T CELL Lymphomas

PERIPHERAL T-CELL LYMPHOMA, 185
UNSPECIFIED
ANAPLASTIC LARGE-CELL 185
LYMPHOMA
ANGIOIMMUNOBLASTIC T-CELL 187
LYMPHOMA
RARE TYPES OF T-CELL 187
LYMPHOMA
Adult T-Cell Lymphoma/Leukemia / 187
Extranodal NK/ T-Cell Lymphoma,
Nasal-Type / 189
Enteropathy-Type T-Cell Lymphoma / 190
Hepatosplenic T-Cell Lymphoma / 191
Subcutaneous Panniculitis-Like
T-Cell Lymphoma / 191
T-CELL
LYMPHOMAS
Jenny Pozadzides
Madeleine Duvic
Barbara Pro
PERIPHERAL (MATURE) T-CELL LYMPHOMAS 184
CLASSIFICATION 184
PRESENTATION 184
PROGNOSIS 184
183
C H A P T E R
9
NOVEL TREATMENTS 198
FUTURE DIRECTION FOR T-CELL LYMPHOMAS 198
APPROACH TO THERAPY 192
PRIMARY TREATMENT IN PTCLS 192
Nodal PTCL / 192
Extranodal PTCL / 192
Adult T-cell Leukemia/Lymphoma / 193
Hematopoietic Stem Cell Transplant / 193
NOVEL TREATMENT 193
Gemcitabine / 193
Denileukin Diftitox (Ontak) / 194
Pralatrexate / 194
Histone Deacetylase Inhibitors / 194
IMMUNOTHERAPY 194
Alemtuzumab / 194
Zanolimumab / 194
Anti-CD30 Monoclonal
Antibodies / 195
Other Agents / 195
CUTANEOUS T-CELL LYMPHOMAS 195
CLASSIFICATION 195
PRESENTATION AND DIAGNOSIS 196
PROGNOSIS 196
APPROACH TO THERAPY 196
Current Treatment for Early Mycosis
Fungoides / 197
Current Treatment for Intermediate or
Refractory/Transformed MFs and SS / 197
09_Kantarjian_Ch09_p183-202.qxd 2/26/11 6:19 PM Page 183
184 Lymphoma and Myeloma PART II
PERIPHERAL (MATURE) T-CELL
LYMPHOMAS
The term peripheral T-cell lymphoma (PTCL) is used to
describe lymphoid neoplasms of mature T-cell lineage,
as opposed to tumors of thymic origin. The terms post-
thymic and mature T-cell lymphoma also have been
used to describe these tumors. PTCLs represent approx-
imately 10% of all NHLs in most European and US
studies but are more common in other parts of the
world (1-3). Incidences are higher in Asian populations,
possibly related to a high prevalence of human T-cell
lymphotrophic virus type 1 (HTLV-1) and Epstein
Barr virus.
CLASSIFICATION
The International Lymphoma Study Group (ILSG)
incorporated morphologic, phenotypic, molecular, and
clinical information in the REAL (Revised European
American Lymphoma) classification. The revision pro-
vided the basis for WHO (World Health Organization)
classification with the following changes: PTCLs were
divided into nodal, extranodal, and leukemic types; cuta-
neous and systemic anaplastic large-cell lymphomas
(ALCL); updated terminology with subcutaneous pan-
niculitis-type and hepatosplenic gd T-cell lymphomas
were recognized as separate entities (Table 9-1) (1).
The most common histologic subtype is classified
as PTCL not otherwise specified and accounts for
approximately 55% of all PTCL. The second most com-
mon PTCL, ALCL, accounts for 17% of all PTCL, and
angioimmunoblastic T-cell lymphoma (AITL) accounts
for 13%. Other types of PTCL are rare, each <5% of all
cases. Unlike B-cell lymphomas, the classification of
T-cell neoplasms requires much more clinicopathologic
correlation.
PRESENTATION
Patients with T-cell lymphomas are usually adults with
generalized lymphadenopathy as well as frequent
involvement of the skin, spleen, bone marrow, and blood.
Although the subtypes of PTCL are histologically
distinct, they share a very aggressive clinical course
and, with the exception of ALK-positive ALCL, a poor
response to conventional therapy.
The pathologic appearance and immunophenotype
may vary within a given subtype. Therefore, diagnosis
is usually based on a combination of clinical presenta-
tion, pathology, molecular findings, and factors that may
be unique to each subtype. T-cell receptor rearrange-
ments are found in a majority of lymphomas, but can be
inconsistent.
PROGNOSIS
Prognosis varies according to the subtype of PTCL.
With the exception of patients with ALK+ ALCL who
can be successfully treated with standard anthracycline-
based chemotherapy and patients with stage I nasal nat-
ural killer/T-cell lymphomas who may do well with
radiotherapy or combined-modality therapy, most will
have a significantly poorer prognosis than their B-cell
counterparts.
The International Prognostic Index (IPI) provides a
prognostic score based on clinical and laboratory factors
but was developed in aggressive lymphomas before rou-
tine immunophenotyping was utilized. Recently, IPI for
T-cell lymphoma was developed based on a retrospec-
tive review of a large cohort of individuals with PTCL-U
WORLD HEALTH ORGANIZATION
CLASSIFICATION OF T-CELL
LYMPHOMAS
Nodal
Peripheral T-cell lymphoma, unspecified
Anaplastic large cell lymphoma
Angioimmunoblastic T-cell lymphoma
Extranodal
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Leukemic/disseminated
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell leukemia/lymphoma
Cutaneous
Mycosis fungoides/Szary syndrome
Primary cutaneous CD30-positive T-cell lymphoprolifera-
tive disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Borderline lesions
Reproduced, with permission, from Jaffe ES, Harris NL, Stein H, et al.
World Health Organization Classification of tumours. Pathology and
genetics of tumours of hematopoeitic and lymphoid tissues. Lyon, France:
IARC Press; 2001:121253.
T A B L E
9-1
CHAPTER 9 T-Cell Lymphomas 185
following poor prognostic features: older than 60 years,
Eastern Cooperative Oncology Group score 2 or higher,
elevated LDH, and bone marrow involvement. Five-year
overall survival ranged from 62% for those with a score
of 0 to 18% for a score of 3 or 4. This was felt to be more
predictive than IPI. It is less clear how these indices apply
to the less common extranodal and leukemic PTCLs.
Independent prognostic factors included B symptoms,
stage III/IV, LDH greater than normal, and local lymph
node involvement.
PERIPHERAL T-CELL LYMPHOMA,
UNSPECIFIED
PTCL-U represents the largest subtype in North
America (5). In the WHO classification (1), unspeci-
fied PTCL includes all mature T-cell lymphomas that
do not have unique clinical or pathologic features
that allow more specific classification. Unspecified
PTCLs represent approximately 6% of all NHLs and
55% of PTCLs (1-3). Due to the biological hetero-
geneity, PTCL-U is believed to be made up of more
than one disease type but how to differentiate them is
unknown.
Most patients with unspecified PTCLs are adults
who present with generalized lymphadenopathy (6,7).
Extranodal sites including skin, liver, Waldeyer ring,
and lung are also commonly involved. Advanced stage
has elevated LDH and B symptoms (5). PTCL-Us are
diffuse, aggressive neoplasms that require combination
chemotherapy (7). The 5-year overall and failure-free
survival are 26% and 20%, respectively, for patients
treated with doxorubicin-containing chemotherapy
regimens (5-9).
