing Fanconi anemia (n = 2), death before start of treatment (n = 2), major protocol violation
that was not enforced by the course of treatment or disease (n = 7),
patient treated according to pilot protocol (n = 1), and patient
treated in nonmember hospital (n = 1). This series included 47 cases
previously reported.8,22
For all studies, informed consent from the guardians was obtained for
each patient. The treatment protocols had been approved by the local
ethical committee. The diagnosis of ALL and extramedullary disease was
based on standard morphologic studies and cytochemical staining of
leukemic cells as reported previously.8,22,23 Central
nervous system (CNS) disease at diagnosis was defined by a
WBC count of greater than 5 cells/µL with identifiable blasts in
cerebral spinal fluid (CSF) or by a pathological mass detected by
cranial computed tomography, with or without CSF pleocytosis. Blast
cell immunophenotype,28 karyotype,29
ploidy,30 and screening for the MLL fusion
transcripts MLL/AF4, MLL/AF9, and MLL/ENL by
reverse transcriptase-polymerase chain reaction (RT-PCR)31 were determined as described previously.
Therapy stratification.
In all trials, patients were stratified into 1 of 3 treatment arms;
there was no specific therapy branch for infants. In ALL-BFM 83, the
leukemic cell burden as indicated by the BFM risk factor (RF = 0.2 log
[blasts +1] + 0.06 × liver + 0.04 × spleen, with organ
size in centimeters below costal margin)32 was used for stratification. Children with an RF less than 1.2 were assigned to the
standard-risk group (SRG). Patients with an RF between 1.2 and <1.7
were stratified into the medium-risk group (MRG) or were stratified
into the high-risk group (HRG) if they had an RF 1.7 or 5% marrow
blasts on day 40. In addition, the prednisone response was
prospectively evaluated for its prognostic significance, but not yet
used for stratification. The number of leukemic blasts in blood was
calculated on day 8 from the absolute leukocyte count and the
percentage of blasts in a peripheral blood smear. All samples were
centrally reviewed. The presence of more than 1,000 blasts/µL blood
blasts on day 8 was defined as PPR.22 Retrospectively, all
PPR in trial ALL-BFM 83 met the high-risk criteria used for this
protocol and received high-risk therapy. In trials ALL-BFM 86 and 90, the prednisone response was used as an overriding stratification factor
in combination with the RF. Assignment to SRG and MRG required a
prednisone good response (PGR; <1,000/µL blood blasts on day 8).
SRG was also defined by an RF less than 0.8, no CNS disease, no
mediastinal mass, and non-T immunophenotype. Patients were classified
at high risk if they had a PPR or 5% marrow blasts on day 33 or an
acute undifferentiated leukemia. In addition, patients with a
translocation t(9;22) were considered as high risk, regardless of their
therapy response.8,23 In all trials, neither the
translocation t(4;11) nor age less than 1 year was considered as a
stratification factor.
Treatment.
Details of protocols ALL-BFM 83, 86, and 90 were reported
previously.8,22,23 Steroid prephase, induction,
reinduction, and intrathecal therapy were comparable for SRG and MRG
infants within trials ALL-BFM 83 through 90. Infants who were less than 1 year of age at the intended time of cranial irradiation
(CRT at 24 to 26 weeks after initial diagnosis of ALL)
received neither preventive (12 Gy) nor curative (20/18 Gy) CRT. The
major differences between all trials have been (1) the replacement of
intermediate-dose methotrexate (ID-MTX; 500 mg/m2 4 times)
in trial ALL-BFM 83 by high-dose methotrexate (HD-MTX; 5 g/m2 4 times) in trials ALL-BFM 86 and 90 during
consolidation and (2) the introduction of different elements to
high-risk treatment.
Statistical analysis.
EFS was calculated from the date of diagnosis to the last follow-up or
to the first event (failure to achieve remission, early death,
resistant leukemia, relapse, or death of any cause). Patients who
failed to achieve a complete response were assigned to a failure time
of 0. The Kaplan-Meier method was used to estimate survival rates with
comparisons based on the 2-sided log-rank test.33 Standard
errors were calculated using the formula of Greenwood.34 Multivariate risk analysis to estimate the prognostic impact of prednisone response on pEFS was performed using Cox proportional hazards regression analysis.35 Differences in clinical and
biological characteristics at time of diagnosis were analyzed by
Fisher's exact test or Mann-Whitney U-test. The data represent patient follow-up through July 31, 1998. The median observation time for all
patients in complete remission (CR) was 5.5 years; and for the infants
in the most recent trial ALL-BFM 90, the median observation time was
4.9 years (range, 2.6 to 7 years). Computations were performed using
SAS (Statistical Analysis System Version 6.12; SAS Institute Inc, Cary, NC).
