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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1898-1909
Immunophenotypic and Genotypic Features, Clinical
Characteristics, and Treatment Outcome of Adult Pro-B Acute
Lymphoblastic Leukemia: Results of the German Multicenter Trials
GMALL 03/87 and 04/89
By
Wolf-Dieter Ludwig,
Harald Rieder,
Claus R. Bartram,
Barbara Heinze,
Stefan Schwartz,
Winfried Gassmann,
Helmut Löffler,
Dieter Hossfeld,
Gerhard Heil,
Susanne Handt,
Axel Heyll,
Helmut Diedrich,
Konstanze Fischer,
Adelheid Weiss,
Bernd Völkers,
Ülker Aydemir,
Christa Fonatsch,
Nicola Gökbuget,
Eckhard Thiel, and
Dieter Hoelzer
From the Medizinische Fakultät Charité,
Humboldt-Universität, Robert-Rössle-Klinik, Berlin,
Germany; the Klinikum der Philipps-Universität, Marburg, Germany;
Universitätsklinikum, Heidelberg, Germany; Medizinische
Universitätsklinik, Ulm, Germany; Universitätsklinikum
Benjamin Franklin, Berlin, Germany; Städtisches Krankenhaus, 2. Medizinische Klinik, Kiel, Germany; Universitätskrankenhaus
Eppendorf, Hamburg, Germany; Klinikum der RWTH, II. Med. Klinik,
Aachen, Germany; Universitätsklinik, Düsseldorf, Germany;
Medizinische Hochschule, Hannover, Germany; Klinikum der Stadt
Mannheim, Germany; Universitätsklinikum Frankfurt, Germany;
Biometrisches Zentrum für Therapiestudien, München,
Germany; and Institut für Medizinische Biologie der
Universität Wien, Wien, Austria.
 |
ABSTRACT |
In contrast to childhood acute lymphoblastic leukemia (ALL), the
cell-biological features, clinical characteristics, and treatment outcome of CD10 pro-B ALL have not yet been determined
in larger series of adult patients. Therefore, we studied 57 adult
patients with newly diagnosed pro-B ALL (median age, 30 years) enrolled
in two consecutive German multicenter ALL studies (03/87 and 04/89).
Extensive immunophenotypic characterization of leukemic blasts could be
performed on all patients, whereas adequate cytogenetic data were
available in 33 cases and molecular studies in 18 cases, using reverse
transcription-polymerase chain reaction to detect MLL-AF-4 transcripts.
Twenty-two patients demonstrated a t(4;11)(q21;q23) and/or
MLL-AF-4 rearrangements, and 6 patients had other structural
abnormalities, including a t(9;22)(q34;q11) (N = 2). Nine patients
had a normal karyotype. Patients with 11q23 abnormalities tended to be
younger (median age, 29 years) and were characterized by male
predominance (64%), hyperleukocytosis (median leukocyte count, 168 × 109/L), and a frequent coexpression of CD65s (64%) as
compared with patients with other cytogenetic abnormalities or a normal
karyotype. Twelve of 16 (75%) pro-B ALL patients in study 03/87 and 30 of 41 (73%) in study 04/89 achieved a complete remission (CR). Sixteen of 30 patients in study 04/89 remain in continuous CR (CCR) in contrast
to only 2 of 12 patients in study 03/87. Interestingly, all 7 patients
treated with high-dose cytarabine and mitoxantrone as consolidation in
study 04/89 remain alive and leukemia-free. One patient in study 03/87
and 8 in study 04/89 underwent autologous (N = 2) or allogeneic (N
= 7) bone marrow transplantation (BMT). The median remission duration
was 420 days for patients in study 03/87 and has not yet been reached
in study 04/89. The median survival time of all pro-B ALL patients was
571 days in study 03/87 and 747 days in study 04/89. Among the 22 patients with a t(4;11) and/or MLL-AF-4 rearrangements, 17 achieved a CR and 8 are still in CCR, of whom 4 underwent an allogeneic
BMT. Remission duration and overall survival did not differ
significantly between pro-B ALL patients with 11q23 abnormalities and
those with a normal karyotype or other structural abnormalities. These
data indicate that intensification of postremission treatment may
improve the prognosis of adult pro-B ALL, including patients with a
t(4;11).
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
ADVANCES IN immunophenotyping,
cytogenetics, and molecular genetics and their combined application to
characterize leukemic blasts have not only considerably improved our
knowledge of the pathobiology of acute leukemias, but have also
contributed to a refined classification of acute lymphoblastic leukemia
(ALL) subtypes and identification of distinct clinicopathologic
entities.1-5 Especially in B-lineage ALL, it has become
evident that immunophenotypic subgroups mirror a high degree of
genotypic diversity and that multiple, distinct molecular pathways are
involved in ALL pathogenesis (reviewed in Cline1). This
information has been useful to achieve a more precise distinction of
biologically and clinically relevant subgroups, including immature
CD10 B-cell precursor ALL, often associated with
11q23 translocations, and common or pre-B ALL with fusion transcripts
of BCR/ABL due to a t(9;22) (reviewed in Raimondi6), as
well as to adjust treatment protocols to the biological features of the
leukemic cells involved.3-5
The most immature subtype of B-cell precursor ALL, pro-B ALL (also
referred to as pre-pre-B ALL, early-early-B, early B-precursor ALL,
null-ALL, B1, or pre-B1 ALL),7-15 accounting
for approximately 5% of childhood and 10% of adult ALL cases, is
characterized by the expression of CD19, cytoplasmic (cy) or surface
membrane CD22, CD24, and cyCD79a, whereas CD10, cyIg M and surface (S)
Ig are negative. In childhood ALL, the pro-B immunophenotype is often associated with unfavorable clinical features such as age less than 1 year, high leukocyte counts, massive hepatosplenomegaly, and central
nervous system (CNS) disease at diagnosis,9,16-20 whereas
relatively little is known about the correlation between pro-B ALL and
clinical characteristics in adults.