Histologically, in most cases of unspecified PTCL,
the lymph node architecture is diffusely effaced (1,10).
However, in a subset of cases, the neoplasm has a paracor-
tical distribution sparing lymphoid follicles. Cytologi-
cally, the neoplastic lymphoid cells exhibit a spectrum of
cell sizes including small, medium-sized, and large and
can have abundant clear cytoplasm (Figs. 9-1 and 9-2).
Reed-Sternberglike cells may be found. Mitotic figures
are usually easily identified and are often numerous.
Blood vessels (epithelioid venules) may be prominent.
Immunophenotypic studies have shown that PTCL-Us
are of mature T-cell lineage. The neoplastic cells express
pan-T-cell antigens such as CD2, CD3, and CD5, usually
TCR , and are either CD4+ CD8 or CD4 CD8+ (1).
Approximately, 75% of cases will demonstrate an
aberrant T-cell immunophenotype. Cytotoxic proteins
and CD56 are expressed by a subset of cases (1,11).
Approximately, one-third may be CD30+ or EBV+ but
relevance is unknown.
Cytogenetic abnormalities in PTCLs are common,
and karyotypes are often complex. Both numerical
and structural abnormalities are reported, with struc-
tural rearrangements of chromosome 6 being most
common (12).
ANAPLASTIC LARGE-CELL LYMPHOMA
In the WHO classification, two types of systemic ALCL
are recognized, those with translocations involving the
anaplastic lymphoma kinase (alk) gene at 2p23 and
those without. The latter group does not appear to be a
distinct clinicopathologic entity and is more akin to
unspecified PTCL. Studies have shown that tumors
with ALK-pos have a 5-year survival that is superior to
FIGURE 9-2. Peripheral T-cell lymphoma unspecified. The neo-
plastic cells in this case are small and large (hematoxylin-eosin,
1000).
FIGURE 9-1. Peripheral T-cell lymphoma unspecified. The neo-
plastic cells in this case are predominantly small (hematoxylin-eosin,
1000).
those that are ALK-neg (13). Here we focus on ALCL
with alk gene rearrangements that express ALK. ALK-
positive ALCLs represent 2 to 3% of all NHL in adults,
with a higher frequency in children (1).
Patients with ALK-positive ALCL are often younger,
in the first three decades of life, with a male predominance
(1,14). Extranodal sites of disease, B-type symptoms, a
high serum lactate dehydrogenase (LDH) level, and a
high IPI are common. Peripheral blood and CNS involve-
ment is uncommon; when present, however, they
portend a poor prognosis. ALK-positive ALCLs are clini-
cally aggressive but responsive to anthracycline-based
chemotherapy; patients with these neoplasms have a better
prognosis than those with other types of PTCL (14,15).
Histologically, ALK-positive ALCLs exhibit a wide
histologic spectrum (Fig. 9-3). In the most common
or classic cases, ALK-positive ALCLs preferentially
involve lymph nodes sinuses, particularly in lymph
nodes not involved extensively (1,14). With greater
involvement, ALK-positive ALCL replaces the paracor-
tical regions or may diffusely replace lymph node archi-
tecture. Cytologically, the neoplastic cells are large and
bizarre, irregularly shaped, and often have horseshoe-
shaped nuclei with a paranuclear hof (so-called hallmark
cells) (see Fig. 9-3). The nuclear chromatin is vesicular,
with prominent nucleoli. The tumor cell cytoplasm is
abundant and usually basophilic. Other histologic vari-
ants of ALK-positive ALCL are described, the most
common being lymphohistiocytic and small cell, with
other variants being very rare (1,14). The lymphohisti-
ocytic variant is composed of relatively few neoplastic
cells associated with numerous lymphocytes and histio-
cytes. In the small cell variant, large anaplastic neoplas-
tic cells are infrequent and many small neoplastic cells
are present.
Immunophenotypic studies have shown that virtually
all cases express CD30 (1,14). However, CD30 antigen
expression is not specific for ALCL. All tumors discussed
A B
C D
FIGURE 9-3. ALK-positive anaplastic large cell lymphoma. A. In this field the neoplasm is paracortical and spares a central lymphoid
follicle. B. The neoplastic cells are large with horseshoe-shaped nuclei. C,D. The neoplastic cells express CD30 (C) and ALK (D). (A,B,
hematoxylin-eosin; A, 100; B, 1000; C,D, immunohistochemistry; C, 1000; D, 400.)
here also overexpress ALK. Most ALK-positive ALCLs
are of mature T-cell lineage and express T-cell antigens,
are most often CD4+ CD8, and lack B-cell antigens.
Most cases are negative for CD3; absence of CD5 is
also common (16). Approximately, half of ALK-positive
ALCLs lack leukocyte common antigen (CD45). Null-
cell neoplasms lack immunophenotypic evidence of
lineage. Most ALK-positive ALCLs express epithelial
membrane antigen and cytotoxic proteins such as TIA-1
and perforin and are negative for BCL-2 (17,18). Both
T- and null-cell ALK-positive ALCLs have T cell
receptor gene rearrangements.
Chromosomal translocations (or rarely inversions)
involving chromosome 2p23, most commonly the
t(2;5) (p23;q35), are characteristic of ALCL (14,19).
This translocation juxtaposes the alk gene on chromo-
some 2p23 with the nucleophosmin (npm) gene on
5q35. Other abnormalities that result in fusion genes
involving alk are also reported in a small subset of
ALCL cases; all result in overexpression of ALK.
The prognosis of patients with ALK-positive ALCL is
similar regardless of the fusion gene that causes ALK
overexpression (20).
ANGIOIMMUNOBLASTIC T-CELL
LYMPHOMA
AITL was first described in the English literature as
angioimmunoblastic lymphadenopathy with dyspro-
teinemia (AILD) in 1974 (21). This entity has also
been named immunoblastic lymphadenopathy and
lymphogranulomatosis X in the literature. Originally,
AILD was thought to be preneoplastic, but it is now
considered to be a specific type of PTCL and is desig-
nated as AITL in the WHO classification (1).
Clinically, patients with AITL are elderly, with a
median age in the seventh decade, and have advanced-
stage disease with multiple extranodal sites of involve-
ment at onset (22,23). Many patients have constitutional
symptoms such as fever, chills, night sweats, and malaise.
Physical examination reveals generalized lymphadenopa-
thy, fever, hepatomegaly, splenomegaly, and skin rash.
Various laboratory abnormalities are common, including
polyclonal hypergammaglobulinemia, anemia (often
with a positive direct Coombs test), cold agglutinins,
circulating immune complexes, cryoglobulins, antinu-
clear antibodies, and eosinophilia (22). Bone marrow
involvement is common. The outcome of AILT is poor
with a 5-year overall survival of 30% and median sur-
vival of 3 years (5). Infection is the most common cause
of death, followed by the development of malignant
lymphoma.