| |
RESULTS |
Table 1 depicts the presenting features of
the evaluated infants. Distributions of patient characteristics were
comparable between all trials, except for a higher proportion of PPR in
trial ALL-BFM 86 (41%) compared with trials ALL-BFM 83 (15%) and 90 (20%). The 55 girls and 51 boys ranged in age from 5 days to 12 months
(median, 5.8 months). WBC ranged from 1 to 1,290 × 103/µL (median, 120 × 103/µL). CNS
disease was present in one fourth of the infants. The pro-B
immunophenotype predominated with 50%, followed by the common-B and
pre-B immunophenotype in 25% and 20% of the infants each. Fifty-nine
percent of infants were CD10 , and 28% expressed
1 or more myeloid antigens in addition to lymphoid markers.
Successful cytogenetic studies were performed on 59 infants (56%). One
third had a normal karyotype. We observed 1 patient with
hyperdiploidy (DNA index 1.16). Three infants presented with
numerical aberrations (2 with trisomy 8 and 1 with trisomy
10); all were PPR. We found a high frequency of structural chromosomal
aberrations (69%). One half of the infants presented with 11q23
rearrangements (n = 29). The translocation t(4;11)(q21;q23) was present
in 17 patients and predominantly found in infants less than 6 months of
age (81%). Twelve additional infants had other chromosomal aberrations
with breakpoints in 11q23, 4 of whom had t(11;19), t(9;11), or 11q23
variants each. The 59 patients with adequate cytogenetic analysis were
compared as to sex, age, WBC, RF, immunophenotype, prednisone response,
and pEFS with the 47 infants for whom cytogenetics were not available.
There were no significant differences both in the distribution of
presenting clinical features and in pEFS (pEFS, 38% ± 7%
v 50% ± 7%; P = .13).
Univariate analysis for prognostic features associated with poor
prognosis showed significance in descending order for PPR, CNS disease,
the t(4;11), pro-B immunophenotype/lack of CD10 expression, age less
than 6 months, 11q23 rearrangement, and WBC 100 × 103/µL. Neither coexpression of myeloid markers (Table 1)
nor treatment protocol had a significant influence on prognosis. We
noted no significant outcome difference for infants with respect to
specific 11q23 rearrangements. Of the infants with the
t(4;11)/MLL-AF4, 5 of 17 survived (3 in first CR; pEFS,
18% ± 9%). All survivors were PGR. Of the infants with 11q23
rearrangements other than the t(4;11)/MLL-AF4, 6 of 12 survived (5 in first CR; pEFS, 31% ± 14%; P = .17), of whom 5 were PGR. In respect to protocol treatment as a risk
factor, we noted a tendency of steady improvement in pEFS for infants
from trials ALL-BFM 83 to 90 (pEFS, 23% ± 12% [n = 13]
v 37% ± 8% [n = 34] v 51% ± 7% [n = 59]; P = .27). A similar trend could be shown for PGR (pEFS,
27% ± 13% v 53% ± 11% v 60% ± 7%;
P = .16), but the outcome for PPR remained constantly poor
(pEFS, 0% v 14% ± 9% v 18% ± 12%;
P = .99). However, none of the differences was statistically
significant, neither in trend nor when comparing each trial separately.
In the most recent trial ALL-BFM 90, investigation of MLL
fusion transcripts was performed on 24 of the 59 (41%) patients treated in this trial. MLL rearrangement for MLL/AF4,
MLL/AF9, or MLL/ENL was found in 12 infants, with 6 being PGR and 6 PPR. Of the 6 infants with PGR and MLL
rearrangement, 4 survived (3 in first CR and 1 in second CR). In
contrast, of the 6 infants with PPR and MLL rearrangement, 2 survived (1 in first CR and 1 in second CR). Twelve infants presented
with germline MLL configuration, all of whom had a PGR. In this
group, 8 survived (6 in first CR and 2 in second CR).
The overall outcome at 6 years was worse for infants as compared with
older children with ALL (pEFS, 43% ± 5% v 70% ± 2%; P = .0001). Infants with a PPR had a dismal prognosis compared with infants with a PGR (pEFS, 15% ± 7% v 53% ± 6%;
P = .0001; Fig 1); the overall
survival estimate (22% ± 8% v 65% ± 6%; P = .0001; see Table 3) differed slightly from pEFS only.
