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Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 735-746
REVIEW ARTICLE
Biology and Treatment of Childhood T-Lineage Acute Lymphoblastic
Leukemia
By
Fatih M. Uckun,
Martha G. Sensel,
Lei Sun,
Peter G. Steinherz,
Michael E. Trigg,
Nyla A. Heerema,
Harland N. Sather,
Gregory H. Reaman, and
Paul S. Gaynon
From the Children's Cancer Group (CCG) ALL Biology Reference
Laboratory, and Wayne Hughes Institute, St Paul, MN; Group Operations
Center, Children's Cancer Group, Arcadia, CA; the Department of
Pediatrics, Sloan-Kettering Cancer Center, New York, NY; the Department
of Hematology-Oncology, University of Iowa Hospitals and Clinic, Iowa
City; the Department of Medical and Molecular Genetics, Indiana
University School of Medicine, Indianapolis; the Department of
Preventive Medicine, University of Southern California, Los Angeles,
and Group Operations Center, Children's Cancer Group, Arcadia, CA; the
Department of Hematology-Oncology, Children's National Medical Center,
and the George Washington University, Washington, DC; and the
Department of Pediatric Hematology-Oncology, University of Wisconsin,
Madison.
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INTRODUCTION |
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) is the
most prevalent type of cancer, as well as the most common form of
leukemia in children.1 This lymphoid malignancy, manifested
by the proliferation of lymphopoietic blast cells, represents a
heterogeneous group of diseases that vary with respect to
morphological, cytogenetic, and immunologic features of the transformed
cells. Technical improvements in immunofluorescence staining and flow
cytometry together with the availability of numerous monoclonal
antibodies (MoAbs) that recognize lineage-associated membrane molecules
have illuminated the immunophenotypic heterogeneity in ALL. We now know
that leukemia cells from patients with ALL may express various
combinations of surface antigens that are found normally on lymphocyte
precursors at discrete stages of maturation.2,3 Thus, the
malignant clones in patients with ALL are thought to originate from
normal lymphoid progenitor cells arrested at early stages of B- or
T-lymphocyte ontogeny. Although cells from the majority ( 85%) of
pediatric patients express B-lineage-associated antigens, those from
approximately 15% of patients express the T-lineage-associated
antigens CD1, CD2, CD3, CD4, CD5, CD7, or CD8.4-6 T-lineage
ALL in children is associated with numerous unfavorable presenting
features, thus it is not surprising that children with T-lineage ALL
frequently have been reported to have a worse prognosis than children
with B-lineage ALL.4,5,7-10 However, a number of
encouraging reports from recent clinical studies using contemporary
risk-adjusted multiagent chemotherapy programs have documented
remarkably improved outcomes for patients with T-lineage
ALL.6,10-14 Moreover, advanced preclinical studies have
triggered much optimism that new agent discovery programs may lead to
further improvements in outcome in the near future. In this review, we
discuss current concepts regarding the etiology, biological
characteristics, clinical features, and treatment of pediatric
T-lineage ALL.
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ETIOLOGY |
The role of numerous epidemiological factors, including maternal and
paternal exposure to radiation, history of maternal fetal loss or
fertility problems, higher birthweight at diagnosis, and use of
exogenous growth hormone, remains controversial in the cause of
pediatric ALL.15-17 A recent comprehensive review found no
relationship between exposure to electromagnetic field
(EMF) radiation and incidence of childhood
ALL.18 The reported space-time clustering of ALL cases,
which might suggest an etiologic agent such as a virus, is also
controversial.19-23 Human T-cell leukemia virus-I and II
may be associated with adult, but not pediatric T-lineage leukemia or
lymphoma,24,25 and Epstein-Barr virus infection has been
linked to a limited number of cases of T-cell lymphoma, but not
T-lineage ALL, in children.26
The autosomal recessive disorder ataxia telangiectasia (AT) appears to
be a true etiologic factor because patients with AT have an increased
risk of developing lymphoid malignancies, including T-lineage
ALL.27 Translocations involving the T-cell receptor (TCR)
loci are reported in approximately 10% of the T cells from patients
with AT,28 but interestingly, the most frequent of these
translocations appear to involve different regions within the TCR loci
compared with those observed in patients with T-lineage ALL without
AT.29-31 The molecular basis for these effects as well as
other genetic abnormalities that may play a role in T-lineage leukemia
will be discussed below. Taken together, these data suggest that
multiple factors may be involved in the origin of T-lineage ALL.
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BIOLOGICAL FEATURES OF T-LINEAGE ALL |
Because leukemic cells are thought to originate from normal
T-lymphocyte precursors arrested at early stages of
ontogeny,2,32 every pathway that ensures homeostasis of a
functional immune system is a potential target for disruption. Still,
the fundamental issue of how many different mutations are required for
malignant transformation to the leukemic state remains to be
delineated. Nevertheless, clear associations have been identified
between the occurrence of nonrandom translocations or other gene
mutations and the development of T-lineage ALL. Below, we describe the
specific molecular defects found in T-lineage leukemias and discuss
altered signal transduction pathways that may contribute to the
malignancy.