Histologically, the diagnosis of AITL is based on a
constellation of findings, including (1) partial to complete
obliteration of lymph node architecture, based initially in
the paracortical region (Fig. 9-4); (2) a polymorphous
infiltrate of neoplastic small and medium-sized lymphoid
cells, often with clear cytoplasm, associated with plasma
cells, eosinophils, and immunoblasts; (3) arborizing small
blood vessels corresponding to epithelioid venules; and
(4) absence (in most cases) of reactive lymphoid follicles
(21,24). In many cases small and atrophic (so-called
burned-out) germinal centers are present. In rare instances,
however, cases of AITL display prominent reactive
lymphoid follicles (25).
Immunophenotypic studies of AITL have shown
that these lesions are composed predominantly of mature
T cells that are usually of T-helper cell lineage (1).
Expansion of interfollicular regions of CD3+, usually
CD4+, cells are found. AILT has prominent vascu-
larization by arborizing venules, expansion of CD21+
follicular dendritic cell (FDC) networks (26). CXCL13,
a chemokine up-regulated in germinal center T-helper
cells, may also be a useful marker in AILT (27,28). An
aberrant T-cell immunophenotype is often identified
and the neoplastic cells can express CD10 and BCL-6 in
a subset of cases (24). Numerous follicular dendritic
reticulum cells are common in AITL. B cells may be
common in AITL, unlike most other types of PTCL, and
can be numerous in early lesions.
Nonrandom chromosomal abnormalities have been
identified in AITL (12,29). Trisomy 3 and trisomy 5 are
most common, having been found in 15 to 20% of cases
in one study (12). EBV is commonly associated with
AITL, as shown by a variety of molecular methods (30).
Patients with AITL are at risk for developing diffuse
large B-cell lymphoma (1). Diffuse large B-cell lym-
phomas arising in the setting of AITL express B-cell
antigens, carry Ig gene rearrangements, and usually
have abundant EBV (31). One hypothesis to explain
this finding is that immunosuppression associated with
AITL predisposes to EBV infection of B cells, increas-
ing the likelihood of secondary molecular aberrations in
B cells that result in DLBCL.
RARE TYPES OF T-CELL LYMPHOMA
A number of other types of mature T-cell lymphoma are
described, each type being rare and representing <5%
of all T-cell lymphomas.
Adult T-Cell Lymphoma/Leukemia
Adult T-cell lymphoma/leukemia (ATLL) is a distinct
clinicopathologic entity associated with infection by the
A B
C D
FIGURE 9-4. Angioimmunoblastic T-cell lymphoma. A. The neoplasm has a paracortical distribution. B. The neoplasm is composed of
numerous cells with clear cytoplasm. C. In this field arborizing blood vessels are shown. D. The neoplastic cells are positive for CD3. (A -C,
hemotoxylin-eosin; A, 100; B, 1000; C, 200; D, immunohistochemistry, 400.)
human T-cell leukemia/lymphoma retrovirus (HTLV-I)
(1). HTLV-I is a single-stranded RNA retrovirus that is
lymphotropic for T lymphocytes (32). ATLL develops in
only 2 to 4% of patients who are carriers of the HTLV-1
virus (33). The virus is transmitted by sexual inter-
course, breast milk, shared needles among intravenous
drug users, and transfusion of blood products. The incu-
bation period for development of ATLL ranges from
20 to 40 years. Patients with ATLL are usually adults,
with a median age in the sixth decade (34). ATLL
accounts for the high incidence of T-cell lymphoma in
Japan. Clusters of cases have also been reported in
Pacific Ocean islands, the Caribbean, Europe, and the
southeastern United States.
ATLL is classified into four subtypes based on clini-
copathologic features and prognosis: acute, lymphoma,
chronic, and smoldering. Patients with acute ATLL, the
most common form of the disease, have generalized
lymphadenopathy, hepatosplenomegaly, skin lesions,
peripheral blood involvement, lytic bone lesions, and
hypercalcemia. Hypercalcemia may also develop in the
absence of bone lesions, secondary to secretion of
parathyroid hormonerelated peptide (with activation
of osteoclasts) by the neoplastic cells (35) (Fig. 9-5).
The cerebrospinal fluid (CSF) is commonly involved.
Patients with acute type had a median survival time of
approximately 6 months. Lymphomatous ATLL is the
second most common form of the disease. Patients present
with prominent lymphadenopathy and tumors in other
organs without hepatosplenomegaly or hypercalcemia
or peripheral blood involvement. The prognosis of
these patients is better than that of patients with acute
ATLL with a median survival time of 10 months.
Patients may also present with chronic ATLL, with an
absolute lymphocytosis and cytologically abnormal cells
in the peripheral blood. Skin lesions, lymphadenopathy,
and involvement of other viscera may occur. These
patients had a median survival time of 24 months.
Finally, patients have been described with smoldering
ATLL. These patients have chronic disease for years, usu-
ally skin lesions, with minimal peripheral blood
involvement; the viscera are usually spared. The median
survival time of patients with the smoldering type had
not yet been reached.
In the peripheral blood, the neoplastic cells are
medium-sized, with basophilic cytoplasm and markedly
irregular, multilobulated nuclei, including cloverleaf
shapes (also known as flower cells) (36). The neo-
plastic cells in lymph nodes and viscera involved by
ATLL exhibit a spectrum of cell sizes, including
small, medium-sized, and large, with relatively round or
markedly irregular nuclear contours. Histologic findings
do not correlate with survival (36).
Immunophenotypic studies have shown that ATLLs
have a mature T-cell immunophenotype (1,34). The
tumor cells express pan-T-cell antigens and TCR
and are CD4+ CD8. Characteristically, the neoplastic
cells intensely express the CD25 antigen.
A study done by Itoyama et al (37) examined the
cytogenetic abnormalities in 50 patients with newly
diagnosed ATLL. All had abnormal karyotypes and
almost all chromosomes were affected. Multiple chro-
mosomal breaks (more than 6) and aneuploidy were sig-
nificantly more frequent in patients with the combined
acute and lymphoma subtypes than in those with chronic
ATLL. These results suggest a multistep pathogenesis
for ATLL. The hallmark of ATLL is the demonstration of
HTLV-1, either serologically by detection of serum anti-
bodies or by molecular detection of the virus. The virus
integrates clonally into the host cell genome in random
fashion (32). HTLV-1 proteins, such as TAX, may stimu-
late cell growth by interacting with cell cycle proteins (38).
Extranodal NK/T-Cell Lymphoma, Nasal-Type
The term extranodal NK/T-cell lymphoma, nasal-
type, is used in the WHO classification for a neoplasm
previously designated as lethal midline granuloma, poly-
morphic reticulosis, midline malignant reticulosis, angio-
centric immunoproliferative lesion, and angiocentric
lymphoma (1,39,40).
Clinically, extranodal NK/T-cell lymphomas of
nasal-type have a propensity for involving extranodal
sites, most commonly the nasal cavity, nasopharynx,
and palate (39). However, these tumors can involve other
extranodal sites such as skin, soft tissue, gastrointestinal
tract, and testis at time of diagnosis, and relapses com-
monly involve extranodal sites (41). Lymph node and
bone marrow are rarely involved. These neoplasms can
be associated with a hemophagocytic syndrome clini-
cally characterized by fever, hepatosplenomegaly, pan-
cytopenia, and laboratory evidence of hemolysis (40).