Table 2 shows the influence of prednisone
response on other presenting features that had been assigned to a poor
prognosis within the infant cohort by univariate analysis. Only a
higher WBC (median, 250 × 103/µL for PPR v
96 × 103/µL for PGR; P = .009)
was significantly correlated with PPR. Infants who were less than 6 months of age, lacked CD10 expression, and/or had an 11q23
rearrangement, but demonstrated a PGR, had a favorable outcome (pEFS,
44%, 49%, and 41%, respectively), whereas almost all comparable PPR
died (Fig 2A through C). For infants with
the t(4;11), the pEFS results suggested a better outcome for PGR also,
but were not significant (pEFS, 33% v 0%; P = .06). The predictive value of the prednisone response was statistically not
significant for infants with CNS disease (Table 2), but the overall
result for these children was poor in general.
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Table 2.
Frequency (%) of Presenting Features and Outcome in
Infants With ALL According to Prednisone Response (n = 105)
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| Fig 2.
(A through C) pEFS for infants with ALL (A) less than 6 months of age, (B) lack of CD10 expression, or (C) presenting with
11q23 rearrangements according to prednisone response.
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Table 3 summarizes the outcome including
causes of death and relapse pattern according to prednisone response.
Both groups achieved a similar remission induction rate (93% v
96%). Regardless of prednisone response, the leading cause of failure
was BM recurrence. For PPR, we noted isolated BM (74%) or CNS relapses
(26%) only, whereas the relapse pattern in PGR was distributed to
different sites and combinations. PPR was associated with early
treatment failure. Almost two thirds (15 of 23) of all events took
place during the first 6 months after initial diagnosis: 2 infants
[t(4;11) present] did not achieve remission, 2 infants died in CR
from septicemia and sudden death, and 11 of 18 relapses occurred within 6 months while being on intensive treatment (BM, 7; CNS, 4). In contrast, in the PGR group, one third (11 of 31) of all events took
place within 6 months. Three infants, 2 of whom had a translocation t(4;11), did not achieve remission, and 8 additional patients relapsed
while on intensive treatment.
In this study, 9 infants developed an isolated CNS relapse. We noted a
suggestive, but not significant association of isolated CNS relapse
with PPR (5 of 9 infants) and CD10 expression (7 of 9 infants). Neither
CNS disease at diagnosis of ALL, age less than 6 months, WBC 100 × 103/µL, nor treatment protocol including cranial
irradiation were related to the risk of isolated CNS relapse.
In stepwise Cox regression analysis, PPR emerged as the most
significant adverse prognostic factor, followed by age less than 6 months and CNS disease. Infants with PPR had a 3.3-fold increased risk
for relapse compared with other infants (95% confidence interval, 1.9- to 5.8-fold; P < .0001; Table 4).
The presence of 11q23 rearrangements including the t(4;11) did not have
a significant effect on prognosis in the multivariate model, but
cytogenetic data were available in one half of the patients only (Table
4). Cox regression analysis for adverse features with data from infants for whom all data were available (n = 58) showed the same risk ratios,
but, whereas PPR retained its statistical power (P = .002), age
(P = .3) and CNS disease (P = .1) lost their
statistical significance. Inclusion of protocol treatment as a risk
factor showed no significance for treatment in the multivariate model.
| |
DISCUSSION |
In this large series of infants (n = 106) treated with effective
risk-based ALL therapy, the prednisone response was the strongest prognostic parameter for outcome. A PGR identified three fourths of
infants who achieved an EFS at 6 years of 53% with conventional therapy, whereas infants with PPR had an almost fatal outcome despite
therapy intensification (pEFS, 15%; P = .0001). Of the other
potential adverse prognostic factors studied, including WBC 100 × 103/µL, lack of CD10 expression, cytogenetic
11q23 rearrangements, the specific translocation t(4;11), and
coexpression of myeloid markers, only age less than 6 months and CNS
disease achieved marginal significance levels in the multivariate
model. It should be noted that our patients were not treated uniformly.
However, pEFS did not differ significantly for infants in trials
ALL-BFM 83 versus 86 versus 90, neither for the overall cohort nor for PGR or PPR.