More recently, significant associations between a
CD10 B-cell precursor immunophenotype and
abnormalities of chromosome 11, band q23, have been described,
particularly in infant ALL (reviewed in Pui et al21 and
Rubnitz et al22). Structural lesions involving chromosome
11, band q23, are among the most common cytogenetic abnormalities seen
in hematopoietic malignancies. They occur in approximately 5% to 10%
of ALL and comprise a heterogeneous collection of gene rearrangements,
with most of them involving the MLL gene (also termed
HRX, ALL-1, or Htrx1). The MLL gene has
recently been cloned,23,24 and three regions of the MLL
protein show a significant homology with the Drosophila
trithorax protein. The breakpoints in MLL are restricted to an
8.3-kb region of the gene that is involved in reciprocal
translocations, with at least 25 chromosomal regions in a number of
phenotypically distinct acute leukemias, including ALL, de novo acute
myeloid leukemias (AML), and some types of chemotherapy-related
AML.25-27 Although little is known about the normal
physiological function of the 431-kD protein encoded by the MLL gene
and the cellular mechanisms of MLL-induced leukemogenesis, the
involvement of MLL in both lymphoid and myeloid disorders and its
structural features suggest that it is involved in the regulation of
differentiation pathways, both through direct DNA binding and via
interactions with other transcription factors (reviewed in Rubnitz et
al22).
Of all the various chromosomal loci participating in 11q23
translocations, the t(4;11)(q21;q23) is by far the best characterized structural lesion, with specific biological and clinical features. This
chromosomal abnormality has been detected by standard cytogenetic techniques in 30% to 50% of infant ALL and in about 2% to 6% of older children or adult patients with ALL. A unique constellation of
phenotypic and clinical characteristics has been associated with the
t(4;11), regardless of the age of the patients (reviewed in
Léglise et al,28 Pui,29 and Hilden et
al30). These characteristics include a
CD10, CD19+, CD24 or
weakly + B-cell precursor phenotype with a high frequency of
myeloid-associated (ie, CD15 and/or CD65s) antigen expression,
hyperleukocytosis, organomegaly, a high incidence of CNS leukemia, and
a dismal prognosis, especially in infant ALL.18,19,31-43
The characteristic antigen expression has been interpreted as evidence
for the hypothesis that the transformation event in these leukemias
involves a stem cell or an early committed progenitor cell with the
potential for both lymphoid and myeloid differentiation.
As stated above, relatively little is known about the relationship of
immunophenotypic features and 11q23 translocations involving the MLL
gene for prognosis in adult patients with pro-B ALL compared with
childhood ALL, because in most studies the prognostic relevance of
immunophenotype and genotype could not be evaluated due to the small
number of patients and heterogeneous treatment
protocols.15,36,42-45
In the present study, we therefore studied immunophenotypic and
genotypic features in 57 adults with pro-B ALL, the largest series
reported to date, to elucidate the biological heterogeneity of this
immature B-lineage ALL subtype, to correlate pro-B ALL with clinical
characteristics, and to assess the prognostic value of pro-B ALL
according to its genotypic features.
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MATERIALS AND METHODS |
Patients.
From March 1987 to March 1993, central immunophenotyping was
successfully performed in 611 adult patients aged 15 to 65 years with
newly diagnosed ALL (B-ALL not included), of whom 65 (10.6%) exhibited
a pro-B ALL phenotype. All patients were enrolled in two successive
clinical trials of the German multicenter study group for treatment of
adult ALL (GMALL 03/87 and 04/89).
Morphology and cytochemistry.
Bone marrow and peripheral blood smears were stained using the
May-Grünwald-Giemsa technique, and the morphological appearance of blasts was classified in accordance with the criteria of the French-American-British (FAB) Cooperative Group by H. Löffler and
W. Gassmann at the central reference institution (Kiel,
Germany).46 In addition, the following cytochemical
reactions using standard procedures were performed: myeloperoxidase
(MPO), naphthyl acetate esterase, acid phosphatase,
dipeptidylaminopeptidase IV, and periodic acid Schiff reaction.
Immunophenotyping.
Immunophenotyping was performed at the central reference laboratory of
the GMALL studies (Universitätsklinikum Benjamin Franklin, Free
University of Berlin, Berlin, Germany). Leukemic cells from heparinized
fresh bone marrow or peripheral blood samples were isolated by
Ficoll-Hypaque (Pharmacia, Biotech, Freiburg, Germany) density gradient
centrifugation, and cell-surface antigens were detected by a standard
indirect immunofluorescence (IF) assay, as previously
described.7,47 Nonspecific binding was avoided by adding
heat-inactivated 10% rabbit serum (GIBCO BRL, Eggenstein, Germany)
before immunostaining as well as in subsequent incubation steps with
primary or secondary reagents. Fluorescent labelings of surface
membrane antigens were immediately evaluated by flow cytometry using a
FACScan (Becton Dickinson Immunocytometry Systems, Mountain View, CA).
Data acquisition in flow cytometry was performed with FACScan research
or Lysis II software (Becton Dickinson). Isotype-matched nonreactive
mouse monoclonal antibodies (MoAbs) with the same protein
concentrations were used as negative controls in all experiments.
Although the viability in percent of fresh leukemic cell suspensions
usually exceeded 90%, dead cells were excluded from flow cytometric
analysis with propidium iodide (Sigma Chemical Co, St Louis, MO)
gating.
The following MoAbs, all available from commercial sources, were used:
(1) T- and B-lineage-associated antigens: CD3/Leu-4, CD7/Leu-9,
CD19/HD37, CD20/B1, and CD24/OKB2; (2) panmyeloid antigens: CD13/My7,
CD33/My9, and CD65s/VIM-2; and (3) nonlineage-restricted antigens:
CD10/J5, CD34/My10, and HLA-DR/OKIa1.