EBV is thought to play a role in tumor pathogenesis, but
the mechanism is unknown. NK/TCLs are dominant
PTCL type in Asian populations (42). It has an aggres-
sive course with 5-year overall survival ranging from
25 to 50% (43).
Histologically, extranodal NK/T-cell lymphomas
of nasal-type are composed of a mixture of atypical
lymphoid cells admixed with reactive lymphocytes
and histiocytes (1,39). Eosinophils and neutrophils are
rare or absent. In the early stages of disease, relatively
few neoplastic cells are present, and they may be of
small size. Over time, these neoplasms accrue greater
numbers of large atypical cells and the diagnosis is
B
A
FIGURE 9-5. Adult T-cell leukemia/lymphoma involving bone.
A. In this field, numerous osteoclasts are surrounding and resorbing
bone. B. The neoplastic cells are large. (A,B, hematoxylin-eosin;
A, 400; B, 1000.)
FIGURE 9-6. Extranodal NK/T-cell lymphoma, nasal-type,
involving nasopharynx. Extensive necrosis (left of field) is common
in these neoplasms (hematoxylin-eosin, 200).
more easily established. These neoplasms can display a
marked propensity for invading and destroying blood
vessels, but angiocentricity is not a universal feature (1).
Necrosis is common (Fig. 9-6).
Immunophenotypic studies of extranodal NK/T-cell
lymphomas of nasal type suggest that most neoplasms
are of NK-cell origin, although rare cases are of T-cell
lineage. Thus, most neoplasms express the NK cell
associated antigen CD56 and NK/T cellassociated
antigens such as CD2, CD7, and CD8. These tumors also
express cytoplasmic CD3 but are negative for T cell
specific antigens such as surface CD3, CD5, and T-cell
receptors. CD16 and CD57 are often negative.
Molecular studies of extranodal NK/T-cell lym-
phomas of nasal type have demonstrated an absence of
TCR and Ig gene rearrangements in most cases studied
(36). EBV genomes have been identified in the neoplas-
tic cells (44,45). Comparative genomic hybridization
studies have shown chromosomal losses at 1p, 12q, and
17p and chromosomal gains at 2q, 10q, and 13q in sub-
sets of tumors (46).
Enteropathy-Type T-Cell Lymphoma
These neoplasms are rare and have been designated pre-
viously as enteropathy-associated T-cell lymphoma and
intestinal T-cell lymphoma (1). Patients with enteropathy-
type T-cell lymphoma (ETL) present with abdominal
pain or weight loss (47). Although initially described in
patients with a history of gluten-sensitive enteropathy or
celiac disease, who are known to have an increased inci-
dence of lymphoma, these tumors also arise commonly
in patients without a known history of celiac disease
(47,48). Clinically, it affects older males presenting with
abdominal pain, diarrhea, and intestinal perforation or
obstruction. Dissemination to the liver, spleen, lung,
skin, and bone marrow can occur. Survival is extremely
poor (49).
Grossly, the involved intestine demonstrates mul-
tiple ulcers (Fig. 9-7); a distinct mass may not be
found. The ulcers may extend deeply into the bowel
wall, often resulting in perforation. The jejunum is
the most common site of involvement. Histologically,
the intestine not involved by neoplasm may exhibit
blunting of villi as is seen in celiac disease (48). These
neoplasms are diffuse and the neoplastic cells are a
mixture of small, medium-sized, and large lymphoid
cells (Fig. 9-7).
Immunophenotypic studies have shown that ETLs
express pan-T-cell antigens, are often CD4 CD8 or
CD4CD8+, and usually have a cytotoxic profile, positive
A
B
FIGURE 9-7. Enteropathy-type T-cell lymphoma. A. This field
shows the transition from benign mucosa (left of field) to lymphoma
and ulcer. B. The neoplastic cells are large. (A,B, hematoxylin-eosin;
A, 20; B, 400.)
for TIA-1, granzyme B, and perforin. A subset of tumors
is positive for EBV, CD30, CD56, or CD103 (48,50).
Hepatosplenic T-Cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is a rare neo-
plasm that most commonly affects young adults, who
present with marked hepatosplenomegaly and minimal
or absent lymphadenopathy; there is a male predomi-
nance (51,52). Bone marrow involvement is common
but often subtle (53). Skin lesions may occur. B symp-
toms such as fever, weight loss, and night sweats were
frequently reported, as well as fatigue, arthralgia, myal-
gia, and abdominal pain (54-56). These tumors were
originally called hepatosplenic / lymphoma (51).
However, as a subset of cases may express the TCR /,
the WHO classification designates these neoplasms as
HSTCLs (1).
Fewer than 200 cases of HSTCL reported in the liter-
ature (1). Although the majority of these cases seem to
have developed de novo, approximately a third have
been associated with immunosuppressive therapy for
various reasons, mostly for organ transplantations and
other conditions that require immune-modifying agents;
most cases involving thiopurines (54,57). Several
immunocompromised conditions described in the litera-
ture include renal transplantation, heart transplantation,
Hodgkin lymphoma, acute myelogenous leukemia,
inflammatory bowel disease, and malaria infection
(58-62). Cases of HSTCL are also associated with viral
infections, including human herpes virus 6, hepatitis B
virus, and EpsteinBarr virus (63,64).
HSTCL has a very aggressive clinical course. The
long-term outcome is poor as many patients die within 1
year after diagnosis (8). A variety of therapeutic options
have been explored, including splenectomy, CHOP-like
combination of cytotoxic regimens, purine analogues,
monoclonal antibodies, and autologous and allogeneic
stem cell transplantation. However, no treatment option
seems to improve life expectancy (65).
Histologically, these neoplasms are diffuse and com-
posed of medium-sized lymphoid cells with slightly
irregular nuclear contours, condensed chromatin, and
small nucleoli (51). In the liver, HSTCL infiltrates sinu-
soids and spares portal tracts. In the spleen, the red pulp
is involved and the white pulp spared (Fig. 9-8). In the
bone marrow, the neoplastic cells can resemble blasts in
aspirate smears and are commonly intrasinusoidal in
core biopsy specimens (53).
Immunophenotypic studies have demonstrated that
HSTCLs have a mature but aberrant T-cell immunophe-
notype. Most cases are negative for CD4 and CD8, but a
subset may express CD8. CD5 is usually absent. CD56
is usually positive, a subset may express CD16, and
CD57 is negative. These neoplasms commonly have a
nonfunctional (or immature) cytotoxic profile, positive
for TIA-1 but negative for granzyme B and perforin (66).
At the cytogenetic level, HSTCLs often carry a charac-
teristic cytogenetic abnormality, isochromosome (7q),
and trisomy of chromosome 8 (67).
Subcutaneous Panniculitis-Like T-Cell
Lymphoma
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
is the least well-defined and rarest type of PTCL.
Patients with SPTCLs are usually adults, who present
with multiple subcutaneous nodules, resembling lipomas
(1,68). Approximately, one-third of patients present with
a hemophagocytic syndrome, causing systemic symptoms
with pancytopenia, fever, and hepatosplenomegaly.
Additional patients develop hemophagocytic syndrome
at some point in the course of their disease.