Regarding frequency and distribution of reported adverse prognostic
features in infant ALL, we demonstrated similar results as other
investigators in respect to age less than 6 months,4,10 WBC
100 × 103/µL,4,36 CNS
disease,6,10,36 pro-B immunophenotype with lack of CD10
expression,6,10,37 lack of
hyperdiploidy,7,38 and cytogenetic 11q23
rearrangements,4,5,7,10,13,14,20,21,39 including the
t(4;11),4,7,10,13,39 the t(9;11),7,13,15,21 and
the t(11;19).7,20,21
Age less than 6 months retained significance as a poor prognostic
factor in the multivariate model, but a PPR seemed to have a major
impact in this age group, as indicated by the fatal outcome of PPR
compared with PGR (pEFS, 0% v 44%; P = .0001; Table 2 and Fig 2A). It is noteworthy that age seemed to
influence the prognostic power of a t(4;11). During trials ALL-BFM 83 through 90, infants with a t(4;11) (n = 17) fared worse as compared
with children (n = 17) who presented with the same translocation but were older than 1 year of age (pEFS, 18% ± 9% v 47% ± 12%; P = .06; Fig 3).
Similar results from 32 children with ALL (pEFS, 17% ± 9%
v 63% ± 19%; P = .04) were reported by Pui et
al.40 These findings are interesting, because at the
molecular level, children with a t(4;11) who were 1 to 9 years of age
at diagnosis have been shown to display similar defects as infant
cases.41,42
In contrast to other reports,9,10 we found a significant
difference in the outcome of infants with or without CNS disease at
diagnosis. However, an obvious explanation for this observation is
missing. We noted neither an influence of the different protocols, in
particular with regard to the dosage of MTX or CRT, nor a significant correlation of CNS disease with age less than 6 months, WBC 100 × 103/µL, lack of CD10 expression, 11q23
rearrangement, or PPR.
We confirmed the significant better outcome for infants with
CD10+ compared with CD10
ALL.4,6,7,9,15,37 In contrast to other investigators, who
demonstrated a significantly better pEFS in myeloid antigen-negative as
compared with myeloid antigen-positive cases,37
coexpression of myeloid antigens had no influence for prognosis of
infants in these ALL-BFM trials.
Cytogenetic abnormalities involving chromosome band 11q23 have been
correlated with a dismal prognosis in infant ALL,5 particularly the t(4;11).5-7,14-16,19 In the present study,
infants with 11q23 rearrangements (pEFS, 28% ± 8%) and/or the
specific translocation t(4;11) (pEFS, 18% ± 9%) fared poorly as
well. However, infants with 11q23 rearrangements, including those with
the t(4;11), but a PGR had a relatively favorable outcome as indicated
by an pEFS of 41% ± 12%, whereas almost all comparable PPR died
(P = .03). Whereas 1 study suggested that infants with 11q23
partners other than the AF-4 gene may have a better outcome (P = .09),7 we found no significant difference (pEFS, 31 ± 14 v 18 ± 9; P = .17), which is in accordance with
most other reports.15,17,43-45
Most recently, rearrangement of the MLL gene at chromosome band
11q23 has been associated with a dismal prognosis (pEFS, 5.3% to 28%)
in infant ALL. The reported frequency of MLL rearrangement differed markedly between 50% and
81%,13-16,20,21 but has been 72% to 81% in the
larger series.14,15,21 The present study lacked sufficient
data regarding MLL status. Because of selection bias (screening
for the specific fusion transcripts MLL/AF4, MLL/AF9, and MLL/ENL only), small sample size (n = 24), and the use of RT-PCR only, we were unable to draw firm conclusions regarding prognosis of MLL rearrangement and its association to
prednisone response. However, we noted a correlation of germline
MLL with PGR, because all 12 infants with germline MLL
were PGR. Eight of them survived, of whom 6 were in first remission
(pEFS, 58% ± 14%); 2 patients were in second CR after
allogenic BMT, which is in accordance with reported
results.14,15,20,21 Of the 12 infants with MLL
rearrangement, 6 were long-term survivors (4 in first CR [3 PGR/1
PPR]; 2 remained in second CR [PPR/PGR]), which was comparable to
the reported experiences.9,14,21 Therefore, half of the
infants with a PGR who were evaluated for MLL rearrangements
remained in first remission, irrespective of their MLL status
(pEFS, 56% ± 12%). Various reports suggested that infants with
MLL rearrangement may not represent a homogenous group.46,47 It remains to be evaluated whether the
MLL gene rearrangement itself,13,41 the partner
genes,21 or the fusion transcripts48 influence
prognosis in infant ALL.
In all studies evaluating prognostic factors in infant ALL, patient
numbers were relatively small and, in particular,
11q23/t(4;11)/MLL, CD10-/pro-B, and age less than 6 months were
highly interrelated. Therefore, the identification of independent
prognostic factors by multivariate analysis was
impeded.14,15,17,20,21,49 Only 2 reports could demonstrate
a significant prognostic value of MLL gene
rearrangement13 and/or cytogenetic 11q23
rearrangements5 by multivariate analysis.