Coexpression of lymphoid and myeloid antigens was confirmed by standard
two-color flow cytometric analysis using appropriate MoAbs directly
conjugated to fluorescein isothiocyanate or phycoerythrin.
For cytoplasmic and nuclear staining, cytospin preparations of leukemic
blasts were fixed in acetone (cyCD3, cyIgM) or methanol (terminal
deoxynucleotidyl transferase [TdT]), subsequently assayed for direct
(cyIgM) or indirect IF using Leu-4 MoAb (cyCD3) or heterologous
antisera (goat antimouse IgM, rabbit anti-TdT antiserum; Supertechs, Bethesda, MD), and evaluated for IF using
Zeiss microscopes (Zeiss, Oberkochen, Germany) equipped with
epi-illumination and phase-contrast devices.
A sample was considered positive for surface antigens if more than 20%
of the leukemic cells expressed fluorescence intensity more than 98%
of the negative control cells. Positivity for TdT and cytoplasmic
antigens was arbitrarily defined as more than 10% of the cells
exhibiting nuclear or intracytoplasmic fluorescence as compared with
negative controls.
Immunophenotypic subgroups of B-cell precursor ALL were defined as
follows: pro-B ALL, TdT+ CD19+
CD10 cyIgM
SIg; common ALL, TdT+ CD19+
CD10+ cyIgM SIg;
pre-B ALL, TdT+ CD19+ CD10+
cyIgM+ SIg.14
Cytogenetics.
For cytogenetic analysis, performed in one of the three reference
laboratories (Fonatsch, Lübeck, Germany; Heinze, Ulm, Germany; and Hossfeld, Hamburg, Germany), chromosomes were prepared directly and
after 24, 48, and 72 hours of short-term cultivation. Methods used for
cell harvest, chromosome preparation, and staining by G-banding
technique are described elsewhere.33 Chromosome
abnormalities were identified and assigned according to an
International System for Human Cytogenetic Nomenclature.48
Molecular studies.
RNA was isolated from cryopreserved leukemia cells obtained at initial
diagnosis. MLL-AF-4 fusion transcripts were analyzed by reverse
transcription-polymerase chain reaction (RT-PCR) as described in detail
elsewhere.49
Clinical investigations.
Clinical investigations were composed of physical examination and
peripheral blood and bone marrow analyses. Lumbar puncture for cerebrospinal fluid (CSF) analysis was performed at diagnosis irrespective of whether neurological symptoms were present. Routine laboratory analyses included lactate dehydrogenase (LDH) levels. Furthermore, ultrasonography of the abdomen, x-ray of the chest, computer tomography of the chest and abdomen (if necessary), and echocardiography were performed.
Treatment schedules.
Stratification criteria applied to the definition of low- and high-risk
patients and indications for allogeneic bone marrow transplantation
(BMT) in first complete remission (CR) were previously reported.50 The criteria used for the definition of the
high-risk group in GMALL studies 03/87 and 04/89 were as follows: age
greater than 35 years, white blood cell (WBC) count greater than
30 × 109/L, time to CR greater than 4 weeks, pro-B ALL (formerly designated as null ALL), and Ph+
ALL.
Treatment consisted of induction, reinduction, different consolidation
regimens (depending on study and risk group), maintenance, and CNS
prophylaxis (Fig 1).
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| Fig 1.
Treatment strategies for high-risk patients of GMALL
studies 03/87 and 04/89. The therapy protocols are given in detail in
Table 1.
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The drugs and doses used in the treatment protocols are listed in
Table 1. The induction and reinduction
treatment was similar for all patients in GMALL studies 03/87 and 04/89
and has been described in detail elsewhere.51 Patients with
large tumor mass or high initial white blood cell count (>25 × 109/L) received 1 week of preinduction treatment with 60 mg/m2 prednisolone orally (PO; days 1 through
7) and 2 mg vincristine intravenously (IV; day 1). The
induction was composed of eight cytotoxic drugs administered
sequentially in two phases over an 8-week period. During the first 4 weeks (phase I), the patients received 60 mg/m2
prednisolone PO daily (days 1 through 28) plus 45 mg/m2
daunorubicin and 2 mg vincristine IV weekly (days 1, 8, 15, and 22).
L-asparaginase (5,000 U/m2) was administered IV daily (days
15 through 28). In the second 4 weeks (phase II), patients received two
doses of 650 mg/m2 cyclophosphamide IV (days 29 and 57)
together with 60 mg/m2 6-mercaptopurine PO daily (days 29 through 57) and four courses of 75 mg/m2 cytarabine IV
(days 31 through 34, 38 through 41, 45 through 48, and 52 through 55).
In study 04/89, one additional dose of cyclophosphamide was
administered on day 43. Reinduction treatment was scheduled to begin
week 21. The first 4-week cycle of reinduction was identical to phase I
of induction, except for daunorubicin, which was substituted by 25 mg/m2 adriamycin, and L-asparaginase, which was omitted.
During phase II of reinduction, patients received 650 mg/m2
cyclophosphamide IV once (day 29), 60 mg/m2 thioguanine PO
(day 29 through 42), and two cycles of 75 mg/m2 cytarabine
(days 31 through 34 and 38 through 41).
Consolidation treatment was different in studies 03/87 and 04/89. In
GMALL study 03/87, high-risk patients received one cycle of high-dose
(HD) cytarabine (3 g/m2, every 12 hours as a 3-hour
infusion, days 1 through 4) plus 10 mg/m2 mitoxantrone IV
(days 2 through 6). For patients older than 50 years, the dose of
cytarabine was reduced to 1 g/m2. After reinduction,
maintenance was started with daily oral doses of 60 mg/m2
mercaptopurine and 20 mg/m2 methotrexate IV weekly from
week 28 to 132, without further consolidation cycles. In GMALL study
04/89, younger patients (15 to 50 years of age) in the high-risk group
were scheduled for allogeneic BMT after induction phase II if a
HLA-compatible sibling donor was available. Patients without a donor
were randomized to receive either one cycle of HD cytarabine and
mitoxantrone (week 13), as described above, or three cycles of HD
methotrexate and L-asparaginase (weeks 13, 15, and 17). The dosage of
cytarabine was reduced to 1 g/m2, and mitoxantrone
treatment was shortened (days 2 through 5). HD methotrexate was
administered as a 24-hour infusion at the dose level of 1,500 mg/m2 (1/10 during the first 30 minutes and 9/10 during
23.5 hours) on day 1, followed by 10,000 U/m2
L-asparaginase as a 1-hour infusion on day 2 and a leucovorin rescue.