Histologically, SPTCLs involve subcutaneous tissue,
with minimal involvement of overlying dermis (1). The
neoplastic cells infiltrate the septa of adipose tissue and
surrounding fat cells; marked coagulative necrosis
and fat necrosis are common, resembling panniculitis
(Fig. 9-9). Nevertheless, at high power, the tumor cells
are cytologically atypical and may be a mixture of small
and large cells or predominantly large cells. Large cells
accrue over time. Karyorrhexis is often prominent and
mitotic figures are easily identified.
Immunophenotypic studies have shown that SPT-
CLs have a mature T-cell immunophenotype (1,69).
Most cases of SPTCL express TCR /. A subset of cases
of SPTCL that express TCR / have been reported.
FIGURE 9-8. Hepatosplenic T-cell lymphoma involving spleen
(hematoxylin-eosin, 400).
These cases have a more aggressive clinical course, and
a consensus is building for considering these neoplasms
a distinct disease (70). SPTCLs have a cytotoxic T-cell
profile, positive for TIA-1, perforin, and granzyme B.
SPTCLs are usually BCL-2negative (69).
APPROACH TO THERAPY
PTCLs are generally treated much the same as other
aggressive B-cell non-Hodgkin lymphomas where
most patients will receive the CHOP regimen. In one
study, the complete response rate reported for PTCL
was about 19% with the overall response rate about 20
to 25% (71). A recent retrospective analysis of T-NHL
patients treated at MD Anderson Cancer Center showed
that patients treated with CHOP had similar survival
outcome as those treated with more intensive regimens
(73). Given the poor outcome with conventional
chemotherapy, increasingly more and more patients are
being referred to stem cell transplant in first remission.
However, due to lack of randomized or prospective data,
this approach should be considered investigational.
Retrospective data from Memorial Sloan Kettering
Cancer Center showed that less than 20% of patients
remained in long-term remission after salvage therapy
with ifosfamide, carboplatin, and etoposide (ICE),
followed by autologous stem cell transplant. To improve
the outcome in this patient population, new agents need
to be investigated to find an effective treatment regimen.
PRIMARY TREATMENT IN PTCLS
Nodal PTCL
For ALK-positive ALCL, CHOP-like chemotherapy is
effective with complete response rates similar to diffuse
large B-cell lymphoma and failure-free survival of 58%
at 5 years (7). However, CHOP is inadequate therapy
for most patients with ALK-negative ALCL PTCL (5).
Intensifying chemotherapy by using dose-dense etopo-
side-containing therapy (cyclophosphamide, doxoru-
bicin, vindesine, etoposide, and prednisone [CHOEP-14])
does not seem to have had a significant impact with one
study reporting CR in only 31 (40%) of 77 patients after
three cycles and with 25% either failing to respond or
relapsing before reaching planned autologous stem
cell transplant (ASCT) (72). In addition, neither hyper-
CVAD (cyclophosphamide, vincristine, doxorubicin,
dexamethasone, cytarabine, and methotrexate) regimen
(73) nor intensive anthracycline-based chemotherapy
ACVBP (doxorubicin, cyclophosphamide, vindesine,
bleomycin, and prednisone) (74) has improved out-
come in PTCL patients.
Extranodal PTCL
Patients with IE nasal disease may be successfully
treated with radiotherapy alone provided that doses of 50
to 55 Gy are used (75,76). Five-year overall survival and
progression free survival were 78% and 63%, respec-
tively (76). For invasive disease beyond the nasopharynx,
local nodal involvement, stage IIE disease, and possibly
Ki67 50% or higher, outcome is better when radiotherapy
is administered before chemotherapy. Patients with stage
III/IV disease or nasal type natural killer/T-cell disease
outcome is poor with median overall survival less than 1
year when conventional dose chemotherapy is used.
The use of anthracycline based regimens for
hepatosplenic PTCL is associated with short-duration
responses and overall 5-year survival rates of 12 to 20%
A
B
FIGURE 9-9. Subcutaneous panniculitis-like T-cell lymphoma.
A. The neoplasm involves adipose tissue and is associated with
extensive fat necrosis in this field. B. The neoplastic lymphocytes
surround fat spaces. (Hematoxylineosin; A, 100; B, 1000.)
(54). Patients with enteropathy-type PTCLs are frequently
malnourished and have poor performance status. Median
survival is 7.5 months (77) with standard chemotherapy.
Patients with subcutaneous panniculitis-like PTCL
presented with hemophagocytic syndrome in 37%.
Anthracycline-based regimens produced durable CR in
30% of patients (78) but presence of HPS or / TCR
was associated with poor survival.
Adult T-cell Leukemia/Lymphoma
Eighty-seven percent of patients fall into the lymphoma
subtype. Five-year overall and failure-free survivals were
14 and 12%, respectively, in the 126 patients diagnosed
in the International T-cell Lymphoma Project (79). A
variety of standard treatment modalities were used, none
of which proved to be superior. Although response rates
to interferon-and zidovudine have been high, remissions
have not been durable. Chemotherapy plus zidovudine
and interferon in one study was associated with a median
survival of 17 months (80).
Hematopoietic Stem Cell Transplant
There is limited experience using either autologous or
allogeneic stem cell transplant in patients with PTCL.
Much of the data comes from small trials or anecdotal
reports. Although autologous SCT appears to be effec-
tive salvage for some and might be recommended in the
first remission for patients with nodal PTCL (excluding
ALK-positive ALCL), outcome is highly dependent
on complete response status at transplant and most of
these studies are overwhelmed by suboptimal complete
response rates to induction therapy, inclusion of patients
with ALK-positive ALCL and under-representation
of adult T-cell lymphoma and extranodal PTCLs. The
allogeneic stem cell transplant experience for PTCL is
more limited. This modality may be of greatest impor-
tance for the more chemo-resistant extranodal tumors
such as the nasal-type natural killer/T-cell lymphomas
and ATLL.
NOVEL TREATMENT
Table 9-2 shows the new agents used to treat peripheral
T-cell lymphoma (81).
Gemcitabine
Gemcitabine is a nucleoside analog with significant
activity in lymphoid malignancies. Gemcitabine has
been shown to be a highly active agent as salvage ther-
apy in both CTCL and PTCL with single-agent activ-
ity of 60 to 70% in both types (82). It competes with
the nucleotide deoxycytidine and inhibits DNA synthase
and ribonucleotide reductase. Combination chemother-
apy incorporating gemcitabine has been of interest
given the single-agent activity of this agent in T-cell
lymphoma.
NEW AGENTS IN PERIPHERAL T-CELL LYMPHOMA
ORR (Complete
Study Target Subtype, N Response) (%)
Nucleoside analog
Gemcitabine Nucleoside analog PTCL, 10 60 (20)
Gemcitabine + cisplatin + dexamethasone Nucleoside analog TCL, 5 40
Gemcitabine + cisplatin + methylprednisolone Nucleoside analog PTCL, 16 69 (19)
Immunotoxins
Denileukin diftitox Interleukin-2 receptor PTCL, 27 48 (22)
Folate analog
Pralatrexate Folate analog PTCL, 109 27 (9)
Monoclonal antibodies
MDX-060 CD30 ALCL, 7 29 (26)
SGN-30 CD30 ALCL, 39 21 (5)
SGN-35 CD30 ALCL, 2 100
Zanolimumab CD4 PTCL, 21 23 (9)
Histone deacetylase inhibitor
Depsipeptide Histone deacetylation PTCL,48 31 (18)
Belinostat Histone deacetylation PTCL,11 18
Abbreviations: ALCL, anaplastic large-cell lymphoma; ORR, overall response rate; PTCL, peripheral T-cell lymphoma; CTCL, cutaneous T-cell lym-
phoma. (Reproduced, with permission, from Pro B. Novel agents in peripheral T-cell lymphomas. In: American Society of Clinical Oncology Education
Booklet 2009;486-489.)