PPR did not correlate with other clinical or blast cell features
evaluated except for high WBC. The association of PPR and high WBC
seemed to be related to the definition of PPR itself. Because PPR is
defined by an absolute blast cell count per microliter on day 8, the
probability of being a poor responder is theoretically higher in
patients with a high WBC at diagnosis. However, multivariate analysis
showed that a WBC of 100 × 103/µL was not
associated with prognosis and barely reached significance in univariate
analysis. This finding might be in accordance with in vitro results
from Ito et al,50 who found no significant correlation
between the prednisolone concentration producing 50% cytotoxicity
(LC50) and patient age, sex, WBC, presence of chromosomal translocations, ploidy, immunophenotype, and percentage of leukemic cells in S phase in BM samples of 28 children with B-lineage ALL.
Because antileukemic treatment itself is an important prognostic
factor,51 the initial response to that applied therapy should be an important prognostic factor as well. Various reports have
identified initial cytoreduction in blood8,22-25,27,52,53 or BM36,54-58 as a powerful prognostic factor in childhood
ALL, despite different treatment regimens or different time points of
evaluation during induction. However, only 2 reports have evaluated infants in more detail. Miller et al56 found, in contrast
to older children with ALL, no significance for percentage of
lymphoblasts on day 14 BMs of infants, but neither provided detailed
data nor included this finding in their discussion. Differences between their study and ours may reflect statistical variation resulting from
small sample size, differences in treatment and outcome, or other
factors not yet identified. In contrast, a retrospective study by the
Children's Cancer Study Group on the prognostic influence of age in
childhood ALL stated that day-14 BM was the most significant predictor
of disease-free survival for the infant group.36 Less infants had M1/M2 BM on day 14 as compared with older children with ALL
(88% v 96%). However, because the frequency of M3 BMs was
comparable (3% v 1%), it was not obvious from these data
whether infants died from nonresponse or any other complications during early induction.
The outcome of infants with PPR and children older than 1 year of age with PPR treated during trials ALL-BFM 83 through 90 differed significantly (pEFS, 15% v 41%; P = .0003).
Blast cells from infants presenting with PPR, 11q23 rearrangement, lack
of CD10 expression, or other factors not yet identified may display different cellular pharmacodynamics that determine the sensitivity to
antileukemic drugs. Kumagai et al59 showed that leukemic cells from infants with 11q23 abnormalities grew better on stromal cell
layers in vitro, which was associated with a poor prognosis. Kersey et
al60 recently demonstrated that MLL-AF4 leukemias were
highly resistant to cell death that results from serum deprivation and
had slower rates of proliferation and decreased cells in S phase
compared with non-MLL-AF4 leukemias. Blast cells from infants with MLL
rearrangements were shown to have a higher cell recovery rate when
inoculated in SCID mice as compared with blast cells from other
children with ALL,61 which correlated with a poor prognosis. In vitro studies showed that blasts from infants and blasts
from children lacking CD10 expression were significantly more resistant
to prednisolone, daunorubicin, and L-asparaginase than blast cells from
other ALL children.62-64 Particularly, blast cells with
11q23 rearrangements are thought to arise in very primitive fetal
hematopoietic precursors65 and may have a higher potential for different blast cell populations,66,67 clonal
evolution,37,68 or lineage switching.67 In
addition, MLL gene rearrangement is frequently observed in
acute myeloblastic leukemia also.13,15 Thus, the prednisone
response may represent 1 subclone of the blast cell population only and
other subclones theoretically could be resistant or less responsive to
standard ALL therapy.
A prospective international study currently in progress should further
clarify the prognostic value of the prednisone reponse and blast cell
markers such as 11q23 rearrangement, the specific translocations
involving chromosome 11, and MLL rearrangement.
| |
ACKNOWLEDGMENT |
The authors thank U. Meyer and J. Regelsberger for data management, M. Zimmermann for statistical analysis, E. Odenwald for the expert
cytology, the staff of the reference laboratories for excellent
cooperation, and the nurses and physicians taking care of the treated infants.
| |
FOOTNOTES |
Submitted November 13, 1998; accepted April 14, 1999.
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 Michael Dördelmann, MD, Medical
School Hannover, Children's Hospital, Department of Pediatric
Hematology/Oncology, Carl Neuberg Str.1, 30625 Hannover, Germany;
e-mail: bfm.studie{at}MH-Hannover.DE.
| |
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TOP
ABSTRACT
INTRODUCTION