Chromosomal translocations.
An array of nonrandom translocations that are specific to T-lineage ALL
have been identified; all appear to occur preferentially in the TCR
loci on chromosomes 14 and 7.33 The breakpoints in many
cases resemble TCR recombination signals, implying that the aberration
arose during TCR rearrangement.34-39 Translocations involving chromosomes 1 and 14, such as t(1;14)(p33;q11) and
t(1;14)(p32;q11), have been estimated to occur in approximately 3% of
T-lineage ALL cases.40 In such rearrangements, the
SCL/TCL5/TAL-1 gene from chromosome 1 and the TCR gene on chromosome
1436,41,42 are juxtaposed, resulting in deregulation of
normal TAL-1 expression.41,43 TAL-1 was predicted to encode
a protein containing a helix-loop-helix DNA binding
motif,42,43 suggesting that the t(1;14) translocations could contribute to leukemogenesis by inducing aberrant expression of
novel or TAL-1-regulated genes.
A distinct TAL-1 disruption occurs via an interstitial deletion between
a locus called SIL (SCL interrupting locus) and the 5 UTR of SCL,
resulting in a fusion transcript SIL/SCL, and is estimated to occur
with a frequency of 16% to 26% in T-lineage ALL.44-46
Presence of a TAL-1 disruption was correlated with high white blood
cell (WBC) count, high hemoglobin level, and
CD2+/CD10 immunophenotypes, and
interestingly, 4-year event-free survival (EFS) was higher for patients
with TAL-1 disruption compared to those without TAL-1 alterations
(59% ± 11% v 44% ± 7%, respectively), although this
difference did not reach conventional significance.46 Although TAL-1 is required for development of all hematopoietic lineages in mice,47 the gene is not expressed in B- or
T-lineage cells,41,48 and interestingly, SCL-transfected,
v-ABL-transformed cells appear to be oncogenic in mice.49
Taken together, these data suggest that disruption of normal TAL-1
expression may contribute to the transformation of T-cell precursors
into leukemic blasts.
The t(10;14)(q24;q11) translocation, first identified in T-cell
neoplasms including T-lineage ALL, involves the TCR /TCR locus on
chromosome 1434,35,50 and the TCL3 locus on chromosome
10.34,35 An open reading frame within TCL3 encodes a novel
homeobox protein, HOX-11, whose expression is deregulated as a result
of the translocation.51-53 Moreover, like TAL-1, HOX-11 is
capable of DNA binding and transcriptional activation of reporter
genes, suggesting a role for this gene in leukemic
transformation.54 Additional studies showed that whereas
HOX-11 was expressed in leukemic cell lines and leukemic blasts, it was
not expressed in normal T lymphocytes,52,53,55 but was
required for normal spleen development.56 Reverse
transcriptase-polymerase chain reaction (RT-PCR) assays have suggested
that HOX-11 alterations may occur with high frequency in patients with
T-lineage ALL.57 Thus, deregulation of HOX-11 is likely to
be a biologically significant factor in development of T-lineage
ALL.
Translocations t(11;14)(p13;q11) and t(11;14)(p15;q11) also are
observed frequently in T-lineage ALL58-60; both involve
breakpoints within diversity or J segments the region the TCR or
TCR genes on chromosome 14.37,61,62 McGuire et
al61 described multiple open reading frames
near the chromosome 11 breakpoints and identified one at 11p15 as the
open reading frame of the TTG-1 gene. Similarly, Boehm et
al63 identified the involved region of 11p15 as the
rhombotin gene. Both genes encode proteins characterized by duplicate
cysteine-rich zinc-finger protein binding homology
domains.61,63 A related gene, rhombotin-2/TTG-2, was shown
to be deregulated in cases involving 11p13.63,64 Consistent
with the predicted structure of the rhombotins, a recent report
described the identification of an ets family transcription factor,
ELF-2, that contains rhombotin-2 binding domains, suggesting a
transcriptional regulatory role for rhombotin-2.65
Clinically, several investigators have associated t(11;14)
translocations with an immature stage of thymocyte
development,37,59,60 but the overall prognostic
significance of this translocation remains unclear.