After reinduction, patients received two cycles of teniposide and
cytarabine (weeks 31 and 35). Teniposide (60 mg/m2) and
cytarabine (75 mg/m2) were each administered as a 1-hour
infusion daily from day 1 to 5. Starting from week 39, maintenance
treatment was administered up to week 142. In patients older than 50 years, consolidation consisted of two further cycles of teniposide and
cytarabine (weeks 13 and 17) instead of the randomized consolidation,
as described above.
CNS prophylaxis, consisting of 15 mg methotrexate, was administered
intrathecally on days 1, 31, 38, 45, and 52 of induction and on day 1 of reinduction. During maintenance, patients received every 2 months
intrathecal (IT) triple chemotherapy with 15 mg methotrexate, 40 mg
cytarabine, and 4 mg dexamethasone, up to a total number of 12 administrations. In GMALL study 04/89, all patients
received cranial irradiation with 24 Gy parallel to induction phase II.
Intrathecal methotrexate was administered as described above.
Intrathecal triple therapy started from days 1 and 29 of reinduction
and was continued during maintenance, as described above. The triple
combination was also administered intrathecally on day 1 of the cycles
with teniposide and cytarabine.
In GMALL study 03/87, all patients with pro-B ALL were treated in
accordance with the high-risk protocol, whereas, in study 04/89,
elderly patients (>50 years) were stratified into the standard-risk group.50
Statistical analysis.
The statistical analysis was performed by the Biometric Centre for
Therapy Studies (Ü. Aydemir, Munich, Germany) and N. Gökbuget (Frankfurt, Germany). The influence of entrance
parameters on the achievement of CR was evaluated by the
 2-test. Median values were compared using the
Wilcoxon-Mann Whitney test. Survival was defined as the time from the
beginning of the therapy to the date of the last review or death in all
evaluable patients. Probability of continuous CR (CCR) was determined
from the date of CR to the date of last review or BMT in censored
patients and to the date of relapse or death in CR in patients with
events. The probability of surviving and remaining in CR was estimated by the Kaplan and Meier method.52 The univariate comparison between survival curves was performed by the log-rank
test.53
The results were updated in May 1997, with a median follow-up time for
censored patients for study ALL 03/87 of 2,547 days and for study ALL
04/89 of 2,051 days.
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RESULTS |
Clinical characteristics of the patients.
Of the 65 pro-B ALL patients from 28 different centers enrolled in two
consecutive studies (GMALL 03/87 and 04/89), 57 patients were
evaluable. Reasons for exclusion were refusal of the treatment protocol, psychotic depressive disorder, and pro-B ALL as second neoplasm. The clinical characteristics of the evaluable patients are
shown in Table 2. Pro-B ALL patients in
GMALL study 04/89 had a higher median WBC count compared with study
03/87 (85.3 v 14.5 × 109/L; P = .007). Thirty-eight percent of the patients in GMALL study 03/87 as
compared with 12% in study 04/89 had initial infections (P = .03). There was a higher proportion of patients older than 50 years in
GMALL study 03/87 (44%) and a higher median age (42.5 years) compared
with study 04/89 (17% and 28 years, respectively). However, these
differences did not reach statistical significance. The other clinical
characteristics did not differ significantly between both studies.
Morphology and cytochemistry.
Of the 53 evaluable patients with pro-B ALL, 79% disclosed a L2
morphology as compared with 66% of common ALL patients analyzed in
parallel. No clear-cut differences could be observed between pro-B and
common ALL with regard to cytoplasmic or nuclear features and
cytochemical stainings. In none of the patients were MPO-positive blasts found.
Immunophenotyping.
Although the total number of patients varied for each marker tested,
mainly because of insufficient cell numbers, the diagnostically relevant B-, T-, and myeloid-lineage, as well as
non-lineage-restricted antigens could be analyzed in the vast majority
of the patient population.
By definition, none of the patient samples expressed CD10, whereas
leukemic blasts from all patient samples tested for CD19 (N = 53)
expressed this antigen. Expression of CD24 was found in 35 of 53 patients (66%), and weak expression (20% to 40% positive cells) of
CD20 was found in 3 of 56 patients (5%). In none of the 57 patients
was evidence for coexpression of the T-lineage-associated antigen CD7
found.
Of the panmyeloid antigens analyzed, a coexpression of CD65s was
observed in 24 of 56 patients (43%), whereas a coexpression of CD13
and CD33 occurred much less frequently (10% and 14%, respectively). In all patients, coexpression of B- and myeloid-lineage-associated antigens was confirmed by two-color IF studies or marked numerical overlap of percentage of cells expressing the respective antigens.
HLA-DR was strongly expressed by leukemic blasts from all 57 patients,
and TdT-positivity was found in 51 of 55 patients (93%). CD34
positivity was found in 29 of 50 patients (58%).
Cytogenetic and molecular studies.
Of the 57 evaluable patients, adequate cytogenetic analyses could be
performed in 33 patients and molecular studies could be performed in 18 patients. In 12 patients, both cytogenetic and molecular data were
available.
Nine of the 33 patients with adequate cytogenetic studies had only
normal metaphases. Eighteen patients (54.5%) had a t(4;11)(q21;q23), including 1 patient with the derivative chromosome der (11) involved in
a translocation t(11;17)(p11;q11) (Table
3).