T A B L E
9-2
Several studies were conducted with gemcitabine-
based combinations. Twenty-six patients with PTCL in
a study were treated with a regimen consisting of CHOP
combined with gemcitabine and etoposide (83). The
complete response rate was 62% at a median follow-up
duration of 383 days. Estimated overall survival at 1 year
was 70%. A study at the Royal Marsden Hospital showed
the overall response rate was 69% in 16 patients treated
for refractory PTCL with gemcitabine, cisplatin, and
methylprednisolone. Three patients (19%) had complete
remission. The 1-year overall survival was 68% and
median time to progression was 123 days. However,
hematologic toxicity was significant and two patients
developed bowel perforation (84).
Denileukin Diftitox (Ontak)
Denileukin diftitox is a recombinant cytotoxic protein
comprising the interleukin-2 (IL-2) ligand genetically
fused to the membrane translocation domains of the
diphtheria toxin. Once bound to the IL-2 receptor, the
toxin is endocytosed and cleaved, releasing the toxin
that inhibits protein synthesis, leading to apoptosis.
IL2-receptor (IL-2R) is a marker of T-cell differentia-
tion and the CD25 subunit of this receptor is expressed
in a subset of patients with PTCL-U and CD30+ ALCL.
In a phase II trial, the overall response rate was 48
and 22% of 27 patients with relapsed PTCL achieved a
complete remission. Twenty-nine percent of patients
had stable disease. Patients with CD-25 positive status
had higher response rate (61%) than patients with CD25
negative status (45%). Median progression-free survival
was 6 months. Adverse events were generally mild.
The most common were hypoalbuminemia, transami-
nase elevation, edema, and skin reaction (85). Studies
are ongoing combining this agent with CHOP.
Pralatrexate
Pralatrexate is a novel folate antagonist with a high affin-
ity for the reduced folate carrier (RFC-1) and is more effi-
ciently internalized and retained than methotrexate. At a
dose of 30 mg/m
2
weekly for 6 of 7 weeks, the overall
response rate was 63% in 16 patients with PTCL and
included nine complete responses and one partial
response (86).
A multicenter registration phase II study of prala-
trexate (PDX 008) in patients with relapsed or refrac-
tory PTCL completed accrual. Study design included
supplementation with vitamin B12 and folic acid to
reduce the risk of mucositis. Patients were heavily pre-
treated and had failed a median of three prior regimens.
The overall response rate was 27%, with 9% patients
achieving complete response and 17% partial response.
The most common grades 3 to 4 toxicities were throm-
bocytopenia and mucositis (87). Furthermore, pralatrex-
ate and gemcitabine synergize in a schedule-dependent
manner in cell lines in vitro and lymphoma xenografts
(88). This combination is currently being evaluated in a
phases I to II study.
FDA granted accelerated approval in September
2009 to pralatrexate injection (Fotolyn) for the treat-
ment of patients with relapsed or refractory PTCL based
on the PDX 008 trial. As a condition of the accelerated
approval, randomized controlled trials are required after
approval to verify the clinical benefit.
Histone Deacetylase Inhibitors
Histone deacetylase inhibitors (HDAC inhibitors) are
inducers of acetylation of histones and other nonhistone
proteins. HDAC inhibition results in accumulation of
acetylated nucleosomal histones and induces differenti-
ation and/or apoptosis in transformed cells.
Vorinostat (suberoylanilide hydroxamic acid) is the
first FDA approved HDAC inhibitor for the treatment of
refractory cutaneous T-cell lymphoma (CTCL) in October
2006. The overall response rate was 30% and the median
duration of response was not reached but estimated to be
at least 185 days (89). It is currently under investigation
in combination with other agents for the treatment of
PTCLs. Romidepsin, previously known as depsipeptide
or FK228, has been shown to induce cell cycle arrest and
apoptosis in many cell lines. It demonstrated activity in
relapsed PTCL patients with an ORR 26%. Romidepsin
was recently approved in September 2009 for treatment
of CTCL. Belinostat (PDX101) is another pan-HDAC
inhibitor being tested in PTCL. Ongoing phase II study
reported two complete responses and five cases of stable
disease in 11 patients with PTCL.
IMMUNOTHERAPY
Alemtuzumab
Alemtuzumab, a humanized monoclonal antibody
directed against the CD52 antigen, present on most
malignant T cells, making it an attractive target for
PTCL. As a single agent in heavily pretreated patients
with PTCL the overall response rate with alemtuzumab
was 36% in one report (90).
Zanolimumab
Zanolimumab is a fully human immunoglobulin G1
monoclonal antibody that targets the CD4 antigen present
on T-helper lymphocytes. It inhibits CD4 positive T-cell
by combining signaling inhibition with the induction of
Fc-dependent effector mechanisms. Preliminary result
of a phase II study in 21 patients demonstrated activity
of 23%, with two complete responses, one in a patient
with PTCL-U and another in a patient with AITL. Toxi-
cities include transient myelosuppression and infusion-
related adverse events (91).
Anti-CD30 Monoclonal Antibodies
CD30 is uniformly expressed in ALCL and in 30% of
unspecified PTCL. It is minimally expressed on normal
cells. SGN-30 is a CD30-specific chimeric antibody
constructed from the variable regions of the anti-CD30
murine monoclonal AC10 and the human 1 heavy
chain and light chain constant regions (81).
A multicenter, single-arm phase II trial enrolled
39 patients with refractory or relapsed ALCL treated
with SGN-30 at a planned dose of 6 mg/kg per week
for 6 weeks. Nine patients had received prior stem cell
transplants, and 85% had ALK-negative tumors. Two
patients achieved complete remission and six had a par-
tial remission, for an overall response rate of 21% (92).
MDX-60 is a human anti-CD30 immunoglobulin G1
monoclonal antibody that has been shown to inhibit the
growth of CD30-expressing tumor cells in preclinical
models. Ansell et al. reported results of a phases I to II
study in patients with recurrent HL and ALCL (93). The
treatment was well tolerated. Of the seven patients
with ALCL, two (28%) achieved complete remission.
Ongoing trials are investigating the effect of MDX-060 in
systemic or cutaneous ALCL as single agent (93).
SGN-35 is an antibody drug conjugate consisting of
the chimeric antibody SGN-30 chemically conjugated
to a synthetic analog of the naturally occurring antitubu-
lin agent dolastatin 10. The mechanism is initiated by
binding to CD30 and internalization with subsequent
release of monomethylauristatin E, leading to G2/M
phase cell cycle arrest and apoptosis. A phase I single
arm study of SNG-35 has been conducted in patients
with relapsed CD30-positive lymphomas. Most patients
achieved best clinical response within 12 weeks, and
treatment was well tolerated (94).
Other Agents
Bortezomib, a proteasome inhibitor, showed significant
activity in various lymphomas. A recent phase II study
demonstrated 67% response rate in 12 patients with
recurrent CTCL or PTCL and isolated skin relapse.
Patients received bortezomib at a dose of 1.3 mg/m
2
IV
on days 1, 4, 8, and 11 every 21 days. This agent is
currently being evaluated in PTCL as single agent and
in combination with chemotherapy (95).
Lenalidomide is a structural analog of thalidomide
with demonstrated activity in multiple myeloma and
myelodysplastic syndrome. Early results from an ongoing
phase II multicenter clinical trial demonstrated some evi-
dence of clinical activity. Among nine evaluable patients,
the reported response rate was 44%, with four patients
achieving partial response. The most common toxicities
were hematological and infectious complications (96).
CUTANEOUS T-CELL LYMPHOMAS
CTCLs are a clinically heterogeneous group of post-
thymic lymphomas, accounting for the majority of all
lymphomas arising in skin. Mycosis fungoides (MF)
and Szary syndrome (SS) are defined by their cuta-
neous lesions that result from the accumulation of a
T-helper memory/effector subset with a CD4+, CD8,
CD45RO+CLA+ phenotype in skin and blood (97).
Most commonly, MF starts as an indolent and chronic
dermatitis in the sun shielded areas. A diagnostic biopsy
is difficult to obtain in early MF because there are simi-
larities with eczema or contact dermatitis.
CLASSIFICATION
MFs is staged using the Tumor Nodes Metastasis classi-
fication schema for the purpose of predicting disease
prognosis (Fig. 9-10). MFs and SS, the most common
variants, are still rare with an annual incidence of three
to four new cases per million or 1200 new cases per year
5
20
40
P
r
o
b
a
b
i
l
i
t
y

(
%
)
60
80
Mycosis Fungoides and Szary Syndrome:
Disease-specific Survival by Clinical Stage
100
10 15 20
Time (years)
IA (155)
III (59)
IIB (84)
IV (34)
IIA (60)
IB (133)
25 30 35
FIGURE 9-10. Mycosis fungoides and Szary syndrome: disease-
specific survival by clinical stage. Disease-specific survival of
525 patients with MF and Szary syndrome was measured according
to clinical stage at diagnosis. (Reproduced, with permission, Kim YH,
Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients
with mycosis fungoides and Szary Syndrome. Arch Dermatol. 2003;
139:857-866. Copyright 2003 American Medical Association. All
rights reserved.)
in the United States (98,99). The next most common
entities are the CD30+ lymphoproliferative disorders:
lymphomatoid papulosus and ALCL. Subcutaneous pan-
niculitic T-cell lymphoma and NK-T-cell lymphomas
are quite rare and more aggressive (Table 9-1).
PRESENTATION AND DIAGNOSIS
The ISCL has developed an algorithm to diagnose early
stage MF. The clinical diagnosis is based on two points
from the following: a chronic, persistant dermatitis, or
poikilodermatous changes or heterogeneous lesions
appearing on sun-shielded areas. Histological factors
include atypical lymphocytes within the epidermis (epi-
dermotropism) and a predominance of CD4+CD8+
cells with loss of other T-cell markers. The finding of
clonality with respect to the T-cell receptor gene
rearrangement is not diagnostic but helps to support
(one point) the diagnosis of lymphoma over reactive
process. MF may progress to a leukemic and erythro-
dermic condition called SS. SS is defined by erythro-
derma of >80% of the body plus the presence of >1000
per L of atypical circulating cells found in the periph-
eral blood. By flow cytometry, most patients have
increased numbers of CD4+CD26 cells. In the skin of
SS patients, the atypical cells have lost epidermotro-
pism and are found around the dermal vessels rather
than in the epidermis. Szary cells secrete Th2 cytokines,
IL-4, and IL-10, causing loss of cellular immunity due to
decreased production of Th1 cytokines, interferon-,
and IL-2 (100). This results in atopy characterized
by erythroderma and staphylococcus colonization,
peripheral eosinophilia, increased IgE production, and
intractable pruritus. Molecular methods have shown
that in MF there is emergence of one or more T-cell
clones of skin-homing CD4+ cells and that with progres-
sion to SS, these appear in the blood and can be detected
by flow cytometry (101).
PROGNOSIS
The predictive factors for survival are the T classifica-
tion, extracutaneous manifestation, and age of the patient
(102). Independent adverse prognostic factors are large-
cell transformation, follicular mucinosis, thickness of
tumor infiltrate, elevated LDH, and
2
-microglobulin
(103,104). Patients with SS have worse prognosis. A high
Szary cell count, loss of T-cell subset markers such
as CD5 and CD7, and chromosomal abnormalities in
T cells are also associated with a poor outcome (105).
APPROACH TO THERAPY
Figure 9-11 summarizes the primary treatment map for
CTCL.
Topical corticosteroids
IA
(limited patch,
plaque)
IB, IIA
(generalized
patch, plaque)
IIB
(tumors)
III
(erythro-
derma)
IVA, IVB
(nodal/visceral
involvement)
Bexarotene gel
CTCL Primary Treatment Map
PUVA + IFN/Other
Oral bexarotene
Vorinostant (Zolinza) & HDAC inhibitors
Denileukin diftitox
Electron beam
Chemotherapy
Experimental therapy
Nitrogen mustard
UVB
PUVA
P
h
o
t
o
p
h
e
r
e
s
i
s
FIGURE 9-11. CTCL primary treat-
ment map.
Current Treatment for Early Mycosis
Fungoides
There are a limited number of FDA-approved therapies
available to treat patients with MF/SS. However, topical
agents used for eczema, psoriasis, and other forms of
lymphoma and phototherapy are used and represent the
standard of care for early MF.
Early MF (stage IA) is characterized by eczematous
or psoriasiform dermatitis limited to less than 10% of
the body surface. Early MF lesions are treated with one
or more of the available skin-directed therapies. Combi-
nation therapy is the norm. The first therapy is usually
topically applied corticosteroids of increasing potency.
For thicker or hypertrophic lesions, the topical retinoid
gels or creams may help to restore normal epidermal
differentiation and reduce the time of clearing with pho-
totherapy. The response rate of targretin gel 1% was 76%
in patients not previously treated and this agent is the
only topical therapy approved for MF (106). We have
also found this gel to be useful for MF of the hands or
feet (107), for aborting lymphomatoid papulosis lesions
(108) or tumors of MF. Nitrogen mustard (mustargen) is
also widely used for the topical treatment of stage I MF.
Although it is not yet approved by the FDA, a randomized,
two arm multicenter trial has recently been completed.
Current Treatment for Intermediate or
Refractory/Transformed MFs and SS
Patients with <10% involvement (IA) who do not
respond to first-line topical therapies or who have >10%
of the body surface area (IB) or dermatopathic nodes
(IIA) often need more extensive therapies such as topical
chemotherapy with mustargen, BCNU, or with a combi-
nation of skin directed therapy plus one or more biological
response modifiers. Agents that are not specifically
approved for MF/SS are commonly used as the standard
of care: topical steroids and mustargen, phototherapy,
interferons, and chemotherapies (Table 9-3). For patch
disease, narrow band UVB is effective and can be effec-
tively combined with topical steroids, retinoids, or inter-
feron. Thick plaque lesions or folliculotropic MF lesions
are more difficult to clear and are treated with PUVA plus
interferon or an oral retinoid (bexarotene, soriatane, or
accutane) but often require radiation. Total electron beam
radiation is reserved for patients who need skin palliation
or who have extensive skin involvement and have failed
to respond to skin-directed therapies, and should be
followed with a form of maintenance therapy such as
mustargen, PUVA, or oral bexarotene.
Intravenous denileukin diftitox (Ontak) and oral
bexarotene have received FDA approval in 1998 and
OVERVIEW OF CURRENT THERAPEUTIC
OPTIONS FOR MF/SS
Skin directed therapy
Topical corticosteroids
Topical chemotherapy (eg, nitrogen mustard, carmustine)
Topical retinoids (bexarotene, tazarotene)
Topical imiquimod
Phototherapy (UVB, NbUVB, PUVA)
Electron beam therapy
Biological therapy
RXR retinoid (bexarotene)
RAR retinoid (isotretinoin)
Interferons
Granulocyte-macrophage colony-stimulating factor
Extracorporeal photopheresis
Fusion protein/toxin (denileukin difitox)
Other systemic therapies
Cytotoxic chemotherapy (methotrexate, doxil, gemcitabine,
etoposide, pentostatin)
Bone marrow/stem cell transplantation
Experimental therapies
HDAC inhibitors (vorinostat, depsipeptide)
Transimmunization extracorporeal photopheresis
Targeted monoclonal antibodies (CD52, CCR4, CD4)
Cytokines (IL-I2, IL-2)
TLR agonists (CpG oligodeoxynucleotides)
Tumor vaccines
UVB, ultraviolet B light; NbUVB, narrow-band ultraviolet B light; PUVA,
psoralen plus ultraviolet A light; RXR, retinoid X receptor; RAR, retinoic
acid receptor; TLR, toll-like receptor 9; IL, interleukin. (Data from Kim EJ,
Hess S, Richardson SK, et al. Immunopathogenesis and therapy of cutaneous
T cell lymphoma. J Clin Invest 2005;115:798-812.)
T A B L E
9-3
1999, respectively, for treatment of the cutaneous man-
ifestations of CTCL. Both are used in the setting of
more advanced skin disease. Ontak received FDA
approval for treatment of CTCL of all stages based on
a randomized two dose arm controlled multicenter
trial showing a response rate of 30% (109). Complete
responses were seen in 10% of the patients enrolled
(109). Capillary leak syndrome is seen in 20 to 30% of
patients but may be decreased with hydration and acute
fusion reactions are blocked by steroid pre-medication.
Our study suggested that high expression of CD25+ in
>20% of the tumor cells was associated with higher
response rates 60% compared to 20% of the low express-
ing patient and 30% in the pivotal trial. Bexarotene and
steroids may increase CD25 expression on T cells as
measured by flow and could suggest synergism (110).
Bexarotene monotherapy has a response rate of 54% at
a dose of 300 mg/m
2
in early patients and 45% in more
advanced patients (111). Its dose-limiting toxicity is
hypertriglyceridemia but can often be controlled with
addition of an HMG-coA reductase and/or a statin (112).
Pralatrexate has also been investigated in MF
patients at decreasing dose schedules. It was found
to be active with a response rate of 57% and a dose of
15 mg/m
2
(117).
Targeted therapy with antibodies against T-cell mol-
ecules are under investigation. HuMax CD4 is being
studied in a multicenter trial and is significantly active
and able to deplete the peripheral T cells. Alemtuximab
(campath-H) targeting CD52 is especially active in SS
and can be used subcutaneously to induce remissions
but it is immunosuppressive. Diptheria fusion protein
coupled to CD3 is also under investigation. Forodesine
is a nucleoside analogue, which inhibits PNP and build
up of d-GTP causing T-cell apoptosis. A multicenter
randomized trial has been conducted but the results are
not available.
Other agents which have been in trials for MF
patients include CpGs which activate Toll-like recep-
tors, oral lenolidamide, sapacitabine (oral nucleoside
inhibitor), and enzastaurin (AKT inhibitor).
FUTURE DIRECTION FOR T-CELL
LYMPHOMAS
T-cell lymphomas represent a heterogenous group of
diseases with poor prognosis. Therapeutic progress has
been slow due to the rarity of the disease. It is strongly
recommended that patients with non-ALK positive
ALCL PTCLs and CTCLs receive treatment on clinical
trials so that progress can be made in the management
of these uncommon neoplasms. Therefore, future stud-
ies will require a multi-institution collaboration.
References
1. Jaffe ES, Harris NL, Stein H, et al. World Health Organization
classification of tumours. Pathology and genetics of tumours
of hematopoeitic and lymphoid tissues. Lyon, France: IARC
Press; 2001:121-253.
2. Armitage J, Weisenburger D. New approach to classifying
non-Hodgkins lymphomas: Clinical features of the major
histologic subtypes. J Clin Oncol 1998;16:2780-2795.
3. The Non-Hodgkins Lymphoma Classification Project: A
clinical evaluation of the International Lymphoma Study
Group Classification of Non-Hodgkins Lymphoma. Blood
1997;89:3909-3918.
4. Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell
lymphoma unspecified (PTCL-U): a new prognostic model
from a retrospective multicentric clinical study. Blood 2004;
103(7):2474-2479.
5. Savage KJ, Chhanabhai M, Gascoyne RD, et al. Characteri-
zation of peripheral T-cell lymphomas in a single North
American institution by the WHO classification. Ann Oncol
2004;15(10):1467-1475.
Patients with transformed MF, tumors, or nodal dis-
ease respond to local radiation, denileukin diftitox
(Ontak), nucleoside analogues (gemcitabine, pento-
statin), doxil, histone deacetylase inhibitors, or combi-
nation chemotherapy but often the duration of response
is limited. Various chemotherapy combinations, while
effective for a limited time, can also induce further
immunosuppression leading to line induced sepsis or
other opportunistic infections.
Generalized exfoliative erythroderma (EE) is found
in patients with blood involvement (SS). Extracorpo-
real photopheresis was approved in 1987 for the treat-
ment of CTCL patients and significant responses were
seen in erythrodermic patients (113). Photopheresis is
usually combined with biological response modifiers,
especially interferon or , and retinoids, for responses
approaching 60 to 70% (114).
NOVEL TREATMENTS
The recent FDA-approved HDAC inhibitors, vorinostat
(Zolinza) in 2006, and depsipeptide (Romidepsin) in
2009, represent a new strategy for targeted therapy of
CTCL and were effective in patients who were highly
refractory to chemotherapy and other agents. Their
mechanism of action, like retinoids, involves inducing
transcription of genes that control differentiation and
apoptosis selectively in malignant cells. Oral Vorinostat
was well tolerated at a dose of 400 mg daily and had a
rapid onset of action. Vorinostat had an overall response
rate of about 30% and had a higher response rate (36%)
in patients with SS compared to other stages. The drug
also improved skin, nodal, and blood involvement as
well as reducing pruritus (115). Romidepsin, previ-
ously known as depsipeptide or FK228, was recently
approved for treatment of CTCL in patients who have
received at least one prior systemic therapy. The overall
response rate was 35% and complete response was 6%.
The recommended dose and schedule of romidepsin is
14 mg/m
2
intravenously over 4 hours on days 1, 8, and
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