Although translocations involving chromosome 7 occur in both
B-precursor and T-lineage ALL, those involving the TCR- locus at
7q32-36 are specific for T-lineage ALL.66 One such
translocation, t(7;19), truncates the lyl-1 gene on chromosome
19,67 presumably resulting in altered DNA-binding ability
for lyl-1.68 Another case, t(7;9), results in truncation of
the TAN-1 gene on chromosome 9.69 The mouse homologue of
TAN-1 is expressed ubiquitously, but is most abundant in lymphoid
tissues, suggesting that normal expression of TAN-1 is disrupted in
t(7;9)+ ALL.69
The distinct translocation t(1;7)(p34;q34) was shown to juxtapose the
TCR- constant region enhancer upstream of the LCK gene, which
encodes an SRC family protein tyrosine kinase that is involved in
signal transduction through CD4.70,71 Notably,
overexpression of LCK in transgenic mice causes thymomas or both
thymomas and peripheral lymphoid malignancies,72,73
suggesting a role for deregulated LCK expression in leukemogenesis. The
c-myc locus on chromosome 8 defines yet another class of translocations
associated with T-lineage ALL. In t(8;14)(q24;q11), c-myc is
translocated with the TCR loci on chromosome 14, resulting in
deregulation of myc expression.74,75 In t(2;8), a fusion
protein is produced that consists of c-myc and the product of an
unidentified locus on chromosome 2.76 The frequency and
significance of these translocations are unclear at present.
We have recently determined the frequency and clinical significance of
chromosomal abnormalities in a large cohort of patients with T-lineage
ALL enrolled on contemporary CCG studies (Heerema N., et
al, submitted for publication). Translocations involving 14q11 and 7q32-q36 were among the most frequent abnormalities, but
non-TCR loci, including 9p, 6q, 11q23, and 14q32, also were frequently
altered. Notably, none of these abnormalities had prognostic significance in the context of the intensive therapies used in contemporary CCG studies. Nevertheless, the array of
chromosomal rearrangements described above are a hallmark of the
biological diversity of T-lineage ALL and are likely to result from
alterations in underlying cellular control mechanisms. Indeed, recent
advances in our understanding of cell signaling and cell cycle control suggest that defective cell surveillance mechanisms are likely to be
the major factors leading both to unrestrained proliferation of
leukemic cells and to the development of chromosomal abnormalities, including translocations, pseudodiploidy, and hyperdiploidy, that are
associated with leukemic cells.77-80 Alterations in such
control mechanisms are discussed below.
Mutation or loss of cell cycle control genes.
Mutations present in malignant cells allow them to circumnavigate
regulators that control proliferation and differentiation. The
retinoblastoma (Rb) gene was originally identified as a tumor suppressor gene because of its inactivation in cases of retinoblastoma; prostate, breast, and lung cancers; and leukemias.81
Notably, the telomeric Rb1 gene is located on the long arm of
chromosome 13 (13q14), which is inactivated or deleted in approximately
6% of T-lineage ALL cases.82,83
In addition to Rb, other proteins that affect cell cycle progression
include the cyclin-dependent kinase inhibitors p21, p27, and p57, as
well as the inhibitors of Cdk4 (Ink4): p15Ink4b,
p16Ink4a, p18Ink4c, and
p19Ink4d.84-89 Among the Ink4 family of
inhibitors, p15Ink4b and p16Ink4a have been
implicated for a role in the biology of T-lineage ALL.90-95 Both genes map to 9p21, a region on the short arm of chromosome 9 previously shown to be deleted frequently in T-lineage
ALL.33,96-98 In addition, Batova et al95
recently reported that the 5 promoter region of the p15
gene is preferentially hypermethylated, presumably resulting in loss of
transcriptional expression in 38% of newly diagnosed T-lineage ALL.
Another critical regulator of cell cycle progression, the p53 gene, is
the most frequently mutated gene in human cancers.81 The
major function of p53 is to ensure that cells arrest and attempt to
repair genotoxic damage before replicating DNA and entering mitosis.99 In p53-deficient mice, the most common tumor
that arises is a T-lineage lymphoid malignancy.100 Although
p53 mutations are infrequently observed at diagnosis, they are
associated with relapse in pediatric T-lineage ALL.101,102
Another sensor for cell damage appears to be the ATM gene product,
which is mutated in patients with AT.103 After insult with
agents that induce sublethal DNA damage, cells from patients with AT
fail to block DNA synthesis and thereby fail to repair the damaged
DNA.104 These effects are apparently caused by a failure of
the mutated ATM gene to regulate p53.105 ATM-deficient mice
develop an aggressive form of T-lineage
leukemia/lymphoma,106,107 and, as described above, children
with AT frequently develop T-lineage ALL,27,108,109
implicating ATM in leukemogenesis.