Six patients had other structural or numerical abnormalities. Two of
these patients had a standard t(9;22)(q34;q11), with 1 of them showing
additional aberrations such as dup(1)(q23q32), del(16)(q11) and
i(17)(q10).54 In both patients with a Ph chromosome, coexpression of myeloid antigens (CD33 and/or CD13) on leukemic blasts was detected by immunophenotyping. Other cytogenetic
abnormalities included 1 patient with hyperdiploidy (56 chromosomes), 1 with complex aberrations, 1 with a dic(7;9)(p11;p11), and 1 with a der(2q).
Molecular studies performed by RT-PCR showed MLL-AF-4 transcripts in 12 of 18 patients analyzed. Of the 10 patients in our study with a t(4;11)
and/or evidence of MLL-AF-4 rearrangements, for whom both
cytogenetic and molecular studies were available, the two methods were
in agreement in 8 cases, whereas molecular studies showed MLL-AF-4
transcripts in 2 patients, with 1 showing a normal karyotype and 1 a
derivative chromosome 2 by cytogenetic analysis (Table 3).
Correlation of surface antigen expression with genotypic features and
initial clinical characteristics in patients with chromosome 11q23
abnormalities.
The initial characteristics of 22 patients ordered by age with a pro-B
ALL and a t(4;11) and/or a MLL-AF-4 rearrangement are summarized in Table 3. Age ranged from 22 to 62 years. The presence of
a t(4;11) or of a MLL rearrangement occurred more frequently in male
patients and, in most cases, was associated with very high leukocyte
counts. Coexpression of CD65s on leukemic blasts was found in 14 of 22 patients; in 2 additional cases, there was a small subpopulation of
leukemic cells disclosing CD65s positivity. In none of the 22 patients,
lymphoblasts demonstrated a clear coexpression of the other panmyeloid
antigens tested (ie, CD13, CD33). In contrast to other B-lineage ALL
subgroups, such as common, pre-B and B-ALL, the percentage of CD19
positive blasts (>70% in all but 1 case) was much higher than that
for CD24 in all patients, with most cases showing low levels (20% to
40% CD24+ cells) or, occasionally, missing CD24
expression.
Clinical features and response to induction therapy according to
cytogenetic and/or molecular analyses.
For comparison of the main pretherapeutic features and response to
induction therapy, the 57 patients were divided into three subgroups
based on the availability and the results of cytogenetic and/or
molecular analyses: (1) patients with a t(4;11) and/or a
MLL-AF-4 rearrangement; (2) patients with a normal karyotype and other
cytogenetic abnormalities without MLL-AF-4 rearrangement; and (3)
patients for whom cytogenetic and/or molecular results were not
available (Table 4). Comparisons between
patients with a t(4;11) and/or a MLL-AF-4 rearrangement and
patients with a normal karyotype or other cytogenetic abnormalities
showed the following significant differences: patients with a t(4;11)
and/or a MLL-AF-4 rearrangement were more often in the younger
age group (P = .007) and had less often initial infections
(P = .01), and their leukemic blasts disclosed more often a
coexpression of CD65s (P = .03). Additionally, there was a male
predominance and a higher median WBC count in patients with a t(4;11)
and/or a MLL-AF-4 rearrangement that, however, did not have
statistical significance. The other clinical characteristics and the CR
rate did not differ significantly between patients with a t(4;11)
and/or a MLL-AF-4 rearrangement and patients with a normal
karyotype or other cytogenetic abnormalities.
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Table 4.
Characteristics of Patients and Response to Induction
Treatment in Pro-B ALL Subtypes According to Cytogenetic and
Molecular Analyses
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Treatment results.
Table 5 summarizes the overall results of
the induction therapy and the subsequent course of adult patients with
pro-B ALL in GMALL studies 03/87 and 04/89. The CR rate did not differ
significantly between both studies. One patient in GMALL study 03/87
and 6 in study 04/89 failed to achieve a CR due to treatment failure,
and 8 patients died during induction therapy within 56 days (early death) because of tumor lysis syndrome (N = 1), infection (N = 5),
hepatic failure (N = 1), or unknown cause (N = 1). Of the 12 patients
who achieved a CR in GMALL study 03/87, 10 relapsed or died in CR and 2 patients remain in CR. One of the 2 patients remaining in CCR received
autologous BMT and the other was treated using HD cytarabine and
mitoxantrone as consolidation. Of the 30 patients who achieved a CR in
GMALL study 04/89, 16 (median age, 25 years; range, 16 to 51 years)
remained in CCR between 883 and 2,886 days. Two patients died in CR and
12 patients relapsed. Of the 16 patients remaining in CCR, 11 received
consolidation therapy with HD cytarabine and mitoxantrone (N = 7), with
HD methotrexate and L-asparaginase (N = 2), or with
teniposide and cytarabine (N = 2). Five of the CCR patients received
allogeneic (N = 4) or autologous (N = 1) BMT. Both patients
with autologous BMT had received consolidation therapy with HD
cytarabine and mitoxantrone before BMT.
The estimated probability of CCR and overall survival is shown in
Figs 2 and
3, respectively. For the 12 CR patients
in GMALL study 03/87, the median remission duration is 420 days and the probability of being in CCR at 5 years is 10%. For the 30 CR patients in GMALL study 04/89, the median remission duration has not yet been
reached and the probability of being in CCR at 5 years is 52% (study
03/87 v 04/89: P = .04). The estimated median
survival is 571 days for all 16 patients in study GMALL 03/87, compared with 747 days for all 41 patients in study 04/89 (P = .21).
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| Fig 2.
Probability of continuous complete remission of 12 adult
patients with pro-B ALL treated in GMALL study 03/87 (0.10; median, 420 days) and of 30 adult patients with pro-B ALL treated in GMALL study
04/89 (0.52; median, not yet reached). P (log-rank) = .04.
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| Fig 3.
