T-cell non-Hodgkins lymphomas are a
heterogeneous group of diseases that differ markedly in terms of
their clinical behavior and prognosis. In recently developed
classification systems, the sites of initial disease presentation
assume a more prominent role in subgroup delineation. CD26, a
structure with an integral role in human T-cell function that serves
as the binding protein to adenosine deaminase, has been identified
recently as a potential marker for certain aggressive T-cell
lymphomas. To translate our knowledge of the basic biology of
CD26/adenosine deaminase into clinical practice and to develop
specific treatment for T-cell lymphomas based on CD26 expression, we,
at M. D. Anderson Cancer Center, have initiated a phase II trial.
This trial will evaluate the effect of pentostatin (Nipent), a potent
adenosine deaminase inhibitor with known efficacy against T-cell
malignancies, on relapsed/refractory T-cell lymphomas in relation to
CD26 expression. [ONCOLOGY 14(Suppl 2):17-23, 2000]
An important change in the
lymphoma classification systems occurred recently with the
publication of the Revised European-American Classification of
Lymphoid Neoplasms (REAL). The REAL classification advocates the
initial division of all lymphomas into two groups based on cell type,
namely, T-cell and B-cell lymphomas. This modification circumvents
the rather troublesome situation associated with the use of the
previously accepted morphology-based Working Formulation, in which
T-cell lymphomas that occur less frequently and have a worse
prognosis are included in a number of different groups
(diffuse-mixed, large cell, or lymphoblastic) and are treated in the
same manner as their B-cell counterparts.
In addition to morphology, biological observation and clinical
experience are used to identify specific entities of the REAL
classification. While most of the REAL classification entities were
recognized in the prior Working Formulation classification, new
subtypes are also described.
The REAL classification divides T-cell lymphomas into two major
groups based on the maturation stage of the malignant T cells: (1)
precursor T-cell neoplasms, and (2) peripheral T-cell and natural
killer (NK)cell neoplasms. Peripheral T- and NK-cell
neoplasms are further subdivided into 10 categories (1 provisional),
with some containing provisional subtypes. Despite these instances of
uncertainty, the REAL classification is a major step forward in
delineating lymphoma entities, especially those of T-cell lineage. It
recognizes another important aspect of T-cell lymphomas: the site of
presentation is one of the cornerstones of distinction, ie,
extranodal lymphomas are intrinsically different from their nodal counterparts.
Subsequent analyses have confirmed that the REAL classification
indeed defines clinical entities that can be diagnosed by expert
hematopathologists and that can predict the patients clinical
course and prognosis, thus making them useful in prescribing and
devising therapies. The largest of these studies, the
Non-Hodgkins Lymphoma Classification Project (NHLCP), found the
prevalence of T-cell lymphoma to be about 12%, with the peripheral
(T-cell) lymphoma group representing the largest majority (7%). In
this analysis, however, the peripheral T-cell lymphoma group
comprised 5 of 10 T-cell lymphoma subgroups as defined in the REAL
classification. Anaplastic large T-/null-cell lymphoma and precursor T-lymphoblastic
lymphoma subgroups each represented 2% of cases. Overall, the newly
described entities of the REAL classification comprised approximately
20% of all cases.
Since the advent of the REAL classification, significant new data
have been generated for some lymphoma subgroups, allowing for the
clarification and proper classification of provisional entities,
especially among T-cell lymphomas. The World Health Organization
(WHO) Classification for Neoplastic Diseases of the Lymphoid Tissues,
which has been in development for the last few years, is based on the
REAL classification and incorporates several additional
modifications. In addition to precursor T-cell neoplasms, the
proposed WHO classification recognizes 14 subgroups among mature T-
and NK-cell neoplasms. Disease site assumes a more prominent role in
subgroup delineation, allowing subgroups to be easily separated as
predominantly leukemic, nodal, extranodal, or cutaneous (Table
Predominantly Leukemic Group
The predominantly leukemic group consists of four entities. T-cell
prolymphocytic leukemia comprises up to 20% of all prolymphocytic
leukemia cases. It is characterized by malignant cells that express
CD2, CD3, CD5, and CD7, and that have prominent nucleoli and abundant
cytoplasm. Cells that are smaller in some cases and that might be
called T-cell chronic lymphocytic leukemia comprise 1% of all chronic
lymphocytic leukemia cases. T-cell prolymphocytic/chronic lymphocytic
leukemia is more aggressive than its B-cell counterpart and is rarely curable.