Other genes implicated in the malignant transformation of leukemic
cells are Ets-1 and IKAROS. The Ets-1 T-lymphocyte transcription factor
is thought to be important for normal thymic development and for
prevention of cell death in normal mature T cells. A mutation in the
DNA binding domain of the Ets-1 was reported in a case of T-lineage
ALL,110 but the clinical significance of this finding remains to be proven. The IKAROS gene encodes a zinc finger DNA binding
protein that is required for lymphoid cell
differentiation.111 Heterozygous transgenic mice harboring
a defective IKAROS gene develop a very aggressive form of T-cell
leukemia, suggesting that IKAROS may serve as a suppressor of leukemic
transformation.112
Leukemic cells also appear to be altered in their responses to various
stimuli that induce apoptosis. Debatin et al113,114 reported that primary leukemic cells and cell lines from adult patients
with T-cell leukemia were sensitive to FasL-induced cell killing in vitro, whereas leukemic cells from pediatric patients with
T-lineage ALL were resistant. Resistance was unrelated to the quantity
of Fas on the cell surface, but was reversed by treatment with the
protein synthesis inhibitor cycloheximide, suggesting that short-lived
proteins were required for maintenance of the resistant phenotype. In
vivo treatment of a human T-lineage ALL-engrafted severe combined
immunodeficiency (SCID) mouse with an anti-Fas antibody resulted in
prolonged survival, but did not eradicate the disease, supporting the
existence of Fas sensitive and insensitive leukemic
cells.115 These data suggest that altered responses to
apoptotic stimuli or regulatory factors may contribute to the ability
of leukemic cells to escape killing by either immune surveillance or
cytotoxic agents.
Bcl-2, which protects cells from non-Fas-mediated
apoptosis,116,117 is expressed in both T-lineage and
B-lineage leukemias, but it is not yet known how this affects their
ability to survive cytotoxic treatments. A related protein,
Bax,118 acts as an antagonist to Bcl-2 and may
confer radiation sensitivity to cells.119 In a recent CCG
study, we found a marked variation in Bcl-2 expression by primary
leukemic cells from 238 children with newly diagnosed ALL, including 52 patients with T-lineage ALL.120 High-risk features, such as
high WBC count, organomegaly, presence of MLL-AF4 or BCR-ABL fusion
transcripts, or leukemic cell growth in SCID mice, were not associated
with Bcl-2 expression in these patients. For patients with T-lineage
ALL, high Bcl-2 expression was predictive of slow early response (ie,
M3 day 14 marrow status). However, with limited follow-up and overall
excellent outcome for patients, this correlation did not extend to
EFS.
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CLINICAL FEATURES AND TREATMENT OF T-LINEAGE ALL |
T-lineage ALL is distinct from B-lineage ALL not only biologically, but
also clinically. Although the basis for these differences is not well
understood, clinical characteristics have been useful prognostic
factors for guiding the use of experimental treatments. Below, we
describe common presenting features, prognostic variables, and
treatment outcome of patients with T-lineage ALL based on data
accumulated over the last decade. We then focus on causes for treatment
failure and discuss new strategies for improving outcome among
subgroups of patients who remain at risk for relapse despite intensive
therapy.
Presenting features.
The relationship between T-lineage markers and unfavorable presenting
characteristics was first noted by Borella, Sen, and others,121-124 and numerous studies have now confirmed that
compared to patients with B-lineage ALL, those with T-lineage ALL more frequently show the highest WBC range ( 50,000/µL), are nonwhite, older, exhibit marked enlargement of the spleen, liver, and lymph nodes, and have a mediastinal mass.5,7,9,10,125
Modal chromosome number is often abnormal among patients with ALL, with
hyperdiploidy (>50 chromosomes) correlated with favorable outcome and
pseudodiploidy associated with poor
outcome.58,98,126-129 The hyperdiploid karyotype is more
often associated with pre-B or early pre-B
immunophenotypes,129 whereas the pseudodiploid karyotype is
more often associated with the T-lineage immunophenotype.33 Also, "near tetraploid" chromosome number (>65) is more often associated with T-lineage ALL and poor outcome.130 As
described above, nonrandom translocations in T-lineage ALL
preferentially occur in the TCR loci on chromosomes 7 and
14,33 and those involving the TCR locus at 7q32-36 and
the TCR 14q11 collectively occur in approximately 20% of all
T-lineage ALL cases.33
Risk classification of T-lineage ALL.
In general, treatment protocols for childhood leukemias have relied on
the known prognostic factors of age and WBC count, as well as
organomegaly rather than immunophenotype for risk assessment. As a
result, even though many patients with T-lineage ALL were previously
misclassified or not immunophenotyped, they were likely to receive
treatment for high-risk ALL based on their other presenting features.
In contemporary trials, various groups have used somewhat different
criteria for classification, which has complicated comparisons of
results between groups, but nevertheless has generally resulted in
similar assignment of patients with T-lineage ALL to more intensive treatment protocols, such as Berlin-Frankfurt-Munster
(BFM),131,132 modified BFM,12 and the New York
(NY) regimen,13 as well as those of the St
Jude Children's Research Hospital133 and Dana Farber
Cancer Institute.11
From 1983 through 1993, children daignosed with ALL who exhibited
National Cancer Institute (NCI) standard risk features134 were classified by the CCG as either low risk (ages 2 through 9 years
and WBC <10,000/µL) or intermediate risk (ages 2 through 9 years
and WBC <10,000 to 49,999/µL, or age 1 year and WBC
<50,000/µL), whereas patients exhibiting NCI poor-risk
characteristics were classified as follows: high risk, ages 1 through 9 years with WBC 50,000/µL or age >10 years; infants, age <1
year; lymphomatous, patients with specific high-risk features, as
described.135 As shown in Table
1, patients with T-lineage ALL more
frequently were assigned to the higher risk than to the lower risk
protocols, which is consistent with their clinical features described
above.
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Table 1.
CCG and NCI Risk Group Classification of Children
With B-Lineage and T-Lineage Acute Lymphoblastic Leukemia
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Treatment outcome in T-lineage ALL.
As noted above, previous studies showed poorer outcomes for patients
with T-lineage ALL compared with patients with B-lineage ALL. For
example, in the BFM group, Henze et al136 reported poor outcome for patients with T-lineage ALL who were treated on
DAL (adapted from St Jude protocol VII), with 9-year
probabilities of continuous complete remission (CCR) of 9% ± 9% and
41% ± 5%, for T-lineage and non-T-lineage, respectively. In
contrast, patients treated on BFM achieved CCR of 52% ± 13% and
65% ± 5%, respectively, suggesting that BFM provided superior
treatment for T-lineage ALL.
Investigators of the Pediatric Oncology
Group7 treated 53 patients with T-lineage ALL
with a modified LSA2L2 regimen that had been
shown to be efficacious for treatment of T-cell non-Hodgkin's lymphoma.
Although complete remission was achieved for 88% of the patients, the
projected overall 3-year EFS was only 40% (SE = 8.3%). Moreover,
for patients with WBC count <50,000, the projected 3-year EFS was
67%, whereas for patients with WBC count >50,000, 3-year EFS was
only 19%. In a follow-up study, 253 children with T-lineage ALL
treated by a modified LSA2L2 regimen together
with cranial radiation therapy and triple intrathecal therapy for
presymptomatic treatment of central nervous system (CNS) disease
achieved an overall 4-year EFS of 43% (SE = 4%).8 Thus,
although outcomes improved, the LSA2L2 regimen
remained ineffective for the majority of patients with T-lineage ALL.
Similarly, in an analysis of data from St Jude studies X and XI,
conducted from 1979 to 1983, 120 children with T-lineage ALL had a
5-year EFS of 46% (SE = 18%).137 In a French trial,
Garand et al10 treated 88 pediatric patients with T-lineage
ALL by protocols such as BFM or FRALLE,138 and an
EFS of approximately 58% was reported for a median
follow-up of 30 months, suggesting that such therapy could improve
outcome for these patients.
Although the studies described above generally found unfavorable
outcomes for patients with T-lineage ALL, other recent studies have
reported improved outcomes through the use of highly intensive treatment protocols. For example, using an intensive four-drug induction and multidrug continuation, including doxorubicin and prednisone together with prophylaxis for CNS disease and high-dose L-asparaginase, Clavell et al11 reported improved outcome
(4-year EFS of 71%) for high-risk patients, including those who had
T-lineage ALL. More recently, in a study by Schorin et al14
20 patients with T-lineage ALL treated with multiagent chemotherapy
together with cranial irradiation and intrathecal methotrexate for 2 years also had favorable outcomes (7-year EFS of 70%,
SE = 10%).14 The favorable outcome was attributed to the
inclusion of L-asparaginase and doxorubicin in the treatment regimen.
Studies by the CCG also have shown improvements in EFS outcome for
high-risk patients with ALL including those with the T-lineage immunophenotype. Steinherz et al13 used an intensive
multidrug chemotherapy (NY regimen) to treat 100 patients with
characteristics previously correlated with a high risk for relapse.
This patient population included 13 patients with T-lineage ALL
(defined as E-rosette-+). Four-year EFS for the entire cohort was 69%
(SE = 5%), whereas 4-year EFS for patients with T-lineage ALL was
75%. Gaynon et al139 used a modified BFM therapy involving
four-drug induction and aggressive continuation therapy to treat
high-risk children, including 60 who were E-rosette-+. Overall 3-year
EFS was 65% (SD = 3.5%); patients with WBC count >50,000 who were
E-rosette-+ had a 3-year EFS of 75% (SD = 6.9%), whereas those who
were E-rosette- had an EFS of 51% (SD = 6.3%).
To investigate the outcome of patients with T-lineage ALL on these
regimens more thoroughly, we recently analyzed data from the large
cohort of patients enrolled on CCG studies conducted between 1983 and
1993.134 Notably, we observed a significant improvement in
outcome of patients with T-lineage ALL compared with those on earlier
studies because of marked decreases in the incidences of induction
failures, early bone marrow relapses, and CNS relapses when more
aggressive therapy was given (Fig 1). The
probability of 3-year survival for patients with T-lineage ALL
increased from 56% in studies conducted between 1978 and 1983, to 65%
in studies conducted between 1983 and 1989, and to 78.8% in studies
conducted between 1989 and 1993 (Table 2).Taken together, these various studies suggest that current risk for
patients with T-lineage ALL treated by intensive therapeutic regimens
is similar to that of patients with B-lineage ALL. Thus, a major
improvement in treatment of T-lineage ALL has been achieved.
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| Fig 1.
Improved EFS of patients with T-lineage ALL in the
context of contemporary intensive chemotherapy programs. EFS for the
entire cohort of patients with T-lineage and B-lineage ALL treated on the 1800 series and 100 series of CCG studies are shown. EFS values at
designated points in follow-up are given in the text.
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Prognostic factors in T-lineage ALL.
A number of risk factors for T-lineage ALL were identified in the
studies described above. For example, Dowell et al9 and Shuster et al8 reported that compared with patients with
T-lineage ALL whose leukemic cells were CD10, those
whose cells were CD10+ were more likely to achieve
remission and have significantly improved EFS outcomes. In another
study, Pui et al137 reported that CD3 positivity in
association with an abnormal karyotype was a significant adverse risk
factor; 5-year EFS for patients with both of these characteristics was
35%. In contrast, Shuster et al8 found no prognostic
significance for CD3 expression; rather, the most important favorable
prognostic factors for patients with low WBC count or high WBC count at
diagnosis were CD5 positivity or expression of the THY antigen,
respectively.
The findings that many patients with T-lineage ALL now can achieve a
much improved outcome has motivated attempts to identify subgroups of
patients within T-lineage ALL that may exhibit improved or reduced probabilities of survival. Two previous CCG studies described above noted a favorable association between outcome and
E-rosette (CD2) positivity among high-risk patients.13,139 To determine comprehensively the clinical significance of CD2 expression in T-lineage ALL, we prospectively immunophenotyped leukemic
cells from the large cohort of children enrolled on CCG studies between
1983 and 1993.140 We noted a statistically significant correlation (P = .0006) between the CD2 antigen expression
frequency (ie, the average percentage of blasts that were positive for
CD2) and EFS. Compared with patients with the highest CD2 expression level, patients with intermediate and low CD2 expression frequencies had relative hazard rates (RHR) of 1.27 and 2.01, indicating an increased risk of treatment failure. After 6 years of follow-up, the
EFS estimates for the three CD2 expression groups (low
expression frequency to high expression frequency) were 49.3%, 63.5%,
and 72.2%, respectively. CD2 expression remained a significant
predictor of EFS after adjustment for the effects of other covariates
by multivariate regression. Expression of other antigens (CD3, CD5, CD10, or CD34) by leukemic cells was not correlated with EFS. Thus, the
expression frequency of CD2 antigen is a powerful predictor of EFS that
may be useful for risk classification or assignment to novel therapies
aimed at improving patient outcome.
Maturation stage of the predominant leukemic clones also has been
suggested as a means for subgrouping patients with T-lineage ALL. Crist
et al4 stratified 101 patients with T-lineage ALL into
three maturation groups according to expression of T-lineage cell
surface antigens, as follows: stage I,
CD2+CD7+; stage II,
CD2+CD7+CD1+CD4+CD8+;
and stage III,
CD2+CD7+CD1(CD4+ or
CD8+)CD3+. Although the percentage of patients
achieving remission following induction therapy was lower for patients
with T-lineage ALL of the earliest maturation stage (79%, 100%, and
94% for stages I, II, and III, respectively), 4-year EFS was equally
poor for all three groups (33%, 32%, and 38%, respectively).
Recently, we analyzed data from a large cohort of patients with
T-lineage ALL treated on contemporary protocols of the CCG to
further investigate the prognostic role of the apparent maturation stage of leukemic T-cell precursors.141 Patients were
immunophenotypically classified as follows: pro-thymocyte leukemia
(pro-TL), CD7+CD2CD5;
immature TL, CD7+(CD2+ or
CD5+)CD3; and mature TL,
CD7+CD2+CD5+CD3+. No
group had a preponderance of favorable or unfavorable presenting characteristics. Four-year EFS was lower for patients with pro-TL (57.1%; SD = 8.4%) compared with patients with immature and mature TL (68.5%, SD = 3.5%; and 77.1%, SD = 4.0%; respectively) with an overall significance of P = .05. Highly significant
differences were found for overall survival (P = .005) as a
result of the deaths of all patients with pro-TL who relapsed. Although
CD2 also was a significant prognostic factor (P = .03), RHRs
of 2.11, 1.51, and 1.17 for patients with pro-TL, CD2
immature TL, and CD2+ immature TL, respectively, suggested
that the pro-TL maturation stage had added prognostic significance (Fig
2). Indeed, multivariate analysis indicated
that the influence of ontogeny group was greater than that of CD2.
Thus, leukemic cells of the pro-TL maturation stage identified a
subgroup of patients with T-lineage ALL who have a significantly worse
EFS outcome than patients whose leukemic cells correspond to a more
mature stage of development.
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| Fig 2.
EFS of patients with T-lineage ALL according to the
apparent maturational stage of bone marrow leukemic blasts. EFS for (A) mature TL, (B) CD2+ immature TL, (C) CD2
immature TL, and (D) pro-TL patients treated on the 1800 series of CCG
protocols are shown. EFS values at designated points in follow-up are
given in the text.
|
|
The variant immunophenotype in which leukemic cells coexpress
T-lineage- and myeloid-associated antigens represents a controversial prognostic factor. Although numerous investigators have reported that
coexpression of myeloid antigens predicted an adverse risk for patients with T-lineage ALL,142,143 others have found
similar outcomes for myeloid antigen negative (My) and
myeloid antigen positive (My+) T-lineage
ALL.144,145 We recently evaluated the influence of myeloid
antigen expression on treatment outcome in a large cohort of children
with newly diagnosed ALL enrolled on risk-adjusted CCG
studies.146 Patients were classified as My
or My+ T-lineage, according to expression of CD7, CD13, and
CD33. Patients with My+ T-lineage ALL were more likely than
patients with My T-lineage ALL to show favorable
presenting features, but induction outcome and EFS outcome were similar
for patients with My+ and My T-lineage ALL,
with 4-year EFS of 72.7% (SD = 7.1%) and 70.1% (SD = 5.7%),
respectively (P = .49; Fig 3).These results show that regardless of treatment intensity, mixed
myeloid-lymphoid phenotype was not an adverse prognostic factor for
childhood T-lineage ALL.
View larger version (18K):
[in this window]
[in a new window]
| Fig 3.
Myeloid antigen expression in T-lineage ALL is not
associated with poor EFS. EFS for My+ TL and
MY TL patients treated on the 1800 series of CCG
protocols are shown. EFS values at designated points in follow-up are
given in the text.
|
|
| |
IMPEDIMENTS TO EFFECTIVE TREATMENT |
Drug resistance.
Despite improvements in overall survival, relapse in the bone marrow,
CNS, and other sites remains a significant problem for high-risk
patients. Pieters et al147 showed that patients with T-lineage ALL were particularly resistant to prednisone (PRED), daunorubicin, cytarabine, mafosfamide, and L-asparaginase, but wide
ranges of resistance levels were observed within each immunophenotypic group. For all patients, the probability of continuous complete remission decreased with increasing resistance to PRED. In a later study, these investigators reported that patients with T-lineage ALL
were more resistant to a host of drugs including those mentioned above
as well as teniposide, ifosfamide, vincristine, vindesine, and
dexamethasone.148 Lauer et al149 found that a
regimen of intensive rotating drug pairs was effective for prevention
of drug resistance in high-risk patients with B-lineage, but not T-lineage ALL, again suggesting that immunophenotype plays a role in
drug sensitivity. Others have attributed methotrexate (MTX) resistance
in patients with T-lineage ALL to a decreased formation of
MTX-polyglutamates, which is a determinant of
toxicity.150,151 Resistance to glucocorticoids is thought
to be caused by low glucocorticoid receptor (GR) levels. However, the
relationship between GR and outcome within the T-lineage
immunophenotype is unclear. Quddus et al152 reported that
leukemic cell GR level did not predict outcome within the T-lineage
group, whereas Costlow et al153 reported that lower GR
levels were correlated with unfavorable presenting features including
T-lineage. Finally, although multidrug resistance is thought to be
mediated by overexpression of P-glycoprotein, the product of the
multidrug resistance gene MDR-1,154 the
specific significance of this phenomenon in T-lineage ALL has not been determined.
| |
INNOVATIVE TREATMENT STRATEGIES FOR T-LINEAGE ALL |
Current strategies for improving treatment of children with ALL have
been aimed at maximizing efficacy of treatment according to risk.
Reliable and accurate methods for predicting prognosis are required to
achieve adequate treatment with the least intensive regimens.
Identification of biological and clinical prognostic factors, as
discussed above, has aided in stratifying patients according to risk.
However, additional methods are required for identifying and more
effectively treating subgroups of high-risk patients who are most
likely to relapse despite intensive therapy.