Probability of survival of 16 adult patients with pro-B
ALL treated in GMALL study 03/87 (0.19; median, 571 days) and of 41 adult patients with pro-B ALL treated in GMALL study 04/89 (0.41;
median, 747 days). P (log-rank) = .21.
|
|
Probability of CCR and overall survival proved to be dependent on age,
with a better outcome for the younger age group (probability of being
in CCR, 0.45; probability of survival, 0.41) compared with older
patients (0.13 and 0.07, respectively). However, these differences only
had statistical significance for survival (P = .006) when both
studies were analyzed together. When looking at different age groups in
GMALL studies 03/87 and 04/89 with regard to their treatment outcome,
the median remission duration (not yet reached) and probability of
being in CCR (59%) in the younger age group were better for 26 CR
patients in study 04/89 when compared with 8 CR patients in study 03/87
(median, 334 days; probability of CCR, 16%). However, this difference
was not significant (P = .06), probably due to the small number
of patients.
Of the 11 patients in the younger age group receiving consolidation
therapy with HD cytarabine and mitoxantrone in GMALL studies 03/87 and
04/89, 8 remained in CCR more than 3 years. Of the 7 patients receiving
consolidation with HD methotrexate and L-asparaginase in GMALL study
04/89, 2 are still in CCR. Nine patients from both studies underwent
BMT (allogeneic N = 7, autologous N = 2), and 6 of them remain in CCR
(allogeneic N = 4, autologous N = 2). The median age of the patient
groups receiving either different consolidation regimens or BMT is
comparable (HD cytarabine plus mitoxantrone, 22 years; HD methotrexate
plus L-asparaginase, 26 years; and BMT, 24 years). The median remission
duration for consolidation with HD cytarabine and mitoxantrone has not
been reached (probability of being in CCR, 68%) compared with 576 days
(probability of being in CCR, 29%) for consolidation with HD
methotrexate and L-asparaginase (P = .07).
Of the 57 patients with pro-B ALL, 22 had a t(4;11) and/or
molecular evidence of MLL-AF-4 fusion transcripts, of whom 17 (77%) achieved a CR. Fifteen of the patients who achieved a CR were in the
younger age group, with 8 of them still being in CCR. The patients with
a t(4;11) and/or MLL-AF-4 transcripts did not differ with
respect to the estimated probability of CCR (40%) and overall survival
(41%) from patients with a normal karyotype or with other cytogenetic
abnormalities (probability of CCR, 45%; overall survival, 40%;
P = .46 and .53, respectively; Figs
4 and 5). Pro-B ALL patients whose
leukemic blasts disclosed a coexpression of myeloid-associated antigens, mainly CD65s, did not differ significantly regarding duration
of remission and survival from patients with a
myeloid-antigen-negative pro-B ALL (data not shown).
View larger version (13K):
[in this window]
[in a new window]
| Fig 4.
Probability of CCR for pro-B ALL patients treated in
GMALL studies 03/87 and 04/89 according to the results of the
cytogenetic and molecular analyses. Seventeen patients with a t(4;11)
and/or MLL-AF-4 fusion transcripts (0.40; median, 576 days) and
11 patients with a normal karyotype or with other cytogenetic
abnormalities (0.45; median, 1,906 days). P (log-rank) = .46.
|
|
View larger version (13K):
[in this window]
[in a new window]
| Fig 5.
Probability of survival for pro-B ALL patients treated in
GMALL studies 03/87 and 04/89 according to the results of the
cytogenetic and molecular analyses. Twenty-two patients with a t(4;11)
and/or MLL-AF-4 fusion transcripts (0.41; median, 484 days) and
13 patients with a normal karyotype or other cytogenetic abnormalities
(0.40; median, 2,373 days). P (log-rank) = .53.
|
|
For high-risk patients with a common or pre-B ALL, the median remission
duration is 309 days and the probability of being in CCR at 4 years
18% in GMALL study 03/87, as compared with a median remission duration
of 317 days and a probability of being in CCR at 4 years of 20% in
study 04/89. In GMALL study 03/87, there was no difference between the
CCR probability for pro-B ALL versus common and pre-B ALL patients
(19% v 18% at 4 years; P = .99), whereas in study
04/89, the CCR probability for pro-B ALL was superior to common and
pre-B ALL (52% v 20% at 4 years; P = .006).
| |
DISCUSSION |
In contrast to childhood ALL, few studies on cell-biological features
and treatment outcome in adults with CD10 pro-B ALL
have yet been reported. The present prospective study, including 57 adult patients with pro-B ALL treated on two consecutive multicenter
trials, is the largest report published to date. Our results as to the
frequency of pro-B ALL (~10%) are in agreement with other recent
studies of adult ALL. More importantly, we observed a high incidence
(~50%) of a t(4;11) and/or MLL-AF-4 fusion transcripts with
characteristic associations between immunophenotype, genotype, and
clinical features in adult pro-B ALL, comparable with previous findings
in childhood, especially infant ALL. Furthermore, the treatment outcome
observed in study ALL 04/89 is the first report in adult patients
showing that intensification of postremission treatment by HD
cytarabine and mitoxantrone or allogeneic BMT can lead to a substantial
improvement of prognosis in this high-risk patient population.