Large granular lymphocytic leukemia has been divided in the WHO
classification into two subgroups: T- and NK-cell leukemias. These
are associated with lymphocytosis and neutropenia. The T-cell type
usually has more adverse features, such as anemia, splenomegaly, and
complications secondary to cytopenia. Although the disease is
indolent, an occasional case is associated with Epstein-Barr virus
(EBV) and follows a more aggressive course. Sézary syndrome is
the leukemic variant of mycosis fungoides (described later), although
it can arise de novo. Patients usually also present with erythroderma
and lymphadenopathy. Expected survival is less than 1.5 years,
especially if extracutaneous disease is present.
Predominantly Nodal Group
The predominantly nodal group also combines four entities. Peripheral
T-cell lymphoma, unspecified, is the most common of all the T-cell
subgroups. It typically contains a mixture of small and large
atypical cells that are difficult to subclassify. Patients are
usually adults with aggressive, generalized disease. Relapse is
common and the prognosis is poor.
Angioimmunoblastic T-cell lymphoma, a rare disease with a generally
poor outcome, is composed of small cells, immunoblasts, and
characteristic clear cells. Patients usually present with
generalized lymphadenopathy, constitutional symptoms, and rash.
Polyclonal hypergammaglobulinemia is often present.
Adult T-cell leukemia/lymphoma is caused by the human T-lymphocyte
virus-1, which is transmitted either by infected cells via semen,
blood products, needles, or breast milk, or by transplacental
migration. The incubation period often ranges from 20 to 30 years.
Four clinical types are recognized, the majority being acute with a
median survival duration of less than 1 year. Moreover, autologous
stem-cell transplantation appears to provide little benefit for adult
T-cell leukemia patients.
Primary nodal anaplastic large T-/null-cell lymphoma is characterized
by the presence of large blastic cells that in most cases express
CD30 and have a characteristic chromosomal abnormality (see below).
While patients often present with systemic disease and extranodal
involvement (40% to 70%), treatment with aggressive chemotherapy
results in excellent response in many cases.
Primary Extranodal Lymphomas
The modern definition of primary extranodal lymphomas includes only
cases with limited stage IE and IIE disease, the majority of which
are of B-cell origin. Many cases of extranodal T- and NK-cell
lymphomas are associated with EBV and occur with increased frequency
in immunosuppressed patients, especially after organ transplantation.
Each of the four types comprise less than 1% to 2% of the total
number of lymphoma cases but still account for approximately 25% of
all T-cell lymphoma cases.
Nasal NK-/T-cell (angiocentric) lymphoma usually presents with
destructive nasal or midline facial tumor, is EBV-positive, and is
much more common in Asia. Although the disease is often localized,
chemotherapy is generally administered in conjunction with
radiotherapy. However, the relapse rate is high and the prognosis is
generally poor. A common clinical complication is a hemophagocytic syndrome.
Primary Intestinal Lymphomas
Approximately 10% to 25% of primary intestinal lymphomas have a
T-cell phenotype. These lymphomas are usually associated with celiac
disease and are also called enteropathy-type intestinal T-cell
lymphomas. The majority of patients present with a short history of
abdominal pain and weight loss, or are treated with emergency surgery
owing to small-bowel perforation or obstruction. While a tumor mass
is frequently absent, the clinical course is aggressive and the
outcome is poor.
Subcutaneous panniculitis-like T-cell lymphoma is usually manifested
by subcutaneous nodules affecting the extremities. Malignant T cells
are CD8 positive and can have either the alpha-beta or gamma-delta
T-cell receptor. Hemophagocytic syndrome is a frequent complication
that leads to death in the majority of patients, who often present
with fever, pancytopenia, and hepatosplenomegaly. A bone marrow
aspirate showing macrophages containing phagocytosed erythrocytes
confirms the diagnosis.
Hepatosplenic gamma-delta T-cell lymphoma is considered a more
systemic disease. Patients usually present with hepatosplenomegaly
and bone marrow involvement but without lymphadenopathy. The majority
of patients are young males. Clinically, this disease is aggressive,
with a median survival of less than 3 years.
Primary Cutaneous Lymphomas
The definition of primary cutaneous lymphomas includes diseases that
manifest exclusively in the skin with no evidence of extracutaneous
disease at the time of diagnosis or within the first 6 months after
diagnosis. More than 80% of all primary cutaneous lymphomas are of
There are two major types, and the prognosis for both is generally
good. Mycosis fungoides is a low-grade lymphoma of mature T cells,
characterized by three phases of evolution: patch, plaque, and tumor.
All three lesions can occur simultaneously in the same patient.
In rare instances, mycosis fungoides can progress to its leukemic
variant, Sézary syndrome. This syndrome is characterized by
the loss of the panT-cell marker CD7 on CD4-positive malignant
T cells. Extracutaneous disease and the extent and type of skin
involvement are the most important prognostic indicators.
The predominantly cutaneous T-cell lymphoma subgroup also
incorporates rare primary cutaneous anaplastic large-cell lymphoma,
which has an excellent prognosis. It usually occurs in older patients
and presents as a solitary mass with an ulcerated surface. Treatment
generally consists of excision with or without radiation. In
one-fourth of patients, the skin lesions spontaneously regress,
either partially or completely. Primary cutaneous anaplastic
large-cell lymphoma and lymphomatoid papulosis have overlapping
histologic and clinical features, and are considered to represent a
continuous spectrum of the disease.
Many recent reports have provided additional data on various lymphoma
subgroups, including clinical aggressiveness, prognostic factors,
immunophenotype, and molecular genetics. The NHLCP analysis of the
clinical aggressiveness of different lymphoma groups (Table
2) provided contrasting results with regard to different T-cell
lymphoma subgroups: the anaplastic large-cell lymphoma group
clearly had the best prognosis (77% overall 5-year survival rate),
while the T-cell lymphoblastic lymphoma (26%) and peripheral T-cell
lymphoma (25%) groups had the poorest prognosis.
Other studies confirmed that the T-cell phenotype in itself is an
important prognostic factor. Independent of the International
Prognostic Index (IPI), the T-cell phenotype signifies a shorter
disease-free interval, shorter overall survival, or both (except for
CD30-positive anaplastic large-cell lymphoma) as compared with B-cell
lymphomas.[6,7] In addition, the T-cell phenotype appears to confer a
greater likelihood of advanced disease, B symptoms, and elevated
The IPI project did not evaluate the influence of immunophenotype on
overall survival. However, subsequent studies used the IPI to
stratify T-cell lymphoma patients into prognostic groups. This was
done mostly to compare outcomes between groups with the same IPI but
different immunophenotypes (T-cell vs B-cell).
Recently, Gisselbrecht et al reported that the IPI could indeed
stratify T-cell lymphoma patients into statistically significant
prognostic groups. However, Armitage et al used the IPI to
stratify patients in every major lymphoma subgroup and found no
correlation between the T-cell lymphoma subgroups (peripheral T-cell
lymphoma, anaplastic large-cell lymphoma, and lymphoblastic lymphoma).
Similarly, the significance of the molecular genetics of T-cell
lymphomas is less well understood. It has been established that a
large number of T-cell lymphomas are characterized by chromosomal
abnormalities that involve the T-cell receptor genes. A notable
exception is CD30-positive anaplastic large-cell lymphoma, with
respect to both its chromosomal abnormality and our understanding of
its molecular genetics.
Anaplastic large-cell lymphoma is recognized by a strong, but not
specific, association with a t(2;5) translocation that fuses the
nucleophosmin gene from 5q35 to a tyrosine protein kinase (anaplastic
lymphoma kinase) gene on 2q23. Activation of anaplastic lymphoma
kinase results in an unregulated mitogenic signal, ie, cell
proliferation. The translocation is present in most cases of primary
nodal, but not primary cutaneous, anaplastic large-cell lymphoma. The
subset of CD30-positive anaplastic large-cell lymphomas that are
anaplastic lymphoma kinasepositive appears to have the most
In view of the heterogeneity of T-cell lymphomas in terms of clinical
behavior and prognosis, there is a constant search for new prognostic
factors and molecular markers. One example involves research
examining the potential role of CD26 in human T-cell lymphoma. CD26
has been extensively characterized as a molecule with an essential
function in human T-cell physiology. It performs a number of diverse
functions, and has been described as an alternative pathway of T-cell
activation, an exopeptidase with dipeptidyl peptidase IV enzymatic
activity, a functional collagen receptor, and a molecule involved in
thymic ontogeny.[10-16] Notably, CD26 has also been identified as the
adenosine deaminase (ADA) binding protein that is expressed on the
cell surface along with ADA.
Adenosine deaminase is a key enzyme in purine salvage that regulates
intracellular adenosine levels through the irreversible deamination
of adenosine and deoxyadenosine. Widely distributed in mammalian
tissues, ADA displays the highest activity in lymphoid tissues,
particularly in normal circulating T cells. The vital role of ADA in
human lymphocytes is demonstrated by the fact that congenital
deficiency of ADA enzymatic activity is associated with a defect in
the maturation and function of lymphocytes, resulting in severe
combined immunodeficiency disease.
Although most ADA is found in the cytosol, it also appears on the
surface of lymphocytes. Recently, in vitro studies have demonstrated
that ADA cell-surface expression is dependent on CD26 surface
expression and that coexpression of ADA with CD26 on the cell surface
can block the inhibitory effect of accumulated adenosine on
T-cell proliferation. Other studies have shown that the
expression of both ADA and CD26 increases significantly upon T-lymphocyte
activation, while the absence of ADA expression causes anergy.
These data identified a potential new, nonenzymatic role for cell
surface ADA as a costimulatory molecule in conjuction with CD26 in T cells.
CD26 in Human Lymphomas
While the basic role of CD26 in T-cell function is understood,[10-15]
its potential involvement in the development of human lymphomas is
only recently being examined. Italian researchers showed that
CD26 was expressed mostly on CD30-positive anaplastic large-cell
lymphoma (12 of 17 cases) irrespective of antigenic phenotype, and on
T-cell lymphomas (7 of 15 cases). CD26 was not detected among 26
B-cell lymphomas other than B-cell anaplastic large-cell lymphoma,
and was rarely found in Hodgkins disease (2 of 23 cases). In
addition, it was reported that, in contrast to normal T lymphocytes,
CD26 and CD40 ligand were mutually exclusive in human T-cell lymphomas/leukemias.
CD26 expression was restricted mainly to aggressive diseases, such as
T-cell acute lymphoblastic leukemia (12 of 23 cases) and T-cell
CD30-positive anaplastic large-cell lymphoma (5 of 8 cases), whereas
CD40 ligand was expressed on relatively indolent diseases such as
mycosis fungoides (11 of 21 cases). Within aggressive subgroups, CD26
expression appeared to confer a poorer prognosis. Interestingly, the
expression of CD26 was found to be significantly decreased in all 20
patients with adult T-cell leukemia/lymphoma compared with healthy
individuals. Additional evidence supporting the role of this
molecule in the pathogenesis of T-cell malignancies has recently been published.
Extensive immunophenotypic characterization of T-acute lymphoblastic
leukemia cells revealed a close association between CD26 enzymatic
activity, features of T-cell immaturity (ie, lack of CD3 cell-surface
expression), and proliferative activity. Of interest is the fact
that CD26 expression increases in relatively mature human
thymocytes. Furthermore, CD26 enzymatic activity varied with the
stage of differentiation, as well as activation of human alloreactive
T-cell subsets. Similar observations were made in abnormal T
cells, in which the presence (or intensity) of cell-surface CD26
expression was separable from the level of its intracellular
These data suggest that CD26 cell-surface expression and its
enzymatic activity may have independent roles in the pathogenesis of
T-cell malignancies. The significance of CD26 expression and function
in CD26-positive U937 lymphoma cells has been assessed in a study by
Reinhold et al, which suppressed CD26 enzymatic activity by
specific inhibitors. Inhibition of both DNA synthesis and cellular
proliferation, as well as modulation of cytokine production, was
observed, suggesting an important role for the enzymatic activity of
CD26 in the biology of U937 lymphoma cells.
CD26 and Other Neoplasias
Recent findings suggest that CD26 may play an important role in the
development of other neoplasias as well. For example, it is tightly
regulated during the process of neoplastic transformation of
melanocytes, as indicated by its expression on normal melanocytes but
not on melanoma cells. When melanocytes are transformed in vitro
in defined steps, loss of CD26 expression occurs concomitantly with
the emergence of growth independence and the appearance of specific
chromosomal abnormalities. CD26 has also been shown to be (1) a novel
marker for differentiated thyroid carcinoma; (2) expressed on
glioma and neuroblastoma; and (3) a marker capable of
distinguishing adenocarcinoma from other histologic types of lung
cancer. CD26 is aberrantly expressed in human hepatocellular
carcinoma, as compared with normal liver tissue, and is markedly
reduced in metastatic prostate cells, as compared with primary
prostate malignant or benign cells. As an adhesion molecule, CD26
may also have a significant role in the metastatic dissemination of
breast cancer, because it interacts with breast cancer cell
surface-associated polymeric fibronectin.
Pentostatin (Nipent) is a potent inhibitor of ADA that has proven to
be a potent antitumor agent in several hematologic malignancies.
Pentostatin is a purine analog with particularly significant activity
in hairy cell leukemia. It is also active in chronic leukemias
and low-grade lymphomas, although not as active as other purine
analogs.[33,34] By inhibiting ADA enzymatic activity, pentostatin
causes an enhancement in the local concentration of adenosine and an
increase in intracellular deoxyadenosine triphosphate, resulting in
cytotoxicity and growth inhibition. Other cellular events that
have been reported following treatment with pentostatin include
inhibition of S-adenosylhomocysteine hydrolase, single-strand breaks
in DNA, and activation of caspase-dependent apoptosis.[35-37]
Several reports have suggested that pentostatin may have activity
against T-cell malignancies as well, including T-lymphoblastic
leukemia, cutaneous T-cell lymphoma (CTCL), Sézary syndrome,
and adult T-cell lymphoma. Assessment of the response rate in
these studies has been limited by the relatively small number of
patients, the heterogeneity of patient populations, and the
variability in the dose and schedule of pentostatin (Table
3). Higher doses of pentostatin (10 mg/m²/d for 5 days)
caused a number of side effects, including severe renal toxicity and
central nervous system depression. Lower doses were tolerated
much better, and in the majority of reported studies, a dose of up to
5 mg/m²/d was administered for 3 to 5 days.[32,33]
New Trial of Pentostatin in Relation to CD26 Expression
To translate our knowledge of the basic biology of ADA and CD26 into
clinical practice and to be able to develop targeted, specific
treatment for T-cell lymphomas based on CD26 expression, novel
experimental venues are needed. Taking advantage of the fact that
pentostatin is a potent inhibitor of ADA and that CD26 expression is
integral to ADA cell-surface expression and function, our trial at M.
D. Anderson Cancer Center will examine the effect of pentostatin on
relapsed/refractory T-cell lymphomas in relation to CD26 expression.
Response rates will be evaluated separately for CD26-positive and
CD26- negative T-cell lymphomas, in view of the potential differences
in their biology and the possible differences in their response to
pentostatin. A pentostatin dose schedule of 5 mg/m²/d for 3 days
every 4 weeks appears to be optimal and is the starting dose for this trial.
Knowledge gained from this trial will clarify the role of CD26 as a
potential target in the treatment of T-cell lymphomas, as well as
delineate a more precise role for pentostatin in the treatment of
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