Seventy-five percent of children with T-lineage ALL on CCG protocols
fit within the NCI high-risk category based on presenting age and WBC
count.134 Patients with T-lineage ALL with standard risk
represent less than 4% of patients with ALL and less than 6% of all
standard-risk patients. Treatment of patients who have relapsed
generally has consisted of intensive chemotherapy to achieve a second
remission and subsequent use of either nonablative chemotherapy or
ablative radiochemotherapy followed by bone marrow transplantation
(BMT), and recurrence of leukemia is the major obstacle
to the success of either approach. Intensification of cytotoxic therapy
using conventional drugs will likely cause overlapping toxicities and
may result in delays which may erode the intensity of therapy. Overall,
the outcome for patients with relapsed T-lineage ALL is dismal because
only a very small fraction can be saved with high-dose
radiochemotherapy followed by BMT. Consequently, the development of new
potent antileukemia drugs and the design of combinative treatment
protocols using these new agents have emerged as exceptional focal
points for research in modern therapy of relapsed T-lineage ALL.
Immunotoxins and other targeted biotherapeutics.
Immunotoxins (MoAb-toxin conjugates) are a new class of
immunopharmacologic agents that shows considerable promise for more effective treatment of T-lineage ALL. A vast number of MoAbs have been
developed with the intent of specifically targeting cytotoxic agents to
leukemia cells while limiting the deleterious effects on normal
tissues. Immunoconjugates containing toxins such as pokeweed antiviral
protein, ricin, Pseudomonas endotoxin, and diphtheria toxin directed
against T-lineage-specific surface antigens have been developed for
use as systemic therapy of T-lineage ALL.155-158
Murphy et al159 as well as Kreitman et
al160 have pioneered the use of genetic
engineering to redirect the lethal action of diphtheria toxin towards
effective targeting of growth factor receptors on leukemic cells. In
one example, researchers have developed a recombinant fusion toxin,
DAB486IL-2, in which the native receptor binding domain of diphtheria
toxin has been replaced with interleukin-2.161
Deoxyguanosine analogs.
Another new and promising treatment program for T-lineage ALL is based
on the potent antileukemia activity of deoxyguanosine analogs. The
accumulation and the resulting toxicity of dGTP in T lymphocytes was
first described in patients with a genetic deficiency for the enzyme
purine nucleoside phophorylase (PNP).162,163 This observation lead to the search for means by which cytotoxic levels of
dGTP could be achieved in T-lineage leukemias. An analog of deoxyguanosine, Ara-G (9--D-arabinofuranosylguanine) accumulates in
T cells and acts as a poor substrate for endogenous PNP, but is
efficiently phosphorylated by deoxycytidine kinase164,165;
in vitro studies have shown that Ara-G is selectively cytotoxic for
T-cell lines and T-lineage leukemic cells.166,167
Recently, a water soluble pro-drug derivative of Ara-G, known as
compound 506U/C-506 (2-amino-6-methoxypurine arabinoside), was
developed for in vivo therapeutic applications.168
Preliminary results of a Phase I trial of C-506 in adult T-cell
malignancies suggested that daily infusion of C-506 could achieve and
maintain cytotoxic levels of Ara-GTP.169 These data
indicate that C-506 warrants investigation as a new therapeutic drug
for treatment of pediatric T-lineage ALL.
| |
CONCLUSIONS |
The adverse risk previously associated with T-lineage ALL in children
has progressively been surmounted by intensive chemotherapeutic regimens. Still, approximately 20% to 25% of children with T-lineage ALL continue to fail therapy. Further augmentation of the currently used intensive chemotherapeutic regimens may not be warranted because
of the likelihood of significant adverse effects. Thus, the current
challenge is to apply our expanding knowledge of biological regulation
in leukemic cells to the development of novel biologic therapeutics,
particularly those that specifically target leukemic cells. Such agents
could theoretically be used either to trigger cell killing directly or
to alter the leukemic cell's response to radiation or
chemotherapeutics. Finally, the identification of prognostically
distinct patient subgroups may lead to tailored and risk-adjusted
therapies for children with T-lineage ALL. Use of these various
strategies, singly and in combination, should allow further
improvements in outcome for patients with ALL who remain at risk for
treatment failure.
| |
FOOTNOTES |
Submitted May 21, 1997;
accepted October 9, 1997.
Supported in part by research grants including CCG
Chairman's Grants No. CA-13539, CA-51425, CA-42633, CA-42111,
CA-60437, and CA-27137 from the National Cancer Institute, National
Institutes of Health. F.M.U. is a Stohlman Scholar of the Leukemia
Society of America, New York, NY.
Address reprint requests to Fatih M. Uckun, MD, PhD, Children's Cancer
Group ALL Biology Reference Laboratory and Wayne Hughes Institute, 2665 Long Lake Rd, St Paul, MN 55113.
| |
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Introduction
References
Introduction