According to our criteria, 57 of 611 evaluable patients (9%) could be
assigned to the pro-B immunophenotype. Thus, the frequency of pro-B ALL
observed in the studies ALL 03/87 and 04/89 is twice as much when
compared with the data reported in childhood ALL, indicating a higher
proportion of cases in adult ALL being arrested at this very immature
stage of B-lymphoid differentiation.12,20 Our findings are
in line with other recent studies in adult ALL patients applying a
similar panel of MoAbs to the immunophenotypic characterization of
leukemic blasts.10,11,13 However, few of these studies
provided detailed results as to the antigenic profile, including
myeloid-antigen coexpression, as well as immunophenotypic-genotypic associations of this subgroup, and in only one study was the treatment outcome of pro-B ALL reported.13
The results of our detailed immunologic marker analyses underline the
diagnostic value of CD19 for lineage affiliation in immature B-cell
precursor ALL. In view of the strong expression levels of CD19 in all
cases investigated, the application of other, more recently identified
pan-B markers such as CD79a may be restricted to those rare cases
without CD19 expression.55 In the vast majority of adult
ALL patients with a t(4;11) and/or molecular evidence of
MLL-AF-4 fusion transcripts, leukemic blasts disclosed a typical antigenic profile (ie, CD10, CD19+,
CD24 or weakly +, CD65s+). In our
experience, these features, especially the missing or weak expression
of CD24 as compared with CD19, and the coexpression of CD65s, usually
associated with negativity of other panmyeloid antigens (eg, CD13,
CD33), are highly predictive for the cytogenetic and/or
molecular demonstration of MLL rearrangements, mostly due to a t(4;11),
or, more rarely, other 11q23 aberrations. This statement is in line
with our data from a relatively large series of pro-B ALL patients
composed of children and adults49,56 that
documented a significant association of the MLL-AF-4 recombination with
coexpression of CD65s and/or CD15, as well as other previous
studies in childhood and adult ALL based on cytogenetic and/or
molecular analyses.15,17-19,36,39,40,42,43
The recently generated MoAb 7.1, which recognizes the chondroitin
sulfate proteoglycan molecule NG2 expressed by malignant hematopoietic
cells with abnormalities in chromosome band 11q23 but not by normal
hematopoietic cells, may be useful in the future for screening ALL
patients with pro-B ALL for whom cytogenetic and molecular analyses are
not available, both at diagnosis and during follow-up for detection of
minimal residual disease (MRD).57,58
In our study, 22 of 35 adults with adequate genotypic studies disclosed
a t(4;11) and/or MLL-AF-4 rearrangements, the molecular hallmark of a t(4;11). Considering the overall frequency of pro-B ALL
in adult ALL and the usual absence of a t(4;11) and MLL-AF-4 transcripts in other B-lineage ALL subgroups,49 our results match well with a recent large cytogenetic study performed on 443 adult
patients with ALL indicating an incidence of 4% for ALL associated
with a t(4;11).15 However, it should be taken into account
that, in our series, adequate cytogenetic studies could only be
performed in 58% of patients, and molecular analyses were
retrospectively performed in a relatively small proportion of these
patients selected only by availability of cryopreserved cell samples.
In view of the typical antigenic profile (weak or missing expression of
CD24, coexpression of CD65s, and absence of other panmyeloid antigens
such as CD13 and CD33) observed in the additional 6 patients without
cytogenetic and molecular studies, in our results the true incidence of
a t(4;11) in adult pro-B ALL is probably underestimated. Furthermore,
our study did not include a systematic survey, eg, by Southern blot
analysis, of other 11q23 abnormalities that have been recently
described to occur in infant ALL in up to 25% of cases based on
cytogenetic and molecular studies40 and in about 7% of
adult ALL cases based on cytogenetic analyses.15
The results of our molecular analyses demonstrating an MLL-AF-4
rearrangement in 1 patient with cytogenetic abnormalities not involving
chromosome 11 and in 1 patient with a normal karyotype are in
accordance with recent sudies, indicating that cytogenetic studies may
fail to detect 11q23 translocations.24,39,40,49,56 In
contrast, very few studies have yet reported on patients with a t(4;11)
who disclose a germline configuration of the MLL gene on the molecular
level.40 Taken together, our data in adult ALL patients and
other studies, mainly comprising infants with ALL, provide a compelling
reason to test MLL rearrangements by molecular analyses in all newly
diagnosed CD10 B-lineage ALL patients entered into
treatment protocols.
Contradictory findings have been reported on the main clinical risk
factors such as age and WBC count, as well as on other clinical
characteristics such as sex distribution, organomegaly, and initial CNS
manifestation within the group of adult pro-B ALL patients. Our
results, indicating that pro-B ALL patients are slightly older and
usually have higher WBC counts as compared with other B-lineage ALL
subgroups, are in line with a recent report of the French LALA87
study13 including 45 patients with pro-B ALL. Additionally,
there is a slight female predominance and evidence of organomegaly in
about 40% of patients. More importantly, the analysis of clinical
characteristics according to the cytogenetically and/or
molecularly defined subgroups showed a much higher WBC count and a
higher proportion of male patients within the pro-B ALL subgroup
characterized by a t(4;11) and/or fusion transcripts of
MLL-AF-4. Moreover, patients with 11q23 abnormalities were younger at
diagnosis compared with those without these genetic abnormalities. Our
results concerning the mean age, mean WBC counts, and sex ratio are
comparable with a recent review summarizing the clinical data of
children and adults with ALL and a t(4;11).28 Other recent
studies on the correlation between cytogenetic abnormalities and
clinical characteristics in adult ALL patients also uniformly observed
very high WBC counts in ALL cases associated with a
t(4;11).15,42 In one of these studies, which was based,
however, only on 6 cases with a t(4;11), the investigators suggested
that patients greater than 50 years of age may be twice as likely as
children to have t(4;11) ALL.42 In our study, which was
restricted to adult patients between 15 and 65 years of age, no clue as
to an increased incidence of a t(4;11) in the older age group was
found.
Our results, which demonstrate a CR rate of about 75% for pro-B ALL
patients in studies GM-ALL 03/87 and 04/89, are in line with other
studies that did not observe substantial differences in remission rates
for childhood or adult B-cell precursor ALL subgroups. However,
previous studies have reported a worse prognosis for both children and
adults whose leukemic blasts express an immature pro-B phenotype, which
in adult series are usually referred to as
null-ALL.7,13,16,17,20 As pointed out above,
this inferior treatment outcome can be, especially in infant ALL,
explained by the association of this immunophenotype with adverse
biological (eg, 11q23 rearrangements) and clinical features (eg,
hyperleukocytosis), occurring in up to 50% of patients.
In this regard, the treatment outcome of pro-B ALL patients in GMALL
study 04/89 is remarkable for several reasons.
Firstly, remission duration and overall survival of pro-B ALL patients
could be substantially improved in GMALL study 04/89 as compared with
the preceding GMALL trials.7,59 This may be, at least
partially, explained by the intensification of postremission therapy,
either by the administration of HD cytarabine and mitoxantrone or by
allogeneic BMT in first CR. The inferior outcome of pro-B-ALL patients
in GMALL study 03/87 may be due to the higher proportion of elderly
patients older than 50 years of age (see Table 2) who possibly did not
benefit from an intensive consolidation with HD cytarabine and
mitoxantrone,60 and, accordingly, the lower proportion of patients who underwent BMT (8% v 27%). Our
results in GMALL study 04/89, implying an improvement of prognosis for pro-B ALL patients due to more intensive therapy, are corroborated by
the results of the ongoing GMALL study 05/93, including 47 patients
with pro-B ALL who received identical consolidation with HD cytarabine
and mitoxantrone as in study 04/89. In this study, comparable with the
results of study 04/89, a CR rate of 81% and a relatively high
probability of CCR (0.55 at 2 years) could be achieved (Hoelzer et al,
unpublished observations). Interestingly, recent studies
with the 3-(4,5-dimethyl-thiazol-2-yl)-2,5 diphenyl tetrazolium bromide
(MTT) assay indicate a high antileukemic activity of cytarabine as
compared with corticosteroids, L-asparaginase, and anthracyclines in
leukemic blasts from pro-B ALL patients (R. Pieters, personal
communication, April 1997), thus supporting our treatment
results in studies 04/89 and 05/93.
High-risk patients with a common or pre-B ALL phenotype, as compared
with pro-B ALL, had a similar probability of CCR in study GMALL 03/87
and a significantly inferior probability of CCR in study 04/89. These
data suggest that this subgroup of B-lineage ALL, which, however,
includes a large number of Ph+ patients, did not benefit
from an intensification of consolidation treatment.
Secondly, the division of pro-B ALL patients into different subgroups
according to the genotypic features of their leukemic blasts allowed us
to demonstrate that a portion of adult patients with a t(4;11)
and/or MLL-AF-4 transcripts may achieve long-term remission and
probably cure, after having received intensive postremission treatment.
Our recent observations, applying RT-PCR analyses to detect MLL-AF-4
rearrangements in 5 adults with pro-B ALL in CR, all of whom exhibited
MLL-AF-4 transcripts at diagnosis and lacked evidence of minimal
residual disease 8 to 52 months after diagnosis, are in line with this
statement.49 These results are in contrast with previous
reports, mainly based on surveys of literature,28,29,34 or
comprising a relatively small number of patients with, usually, heterogeneous treatment.31,32,42,43 These reports
unequivocally suggested that, of patients with a t(4;11), adults had
the worst prognosis, with median survivals of 7 months,31
even with contemporary intensive treatment strategies, thus justifying
the use of BMT or innovative treatment approaches.34
Thirdly, as opposed to the French LALA87 study group that recently
published their results in 45 adult patients with
CD10 B-lineage ALL,13 our data strongly
suggest that the distinction between CD10 pro-B ALL
and CD10+ common or pre-B ALL provides useful information
for tailoring treatment strategies according to specific subtypes of
ALL. Adult patients with pro-B ALL and 11q23 translocations, in our
series exclusively t(4;11), represent a distinct clinicopathologic
entity that can be recognized easily based on its immunophenotypic and genotypic features. Obviously, further studies, applying cytogenetic and, especially, molecular analyses, are needed to better characterize the biological and clinical features of adult pro-B ALL patients whose
leukemic blasts lack 11q23 translocations, display 11q23 rearrangements
not caused by a t(4;11), or show deletions and inversions affecting the
11q23 region but do not involve MLL rearrangements. Recent results from
the Groupe Francais de Cytogénétique Hématologique suggested that adult patients with breakpoints on 11q23 not involving a
t(4;11) or deletions of 11q23 had the same poor outcome as patients with a t(4;11).15 In contrast, a recent study of 17 childhood ALL cases with a deletion or inversion affecting the 11q23
region without molecular evidence of MLL gene rearrangements suggested that these structural chromosomal abnormalities do not share the unfavorable prognosis of 11q23 translocations and, therefore, represent
clinically and biologically different entities.61
In conclusion, our results in a large series of consecutively studied
adult pro-B ALL patients suggest that current intensive therapies
including consolidation with HD cytarabine and mitoxantrone or
allogeneic BMT may improve the prognosis of this B-lineage ALL subgroup
despite its high-risk genetic and clinical features. Moreover, our data
demonstrate that, in contrast to former results, long-term remission
duration can be achieved in a subset of pro-B ALL patients. In the
future, the combined application of immunophenotyping as well as
cytogenetic and molecular studies will be essential for a more precise
distinction of the biological heterogeneity within this group of
patients and, hopefully, will contribute to individually adjusted
treatment strategies.
| |
FOOTNOTES |
Submitted November 6, 1997;
accepted April 22, 1998.
Supported by the Bundesministerium für Forschung und
Technologie, Federal Republic of Germany, Contract No. 01ZP88045 and by
Deutsche Krebshilfe, Federal Republic of Germany, Contract No.
M84/92Ho1.
Presented in part at the 1994 annual meeting of the American Society of
Hematology.
Address reprint requests to Wolf-Dieter Ludwig, MD,
Robert-Rössle-Klinik, Department of Hematology, Oncology, and
Tumor Immunology, Universitätsklinikum Charité,
Medizinische Fakultät der Humboldt-Universität zu Berlin,
Lindenberger Weg 80, D-13125 Berlin, Germany; e-mail: ludwig{at}rrk-berlin.de.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract