SYMPOSIUM ON ONCOLOGY PRACTICE: HEMATOLOGICAL MALIGNANCIES
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
Non-Hodgkin Lymphoma: Diagnosis and Treatment
STEPHEN M. ANSELL, MD, PHD, AND JAMES ARMITAGE, MD
Non-Hodgkin lymphomas are a heterogeneous group of malignan-
cies of the lymphoid system. Based on the World Health Organiza-
tion classification of hematological and lymphoid tumors, these
diseases have been classified as B-cell and T-cell neoplasms. B-
cell lymphomas account for approximately 90% of all lymphomas,
and the 2 most common histological disease entities are follicular
lymphoma and diffuse large B-cell lymphoma. Approximately
55,000 to 60,000 new cases of non-Hodgkin lymphoma are diag-
nosed annually in the United States, a number that has nearly
doubled during the past 3 decades. The Ann Arbor Staging Classi-
fication is used routinely to classify the extent of disease, and the
International Prognostic Index has been used to define prognostic
subgroups. Also, recent data have identified molecular and ge-
netic markers of prognosis that may be used in the future to
further refine treatment decisions. Treatment of these diseases is
based on the histology and extent of disease. Patients with
follicular lymphomas with early-stage disease generally are
treated with radiation therapy, whereas those with stage III and IV
disease requiring treatment usually are treated with chemo-
therapy, immunotherapy, or radioimmunotherapy. These patients
generally experience long survival, but only a minority are cured.
For patients with diffuse large B-cell lymphoma, treatment of
limited-stage disease generally includes doxorubicin-based che-
motherapy combined with rituximab followed by involved field
radiation therapy. Those with extensive disease are treated with
rituximab combined with chemotherapy alone. Disease relapse is
a problem, and high-dose therapy with stem cell support is the
treatment of choice for chemosensitive relapsed aggressive lym-
phomas. Patients with chemoresistant disease or whose disease
relapses subsequently should be treated with novel experimental
therapies.
Mayo Clin Proc. 2005;80(8):1087-1097
ACVBP = doxorubicin (Adriamycin), cyclophosphamide, vindesine,
bleomycin, and prednisone; CHOP = cyclophosphamide, hydroxydauno-
mycin (doxorubicin), vincristine (Oncovin), and prednisone; CNS = cen-
tral nervous system; CVP = cyclophosphamide, vincristine, and pred-
nisone; FDG-PET = positron emission tomography with fluorodeoxy-
glucose F 18; GI = gastrointestinal; HIV = human immunodeficiency
virus; IPI = International Prognostic Index; LDH = lactate dehydroge-
nase; MALT = mucosa-associated lymphoid tissue; NHL = non-Hodgkin
lymphoma; PET = positron emission tomography; R-CHOP = CHOP
chemotherapy in combination with rituximab
A n estimated 55,000 to 60,000 new cases of non-
Hodgkin lymphoma (NHL) are diagnosed in the
United States annually.1 Data from the National Cancer
Institute have shown that the incidence of NHL increased
by 3% annually in the United States in the past 3 decades
but seems to have stabilized in the 1990s, with some varia-
tion in the rates according to age, ethnicity, and sex.2-4
Non-Hodgkin lymphoma is known to be associated
with chronic inflammatory diseases such as Sjögren syn-
drome, celiac disease, and rheumatoid arthritis. Chronic
infection also is associated with lymphoma pathogenesis
Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
as shown by the association between mucosa-associated
lymphoid tissue (MALT) lymphomas and Helicobacter
pylori infection.5 Human T-lymphotropic virus 1 is associ-
ated with adult T-cell leukemia/lymphoma; Epstein-Barr
virus is associated with Burkitt lymphoma; and primary
effusion lymphomas have been associated with human
herpesvirus 8. Also, an association has been shown be-
tween Chlamydia psittaci and ocular adenexal lympho-
mas.6 Furthermore, there is also evidence of an association
between hepatitis C infections and splenic or large cell
lymphomas.7
Immune suppression also has been associated with an
increased risk of NHL. In patients who undergo solid organ
transplantation,8 the risk of lymphoma has been associated
specifically with the duration of immunosuppression and
with the drugs and doses used. Furthermore, human immu-
nodeficiency virus (HIV) infections have been associated
with a substantially elevated risk of NHL compared with
the risk in the general population.9
DIAGNOSIS
Patients with indolent lymphomas, such as follicular, mar-
ginal zone, and lymphoplasmacytic lymphoma, commonly
present with slowly progressive and usually painless pe-
ripheral lymphadenopathy. Patients sometimes report a
history of the involved lymph nodes getting larger and
then smaller before a diagnosis is made. Spontaneous re-
gression of some of these lymph nodes can occur, which
may delay the diagnostic biopsy while patients receive
therapy for a presumed infectious condition. Primary extra-
nodal involvement or systemic symptoms are less common
at presentation but are seen more commonly as the dis-
ease advances. Systemic B-symptoms, such as fever, night
sweats, and weight loss, may develop and may be associ-
ated with more advanced or aggressive disease. Bone mar-
row involvement in indolent lymphomas is frequent and
From the Division of Hematology, Mayo Clinic College of Medicine, Rochester,
Minn (S.M.A.); and Department of Medical Oncology, University of Nebraska,
Omaha (J.A.).
Address correspondence to Stephen M. Ansell, MD, PhD, Division of Hema-
tology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN
55905 (e-mail: ansell.stephen@mayo.edu). Individual reprints of this article
and a bound booklet of the entire Symposium on Oncology Practice: Hema-
tological Malignancies will be available for purchase from our Web site
www.mayoclinicproceedings.com.
© 2005 Mayo Foundation for Medical Education and Research
• www.mayoclinicproceedings.com 1087
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
TABLE 1. World Health Organization Classification
of Lymphoid Malignancies11*
Percentage of
Classification
I of patients. Patients with lymphoblastic lymphoma often
Peripheral B-cell neoplasms
Precursor B lymphoblastic leukemia/lymphoma
Mature B-cell neoplasms
Chronic lymphocytic leukemia/small
lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal zone lymphoma
Extranodal marginal zone B-cell lymphoma
of MALT (MALT lymphoma)
Nodal marginal zone lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukemia
Hairy cell leukemia
Plasma cell myeloma
Solitary plasmacytoma of bone
B-cell proliferation of uncertain malignant potential
Lymphomatoid granulomatosis
Posttransplantation lymphoproliferative
disorder, polymorphic
II
Precursor T-cell neoplasms
Precursor T-cell lymphoblastic
leukemia/lymphoma
Blastic NK cell lymphoma
Mature T-cell and NK-cell neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell leukemia/lymphoma
Extranodal T/NK-cell lymphoma,
nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides and Sézary syndrome
Primary cutaneous anaplastic large cell
lymphoma
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma
T-cell proliferation of uncertain malignant potential
Lymphomatoid papulosis
*MALT = mucosa-associated lymphoid tissue; NK = natural killer.
sometimes is associated with cytopenias. Splenomegaly is
seen in approximately 30% to 40% of patients, but the
spleen is rarely the only site of disease involvement at
presentation.
The clinical presentation of aggressive lymphomas,
such as diffuse large B-cell lymphoma, is more variable.
Most patients present with lymphadenopathy; however,
many present with extranodal involvement. The most com-
1088 Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
mon extranodal sites are the gastrointestinal (GI) tract,
skin, bone marrow, sinuses, thyroid, or central nervous
system (CNS). B-symptoms are more common in patients
total cases
with aggressive NHL and occur in approximately one third
present with an anterior mediastinal mass that is sometimes
associated with superior vena cava syndrome. Patients in
the United States with Burkitt lymphoma may present with
6.7
a large abdominal mass. Patients with African Burkitt lym-
1.2 phoma may present with a mass at the angle of the jaw or in
<1 the neck.
7.6 No effective methods are available for screening pa-
1.8 tients for lymphoma, and identifying populations at high
22.1 risk of lymphoma is challenging. Currently, patients are
6.0
30.6 identified only after they develop lymphadenopathy or
2.4 other symptoms associated with their disease. Despite
progress in imaging techniques for lymphoma, histology
<1 remains compulsory to establishing the diagnosis because
successful therapy for most patients with NHLs requires an
accurate pathologic diagnosis. Excisional diagnostic bi-
opsy is recommended, and a definitive diagnosis can be
made only after biopsy specimens of the pathologically
involved lymph node are reviewed by an expert hemato-
pathologist. For patients with intra-abdominal and retro-
peritoneal lymphadenopathy as the only sites of disease,
laparoscopy has a role in establishing the diagnosis.
1.7
Laparoscopy often allows for a more substantial biopsy
specimen of intra-abdominal and retroperitoneal disease
than is commonly obtained with a needle biopsy, but with
less morbidity than a laparotomy.
<1 Routine morphologic examination of excisional biopsy
specimens provides the cornerstone for establishing a de-
finitive diagnosis. Fine-needle aspiration biopsies or large
<1 bore-needle biopsies can be used but often lead to chal-
lenges in making a definitive diagnosis. Because of the
<1
limitations of pure morphology, subclassification of NHL
by needle biopsy often requires ancillary studies. The list of
ancillary studies used to complement the routine ap-
2.4 proaches is increasing in both number and complexity, and
limited tissue availability can hamper attempts to confirm
the diagnosis. Because of these challenges and a high like-
lihood of an incorrect diagnosis, the use of fine-needle
aspiration techniques is strongly discouraged.10
Patient disease usually is classified with use of the
World Health Organization classification for lymphoid
malignancies (Table 1),11 which categorizes on the basis
of cytology, immunophenotype, and genetic and clinical
features (Tables 2 and 3). Chromosomal translocations
and molecular rearrangements are used commonly to con-
firm the diagnosis and may play an important role in the
pathogenesis of many lymphomas. The most commonly
associated chromosomal abnormality in NHL is the trans-
• www.mayoclinicproceedings.com
 NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT

TABLE 2. Immunophenotypic Diagnosis of aspirate and biopsy. Lactate dehydrogenase (LDH) levels
Common B-cell Lymphomas*
should be determined as a measure of tumor cell prolifera-
Phenotypic tion and for prognostic purposes. β2-Microglobulin also has
marker MZL/MALT SLL Mantle cell Follicular
been shown to predict response to treatment and time to
CD5 – + + – treatment failure, and testing is performed routinely at
CD10 – – – + some centers.15 Also, diagnostic imaging should be per-
CD20 + dim+ + +
formed including computed tomography of the neck, chest,
sIg + dim+ + +
abdomen, and pelvis, as well as positron emission tomogra-
CD23 – + – –(+)
CD22 ?+ –(dim+) + +
phy (PET) for both staging and prognostic purposes.
CD25 – –(+) – –(+) Positron emission tomography with fluorodeoxyglucose
F 18 (FDG-PET) shows functional metabolic status and
*MZL/MALT = marginal zone/mucosa-associated lymphoid tissue; sIg =
surface immunoglobulin; SLL = small lymphocytic lymphoma; – = gives quantitative information for patients with lymphoma.
negative; + = positive; dim+ = dimly positive. Positron emission tomography provides whole-body im-
ages that allow a comprehensive assessment of disease
extent during the staging and follow-up.16 When used in
location of t(14;18)(q32;q21), which is found in 85% of conjunction with computed tomography, PET provides
follicular lymphomas and 28% of diffuse large B-cell lym- complementary initial staging information. A pretreatment
phomas.12-14 This translocation results in the juxtaposi- FDG-PET study is essential for subsequent accurate as-
tion of the bcl-2 gene on chromosome 18 to the heavy chain sessment of residual masses and early monitoring of re-
region of the immunoglobulin locus on chromosome 14 sponse to treatment. Particularly in diffuse large B-cell and
and leads to cellular resistance to apoptosis. The Hodgkin lymphoma, FDG-PET has shown high accuracy
t(11;14)(q13;q32) translocation, which is associated with in the early prediction of response to chemotherapy and in
mantle cell lymphoma, results in the overexpression of bcl- the evaluation of residual masses after therapy. Persistent
1, leading to increased cell proliferation. Molecular rear- abnormalities on PET during and after chemotherapy ap-
rangements involving bcl-6 or c-myc are seen frequently pear to have a high sensitivity for predicting subsequent
in diffuse large B-cell lymphoma and Burkitt lymphoma, relapse. Normal PET at the end of therapy correlates with
respectively. a highly favorable prognosis. Persistent abnormalities on
The initial evaluation of a patient with recently diag- PET at the end of therapy warrant close follow-up or
nosed lymphoma should include a medical history and additional diagnostic procedures (such as a repeated bi-
physical examination, a complete blood cell count, electro- opsy) because increased FDG uptake may constitute re-
lyte panel, renal and liver profiles, as well as a bone marrow sidual disease. However, despite abnormalities on PET

TABLE 3. Chromosomal Abnormalities in Non-Hodgkin Lymphoma*

Antigen
Cytogenetic abnormality Histology rearrangement Oncogene expression
B-cell lymphoma
t(14;18)(q32;q21) Follicular lymphoma, diffuse large IgH bcl-2
B-cell lymphoma
MALT lymphoma IgH MALT-1
t(1;14)(p22;q32) MALT lymphoma IgH bcl-10
t(11;18)(q21;q21) MALT lymphoma API-2 on chromosome 11
MALT-1 on chromosome 18
t(9;14)(p13;q32) Lymphoplasmacytic lymphoma IgH PAX-5
Trisomy 12 Small lymphocytic lymphoma
t(11;14)(q13;q32) Mantle cell IgH bcl-1
3q27 abnormalities Large cell, follicular grade 3B lymphoma bcl-6
8q24 translocations Burkitt lymphoma and variants c-myc
t(8;14)(q24;q32) IgH
t(2;8)(p11-12;q24) Ig-λ
t(8;22)(q24;q11) Ig-κ
T-cell lymphoma
t(2;5)(p23;q35) Anaplastic large cell (Ki-1 positive) npm, alk
*alk = anaplastic lymphoma kinase gene; API-2 = apoptosis inhibitor 2; IgH = immunoglobulin heavy chain; Ig-κ = immunoglob-
ulin κ light chain; Ig-λ = immunoglobulin λ light chain; MALT = mucosa-associated lymphoid tissue; MALT-1 = MALT
lymphoma gene 1; npm = nucleophosmin gene.

Mayo Clin Proc. • August 2005;80(8):1087-1097 • www.mayoclinicproceedings.com 1089

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
TABLE 4. Modified Ann Arbor Staging Classification
for Non-Hodgkin Lymphoma19
Stage Description
I Involvement of a single lymph node region
IE Localized involvement of a single extralymphatic organ or site
II Involvement of 2 or more lymph node regions on the same side
of the diaphragm
IIE Localized involvement of a single associated extralymphatic
organ or site and its regional lymph nodes with or without
other lymph node regions on the same side of the diaphragm
III Involvement of lymph node regions on both sides of the
diaphragm
IIIE Involvement of lymph node regions on both sides of the
diaphragm accompanied by localized involvement of an
extralymphatic organ
IIIS Involvement of lymph node regions on both sides of the
diaphragm accompanied by involvement of the spleen
IIIE+S Involvement of lymph node regions on both sides of the
diaphragm accompanied by both localized involvement of
an extralymphatic organ or site and the spleen
IV Disseminated (multifocal) involvement of 1 or more
extralymphatic organs with or without associated lymph
node involvement
IVE Isolated extralymphatic organ involvement with distant
(nonregional) nodal involvement
after treatment, some patients may remain in prolonged
remission.
An evaluation of cerebrospinal fluid should be consid-
ered in patients with diffuse large cell NHL with bone mar-
row involvement, a high LDH, or multiple extranodal sites
of disease17,18 as well as in patients presenting with epidural
masses, testicular involvement, paranasal sinus, or naso-
pharyngeal involvement. A cerebrospinal fluid evaluation
also should be performed in patients with high-grade
lymphomas, such as lymphoblastic lymphoma or Burkitt
lymphoma, and in patients with HIV-related lymphomas,
primary CNS lymphomas, and posttransplantation lym-
phoproliferative disorders. A GI evaluation should be con-
sidered in patients with a known GI primary lymphoma or
in patients with mantle cell lymphoma because of a high
incidence of occult GI involvement. Because of a high
TABLE 5. International Prognostic Factor Index
for Non-Hodgkin Lymphoma20*
Factor Adverse prognosis
Age >60 y
Ann Arbor stage III or IV
Serum LDH level Above normal
No. of extranodal sites of involvement ≥2
Performance status ECOG PS ≥2 or equivalent
*ECOG PS = Eastern Cooperative Oncology Group Performance Status;
LDH = lactate dehydrogenase.
1090 Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
incidence of contralateral involvement, ultrasonography of
the opposite testis in patients with testicular lymphoma is
recommended.
STAGING AND PROGNOSTIC FACTORS
The stage of lymphoma is categorized with use of the Ann
Arbor Staging Classification (Table 4).19 This system was
proposed originally for Hodgkin disease and is based on
the distribution and number of involved sites, as well as the
presence or absence of extranodal involvement and consti-
tutional symptoms. Such symptoms include weight loss
greater than 10% of body weight over the preceding 6
months, fever higher than 38°C unrelated to any infections,
and drenching night sweats.
The outcome of patients with lymphoma is highly vari-
able, and the histology and morphology of the lymphoma
are the major determinants of treatment outcome and prog-
nosis. Some patients with indolent lymphoma may remain
well for many years with minimal or no therapy, whereas
the survival of patients with aggressive lymphoma may be
measured only in weeks unless aggressive treatment is
initiated promptly. Even within histological subtypes
there is a wide range of disease outcomes, and factors that
reliably predict the patient’s response to therapy and
eventual outcome are used as a standard for discussing
prognosis, selecting therapy, and comparing results of
clinical trials.
The International Prognostic Index (IPI) was developed
initially to categorize aggressive NHL on the basis of easily
obtained clinical features that were independent predictors
of survival (Table 5).20 This model includes patient age
(>60 vs ≤60 years), Ann Arbor stage (III or IV vs I or II),
LDH level (>1 vs ≤1 × normal level), the number of
extranodal sites (≥2 vs <2), and performance status (East-
ern Cooperative Oncology Group Performance Status 2-3
vs 0-1). Because younger and older patients may have
different outcomes and younger patients may be consid-
ered for more aggressive therapies, an age-adjusted model
for patients aged 60 years or younger also has been devel-
oped. The IPI also appears useful in predicting the outcome
of patients with indolent lymphoma,21 mantle cell lym-
phoma,22 refractory large B-cell lymphoma in those under-
going stem cell transplantation,23 and T-cell lymphomas.24
The IPI was designed for aggressive lymphoma and may
not clearly identify patients with indolent lymphoma who
are at high risk; thus, a new prognostic factor model has
been devised for follicular lymphoma.25 The Follicular
Lymphoma International Prognostic Index uses the pa-
tient’s age (>60 vs ≤60 years), Ann Arbor stage (III or IV
vs I or II), hemoglobin level (<12 g/dL vs ≥12 g/dL),
number of nodal areas (>4 vs ≤4), and serum LDH level
• www.mayoclinicproceedings.com

(Table 6). Nodal areas are defined as cervical, axillary,
inguinocrural, para-aortic and/or iliac, celiac and/or mesen-
teric, and other ancillary nodal sites including the epitroch-
lear and popliteal areas. Within each IPI risk group, the
Follicular Lymphoma International Prognostic Index can
discriminate patients with significantly different death
risks and may better define patient groups that may benefit
from more aggressive therapy.
To determine the biological reason for different out-
comes within a lymphoma subgroup, recent research has
focused on patterns of gene expression that correlate with
different pathologic entities and clinical outcomes. Gene
expression profiling using DNA microarrays has been used
to develop a molecular prognostic model.26 Three molecu-
larly distinct forms of diffuse large B-cell lymphoma have
been categorized. One group has a germinal center B-cell
signature, a second group has a signature of activated B
cells, and a third group (termed type 3) has a signature
suggesting substantial host immune cell involvement in the
area of lymphoma. Patients with the germinal center B-
cell–like diffuse large B-cell lymphoma have experienced
significantly improved survival compared with the other
subgroups. By using a similar microarray technology,27 2
categories of patients have been identified with sub-
stantially different outcomes after 5-year survival follow-
ing treatment: this model effectively delineated patients
in the IPI intermediate-risk categories who were likely to
be cured orto die of their disease. These molecular find-
ings also appear relevant in indolent NHL. Recently, a
study evaluating genes related to cells in the tumor mi-
croenvironment in follicular lymphoma showed that the
intratumoral immune signature has significant prognostic
importance.28
TREATMENT
Non-Hodgkin lymphoma generally responds to most mo-
dalities of treatment including radiation therapy, single-
agent or combination chemotherapy, immunotherapy, or
radioimmunconjugate therapy. Treatment commonly in-
volves a combination of these modalities. Opinions are
reasonably uniform regarding treatment in most clinical
situations; however, some variation exists in the choice of
agents used for treating lymphoma as well as the duration
and doses of treatment.
Surgery is useful only in selected situations, most com-
monly to establish a diagnosis by obtaining an excisional
biopsy specimen. Because lymphoma is a systemic illness,
resection of the sites of disease is used only in selected
situations. Surgery may be particularly useful in GI lym-
phomas when the disease is localized or when there is a risk
of perforation. Furthermore, orchiectomy is commonly the
Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
TABLE 6. Follicular Lymphoma International Prognostic Index25*
Factor Adverse prognosis
Age >60 y
Ann Arbor stage III or IV
Hemoglobin level <12 g/dL
No. of nodal areas >4
Serum LDH level Above normal
*LDH = lactate dehydrogenase.
initial treatment for patients with testicular lymphoma.
Radiation therapy also plays a limited role in the treatment
of NHL but is particularly useful in localized disease or for
palliation of symptoms. However, chemotherapy is the
most important therapeutic modality, particularly for lym-
phomas with an aggressive phenotype such as diffuse large
B-cell lymphoma. In indolent lymphomas, such as follicu-
lar lymphoma, the use of monoclonal therapy as well as
radioimmunoconjugate therapy has become standard and
is used commonly early in the disease course.
FOLLICULAR LYMPHOMA
Follicular lymphomas are characterized by a comparatively
long survival (median survival, 8-12 years). Many patients
are relatively asymptomatic at diagnosis, and most patients
present with advanced-stage disease. Because of the biology
of this disease, most patients are not cured. However, the
goal of treatment should be complete remission. It is impor-
tant to note that patients with follicular grade 3 lymphoma
have a more aggressive disease course and generally are
treated similarly to patients with large cell lymphoma.
The standard treatment for patients with follicular lym-
phoma is controversial and ranges from a watch-and-wait
approach, to targeted treatment with monoclonal antibody
therapy or radioimmunoconjugate therapy, to combination
chemotherapy. A substantial proportion of patients are
asymptomatic at presentation, and the toxicity associated
with treatment needs to be weighed against potential ben-
efit. However, most patients will require treatment within a
few years because of symptoms related to disease progres-
sion, potential organ compromise, cosmetic concerns due
to unsightly nodes, or severe anxiety.
Patients with stage IA to IIA follicular NHL commonly
are treated with radiation therapy, particularly if the dis-
ease appears to be confined to clinically involved lymph
nodes that could be encompassed adequately by an irradia-
tion field with acceptable toxicity.29-31 Radiation typically
is given to the entire involved lymph node region or to the
involved region plus 1 uninvolved region on each side of
the involved nodes. The recommended dose is approxi-
mately 30 Gy for nonbulky disease showing prompt re-
sponse or approximately 36 Gy for bulky or slowly regres-
• www.mayoclinicproceedings.com 1091
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT

TABLE 7. Therapies for Follicular Lymphoma* as CHOP44 and CVP,45 resulting in high complete response
Remission rates and long durations of response. Also, recent data
Therapy rate Durability Morbidity Mortality suggest that continued, scheduled use of single-agent
Watch and wait 0/+ + 0 0 rituximab after initial remission induction results in en-
Single-agent couraging response rates and increased time to subsequent
chemotherapy + + + + treatment.46 The use of cytokines such as interleukin 2,47
CVP, CHOP, FND ++ ++ ++ + interferon α,48 and interleukin 1249 combined with rituximab
Rituximab +/++ ++ + 0
to potentiate the patient’s immune response have been
Radioimmuno-
therapy ++ +++ ++ + shown to be safe; however, response rates appear similar to
Rituximab those seen with rituximab alone. Iodine I 131 tositumo-
chemotherapy ++ +++ ++ + mab50 and yttrium Y 90 ibritumomab tiuxetan51 also have
Autologous been developed for the treatment of follicular B-cell lym-
transplantation +++ +++ +++ ++
phomas. Both contain murine anti-CD20 antibodies with β-
Allogeneic
transplantation +++ +++ +++ +++ emitting radioisotopes; however, iodine I 131 tositumomab
also emits gamma irradiation. Both agents result in a high
*CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), Onco-
vin (vincristine), and prednisone; CVP = cyclophosphamide, vincristine, overall response rate and complete response rates greater
and prednisone; FND = fludarabine, mitoxantrone, dexamethasone; 0 = than those seen with rituximab. However, currently in the
none; + = mild/short; ++ = moderate/intermediate; +++ = severe/long. United States, most patients are treated with combined
chemotherapy and rituximab.
sive disease. With this therapy, 40% to 50% of patients
with stage I follicular grade 1 or 2 lymphoma remain free of MALT LYMPHOMA
disease at 10 years. Most relapses occur outside of the MALT lymphomas are indolent in nature and commonly
radiation fields, suggesting that current staging procedures present with localized disease, but gastric MALT lympho-
are inadequate to determine microscopic sites of disease mas require a different therapeutic approach if associated
outside of what is determined on imaging studies. with H pylori. The stomach is the most frequent site of
Despite having advanced-stage disease, many patients involvement, but MALT lymphomas also may involve the
with follicular lymphoma experience long survival with no lung, thyroid gland, salivary gland, breast, or eye orbit.
initial therapy32-34—a fact that must be considered in making MALT lymphomas that present in organs other than the
a treatment decision. The choice of frontline therapy for stomach are treated with curative intent with local radiation
advanced follicular lymphoma is controversial, and cur- therapy, provided the disease is limited to the involved
rently, multiple strategies are offered, ranging from observa- primary organ or site. In gastric MALT lymphoma, the
tion until symptomatic to combination chemoimmuno- proliferation of the lymphoma cells has been shown to be
therapy (Table 7). Chemotherapy options for these patients associated with the presence of H pylori. Combination
include single-agent chemotherapy such as chlorambucil therapy with omeprazole, metronidazole, and amoxicillin
or cyclophosphamide with or without the addition of to eradicate the infectious agent has resulted in regression
prednisone35,36 or combinations such as cyclophosphamide, in most early cases and is used commonly as frontline
vincristine, and prednisone (CVP) chemotherapy.37 Other treatment. Of note, tumors invading beyond the submu-
options include more aggressive chemotherapy such as cyclo- cosa or lesions with a translocation t(11;18) are less likely
phosphamide, hydroxydaunomycin (doxorubicin), vincris- to respond to H pylori eradication. Radiation therapy for
tine (Oncovin), and prednisone (CHOP)38 or the use of pu- patients not infected by, or failing to respond to, H pylori
rine analogues either alone or in combination, particularly eradication consists of approximately 30 Gy directed to
fludarabine or cladribine.39-41 Rituximab, used either alone or the stomach and perigastric lymph nodes.52,53 For patients
combined with these agents, has resulted in high response in whom this therapy fails, rituximab or chemotherapy, or
rates and long progression-free survival. in some cases surgery, has been used. For patients with
Immunotherapy has become a standard component of MALT lymphoma at other sites presenting with localized
therapy for patients with follicular advanced lymphoma. disease, surgery or radiation therapy produces durable re-
Rituximab is a chimeric human murine monoclonal anti- missions. Patients with disseminated MALT lymphoma are
body that binds CD20 on both malignant and benign B treated similarly to patients with follicular lymphoma.
cells. Response rates of between 30% and 80% have been
seen in patients with indolent lymphoma42,43; however, re- DIFFUSE LARGE B-CELL LYMPHOMA
sponse rates primarily depend on patient selection. Ri- During the past 30 years, treatment of diffuse large B-cell
tuximab also has been combined with chemotherapy such NHL has evolved from the use of radiation therapy alone to

1092 Mayo Clin Proc. • August 2005;80(8):1087-1097 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

the use of combination chemotherapy with the addition of
rituximab. The most commonly used chemotherapy regi-
men for diffuse large B-cell NHL is CHOP combined with
rituximab. Radiation therapy usually is added for patients
with limited-stage disease.
For patients with localized disease, a combination of
anthracycline-based chemotherapy with involved field ra-
diation therapy is currently the standard of care. In a South-
west Oncology Group study, patients with stage I/IE or
nonbulky stage II/IIE disease were randomized to receive
either 8 cycles of CHOP or 3 cycles of CHOP combined
with involved field radiation therapy.54 Patients in the
chemoradiation arm did significantly better regarding dis-
ease-free survival and overall survival. The 5-year disease-
free survival and overall survival showed an advantage in
the chemoradiation arm. However, the combination modal-
ity therapy advantage was lost at 7 and 9 years, as reported
in a recent update.55 A second study by the Eastern Coop-
erative Oncology Group randomized patients with stage I
or II aggressive lymphomas to either CHOP chemotherapy
for 8 cycles or CHOP chemotherapy for 8 cycles plus
involved field radiation therapy.56 This study also showed a
benefit in disease-free survival for patients treated with
combination therapy; however, an overall survival benefit
was not seen. A recent study comparing the doxorubicin
(Adriamycin), cyclophosphamide, vindesine, bleomycin,
and prednisone (ACVBP) chemotherapy regimen to 3
cycles of CHOP plus radioimmunotherapy showed an ad-
vantage to the chemotherapy-only arm.57 Of note, these
studies did not include the use of rituximab; however, until
further studies are done to define the optimal therapy for
limited-stage nonbulky large cell lymphoma, many con-
sider an abbreviated course of CHOP with rituximab plus
involved field radiation therapy to be the initial treatment
of choice. For patients with bulky disease, a minimum of 6
cycles of CHOP chemotherapy combined with rituximab is
typical. Radiation doses of approximately 30 to 35 Gy
delivered to the involved sites is standard.
Over the years, many different chemotherapy regimens
have been used as first-line treatment for patients with
advanced-stage NHL. To determine the best frontline
therapy, a randomized phase III study was performed to
compare CHOP chemotherapy with m-BACOD (metho-
trexate, bleomycin, doxorubicin, cyclophosphamide, vin-
cristine, dexamethasone), ProMACE-CytaBOM (pred-
nisone, doxorubicin, cyclophosphamide, and etoposide
followed by cytarabine, bleomycin, vincristine, methotrex-
ate), and MACOP-B (methotrexate, doxorubicin, cyclo-
phosphamide, vincristine, prednisone, and bleomycin).58
No significant differences were observed between the 4
arms in terms of response rates, disease-free survival, or
overall survival, and CHOP chemotherapy has been re-
Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
garded as the standard of care. More recently, the Groupe
d’Etude des Lymphomes de l’Adulte (GELA) group ran-
domized patients older than age 60 years with advanced
large B-cell lymphoma to 8 cycles of CHOP chemotherapy
or 8 cycles of CHOP chemotherapy combined with
rituximab (R-CHOP).59 With a median follow-up of 5 years
(Figure 1), the group found significant improvement in
event-free and overall survival when rituximab was added
to CHOP chemotherapy.60 Toxicity was not found to be
significantly greater in the R-CHOP arm. The Eastern
Cooperative Oncology Group has confirmed these find-
ings in elderly patients,61 and R-CHOP has been found to
be superior to CHOP in younger patients62 and in a popula-
tion-based study.63 Therefore, R-CHOP has become stan-
dard therapy in the United States for all patients with
large cell NHL. However, not all groups regard R-CHOP
as standard therapy; CHOP with etoposide (CHOEP) and
ACVBP combined with rituximab are regarded as stan-
dard regimens in Europe. Despite being a standard
frontline treatment, R-CHOP is curative in only about
50% of patients, and new treatment approaches are clear-
ly necessary, particularly for patients with poor prognos-
tic features.
PERIPHERAL T-CELL LYMPHOMA
Peripheral T-cell lymphomas are uncommon but often
present with nodal or extranodal disease that is clinically
similar to B-cell lymphomas. In contrast to B-cell lym-
phomas, numerous unusual clinical syndromes may be
associated with peripheral T-cell lymphoma. The hemo-
phagocytic syndrome, characterized by fever, hepatosple-
nomegaly, liver function abnormalities, thrombocytopenia,
and erythrophagocytosis, can be seen in patients with pe-
ripheral T-cell lymphomas. Patients may present with pul-
monary infiltrates and/or CNS involvement and associated
systemic symptoms. Patients also may present with de-
structive, necrotic facial or sinus tumors associated with
an angiocentric proliferation of T cells or with a systemic
illness, liver dysfunction, and unusual organ infiltration by
mature T cells.
The management of peripheral T-cell lymphomas has
not been well-defined, but therapy should be based on the
stage of disease and the specific immunopathologic disease
entity. However, the complete response rate in patients
with peripheral T-cell lymphoma may be lower than in
patients with B-cell lymphomas treated with the same che-
motherapy combination. Because of a paucity of compara-
tive trials for this disease, there is little evidence that any
particular combination chemotherapy is superior to the
others. Therefore, it is reasonable to consider use of an
anthracycline-containing regimen such as CHOP as front-
line therapy for these diseases.
• www.mayoclinicproceedings.com 1093
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT

Certain disease entities deserve special consideration.

1.0 Patients with nasal T/NK-cell lymphomas commonly
present with localized disease and therefore should be
Cumulative proportion surviving

0.8 treated with combination chemotherapy followed by in-

volved field radiation therapy. Other disease entities such
0.6
as hepatosplenic T-cell lymphomas and intestinal T-cell
R-CHOP lymphomas often have an extremely poor prognosis, and
0.4
patients with these entities should be considered for autolo-
gous stem cell transplantation if they respond well to initial
0.2
therapy. Intestinal T-cell lymphoma also may present as a
CHOP
GI emergency (obstruction, perforation, hemorrhage) and
may require surgical intervention.
0.0
0 1 2 3 4 5 6 7
MANTLE CELL LYMPHOMA
Years
For patients with mantle cell lymphoma, the outcome is
poor, with a median survival of approximately 3 years and
1.0 extremely few long-term survivors. Clinical outcome
does not appear to be influenced by conventional chemo-
Cumulative proportion surviving

0.8 therapy. Treatment with doxorubicin, vincristine, and

dexamethasone alternating with cytarabine and metho-
0.6
R-CHOP trexate (hyper-CVAD-AM) has shown significantly in-
creased response rates64; however, the disease-free sur-
0.4
vival curve fails to plateau, with persistent relapses in
this patient population. Many patients are considered
CHOP for autologous or allogeneic stem cell transplantation dur-
0.2
ing their first complete or partial remission, particular-
ly those with advanced-stage disease or poor risk fea-
0.0
0 1 2 3 4 5 6 7 tures.65 Other approaches as initial therapy (some still
investigational) for this disease include the use of R-
Years
CHOP chemotherapy, radioimmunoconjugate therapy,
idiotype vaccines, or nonmyeloablative allogeneic stem
1.0 cell transplantation.
Cumulative proportion surviving

0.8 LYMPHOBLASTIC LYMPHOMA

Patients with lymphoblastic lymphoma currently are treated
R-CHOP
0.6 with acute lymphocytic leukemia–like regimens such as
multiple drug combinations and incorporation of intrathecal
0.4 CHOP
chemotherapy due to the propensity for CNS relapse.66
Maintenance therapy for 2 to 3 years is also necessary, and
0.2 this strategy has resulted in complete response rates of
approximately 80% and long-term survival rates of ap-
0.0 proximately 45%. For patients with adverse prognostic
0 1 2 3 4 5 6 7 features, consolidation therapy within autologous or allo-
Years geneic stem cell transplantation after completion of induc-
tion therapy is a reasonable approach.

FIGURE 1. Event-free survival (top), progression-free survival BURKITT LYMPHOMA

(middle), and overall survival (bottom) with a median follow-up of 5
years in elderly patients with diffuse large B-cell lymphoma treated
with cyclophosphamide, hydroxydaunomycin (doxorubicin), vincris-
tine (Oncovin), and prednisone (CHOP) and rituximab plus CHOP (R-
CHOP). Log-rank test P values are <.001, <.001, and .007, respec-
tively. From Feugier et al,60 with permission from the American
Society of Clinical Oncology.
Patients with Burkitt lymphoma or one of its variants are
treated commonly with a brief-duration, high-intensity
regimen incorporating CNS prophylaxis.67,68 Selected pa-
tients with high-risk features are then candidates for autolo-
gous or allogeneic bone marrow transplantation during

1094 Mayo Clin Proc. • August 2005;80(8):1087-1097 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

their first complete or partial remission. Today, most adult
patients with Burkitt lymphoma are cured.
STEM CELL TRANSPLANTATION
In patients with relapsed follicular NHL, high-dose chemo-
therapy followed by autologous stem cell transplantation
has been shown to be superior to standard therapy in a
randomized study regarding progression-free survival and
overall survival.69 Salvage chemotherapy for patients with
large cell lymphoma that relapses also commonly includes
high-dose chemotherapy followed by peripheral blood
stem cell transplantation. The Parma study, which ran-
domized patients with relapsed large cell lymphoma to
either high-dose chemotherapy with autologous stem cell
transplantation or to conventional chemotherapy with
DHAP (dexamethasone, cisplatin, cytarabine) plus in-
volved field radiation therapy to sites of bulky disease,
showed a benefit for patients treated in the stem cell
transplantation arm.70 Transplantation currently does not
have a well-defined role in the primary therapy for ag-
gressive lymphomas but is considered for high-risk pa-
tients who achieve a complete response to initial con-
ventional chemotherapy. However, the late effects of
transplantation need to be considered because the risk of
myelodysplastic syndrome and acute myeloid leukemia is
significant.71,72
Although lower relapse rates are reported after allo-
geneic stem cell transplantation, this treatment usually
is reserved for relapse after autologous transplantation,
primarily because of a high incidence of treatment-related
mortality. However, allogeneic transplantation has an
important antilymphoma effect in patients with follicu-
lar lymphoma and should be considered in younger pa-
tients with this disease. The use of nonmyeloablative
or reduced-intensity allogeneic transplants has signifi-
cantly decreased the early treatment–related mortality;
however, the long-term immunological effects related
to graft-vs-host disease remain similar between non-
myeloablative allogeneic transplants and full allogeneic
transplants.73,74
THE FUTURE
Currently, multiple new and novel agents are being devel-
oped for treatment of NHL. Molecular profiling of tumors
has allowed the prognosis to be determined more accu-
rately and has potentially identified new targets for treat-
ment. New monoclonal antibodies against a wide range of
T-cell and B-cell surface markers are in clinical develop-
ment. Other strategies, including vaccine strategies,
antisense oligonucleotides, and other novel small mol-
ecules, are being developed for treatment of this disease.
Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
Future studies will need to be done to determine their role
in NHL.
REFERENCES
1. American Cancer Society. Cancer Facts & Figures 2002. Atlanta, Ga:
American Cancer Society; 2002.
2. Howe HL, Wingo PA, Thun MJ, et al. Annual report to the nation on the
status of cancer (1973 through 1998), featuring cancers with recent increasing
trends. J Natl Cancer Inst. 2001;93:824-842.
3. Clarke CA, Glaser SL. Changing incidence of non-Hodgkin lymphomas
in the United States. Cancer. 2002;94:2015-2023.
4. Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance
series: non-Hodgkin’s lymphoma incidence by histologic subtype in the
United States from 1978 through 1995. J Natl Cancer Inst. 2000;92:1240-
1251.
5. Stolte M, Bayerdorffer E, Morgner A, et al. Helicobacter and gastric
MALT lymphoma. Gut. 2002;50(suppl 3):III19-III24.
6. Ferreri AJ, Guidoboni M, Ponzoni M, et al. Evidence for an association
between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer
Inst. 2004;96:586-594.
7. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic
lymphoma with villous lymphocytes after treatment of hepatitis C virus infec-
tion. N Engl J Med. 2002;347:89-94.
8. Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney
and heart transplant recipients. Lancet. 1993;342:1514-1516.
9. Cote TR, Biggar RJ, Rosenberg PS, et al, AIDS/Cancer Study Group.
Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation
and public health burden. Int J Cancer. 1997;73:645-650.
10. Hehn ST, Grogan TM, Miller TP. Utility of fine-needle aspiration as a
diagnostic technique in lymphoma. J Clin Oncol. 2004;22:3046-3052.
11. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organi-
zation Classification of Tumours: Pathology and Genetics of Tumours of
Haematopoietic and Lymphoid Tissues. Geneva, Switzerland: World Health
Organization; 2001.
12. Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen
M. Multiple recurrent genomic defects in follicular lymphoma: a possible
model for cancer. N Engl J Med. 1987;316:79-84.
13. Richardson ME, Chen QG, Filippa DA, et al. Intermediate- to high-grade
histology of lymphomas carrying t(4;18) is associated with additional nonran-
dom chromosome changes. Blood. 1987;70:444-447.
14. Fifth International Workshop on Chromosomes in Leukemia-Lym-
phoma: correlation of chromosome abnormalities with histologic and immuno-
logic characteristics in non-Hodgkin’s lymphoma and adult T cell leukemia-
lymphoma. Blood. 1987;70:1554-1564.
15. Johnson PW, Whelan J, Longhurst S, et al. Beta-2 microglobulin: a
prognostic factor in diffuse aggressive non-Hodgkin’s lymphomas. Br J Can-
cer. 1993;67:792-797.
16. Friedberg JW, Chengazi V. PET scans in the staging of lymphoma:
current status. Oncologist. 2003;8:438-447.
17. Haioun C, Besson C, Lepage E, et al, Groupe d’Etudes des Lymphomes
de l’Adulte. Incidence and risk factors of central nervous system relapse in
histologically aggressive non-Hodgkin’s lymphoma uniformly treated and re-
ceiving intrathecal central nervous system prophylaxis: a GELA study on 974
patients. Ann Oncol. 2000;11:685-690.
18. van Besien K, Ha CS, Murphy S, et al. Risk factors, treatment, and
outcome of central nervous system recurrence in adults with intermediate-
grade and immunoblastic lymphoma. Blood. 1998;91:1178-1184.
19. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report
of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res.
1971;31:1860-1861.
20. International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A
predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med.
1993;329:987-994.
21. Foussard C, Desablens B, Sensebe L, et al, GOELAMS Group, France. Is
the International Prognostic Index for aggressive lymphomas useful for low-
grade lymphoma patients? applicability to stage III-IV patients. Ann Oncol.
1997;8(suppl 1):49-52.
• www.mayoclinicproceedings.com 1095
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
22. Bosch F, Lopez-Guillermo A, Campo E, et al. Mantle cell lymphoma:
presenting features, response to therapy, and prognostic factors. Cancer. 1998;
82:567-575.
23. Moskowitz CH, Nimer SD, Glassman JR, et al. The International Prog-
nostic Index predicts for outcome following autologous stem cell transplanta-
tion in patients with relapsed and primary refractory intermediate-grade lym-
phoma. Bone Marrow Transplant. 1999;23:561-567.
24. Ansell SM, Habermann TM, Kurtin PJ, et al. Predictive capacity of the
International Prognostic Factor Index in patients with peripheral T-cell lym-
phoma. J Clin Oncol. 1997;15:2296-2301.
25. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma interna-
tional prognostic index. Blood. 2004;104:1258-1265.
26. Rosenwald A, Wright G, Chan WC, et al, Lymphoma/Leukemia Mo-
lecular Profiling Project. The use of molecular profiling to predict survival
after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;
346:1937-1947.
27. Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma
outcome prediction by gene-expression profiling and supervised machine
learning. Nat Med. 2002;8:68-74.
28. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular
lymphoma based on molecular features of tumor-infiltrating immune cells. N
Engl J Med. 2004;351:2159-2169.
29. Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II
low-grade follicular lymphoma? results of a long-term follow-up study of
patients treated at Stanford University. J Clin Oncol. 1996;14:1282-1290.
30. Pendlebury S, el Awadi M, Ashley S, Brada M, Horwich A. Radio-
therapy results in early stage low grade nodal non-Hodgkin’s lymphoma.
Radiother Oncol. 1995;36:167-171.
31. Wilder RB, Jones D, Tucker SL, et al. Long-term results with radio-
therapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys.
2001;51:1219-1227.
32. Horning SJ. Follicular lymphoma: have we made any progress? Ann
Oncol. 2000;11:23-27.
33. Brice P, Bastion Y, Lepage E, et al, Groupe d’Etude des Lymphomes de
l’Adulte. Comparison in low-tumor-burden follicular lymphomas between an
initial no-treatment policy, prednimustine, or interferon alfa: a randomized
study from the Groupe d’Etude des Lymphomes Folliculaires. J Clin Oncol.
1997;15:1110-1117.
34. Horning SJ, Rosenberg SA. The natural history of initially untreated
low-grade non-Hodgkin’s lymphomas. N Engl J Med. 1984;311:1471-1475.
35. Knospe WH, Loeb V Jr, Huguley CM Jr. Proceedings: bi-weekly
chlorambucil treatment of chronic lymphocytic leukemia. Cancer. 1974;33:
555-562.
36. Ezdinli EZ, Anderson JR, Melvin F, Glick JH, Davis TE, O’Connell MJ.
Moderate versus aggressive chemotherapy of nodular lymphocytic poorly
differentiated lymphoma. J Clin Oncol. 1985;3:769-775.
37. Bagley CM Jr, Devita VT Jr, Berard CW, Canellos GP. Advanced
lymphosarcoma: intensive cyclical combination chemotherapy with cyclo-
phosphamide, vincristine, and prednisone. Ann Intern Med. 1972;76:227-234.
38. McKelvey EM, Gottlieb JA, Wilson HE, et al. Hydroxyldaunomycin
(Adriamycin) combination chemotherapy in malignant lymphoma. Cancer.
1976;38:1484-1493.
39. Redman JR, Cabanillas F, Velasquez WS, et al. Phase II trial of
fludarabine phosphate in lymphoma: an effective new agent in low-grade
lymphoma. J Clin Oncol. 1992;10:790-794.
40. Solal-Celigny P, Brice P, Brousse N, et al. Phase II trial of fludarabine
monophosphate as first-line treatment in patients with advanced follicular
lymphoma: a multicenter study by the Groupe d’Etude des Lymphomes de
l’Adulte. J Clin Oncol. 1996;14:514-519.
41. Fridrik MA, Jager G, Kienzer HR, et al. Efficacy and toxicity of 2-
Chlorodeoxyadenosine (Cladribine)—2 h infusion for 5 days—as first-line
treatment for advanced low grade non-Hodgkin’s lymphoma. Eur J Cancer.
1998;34:1560-1564.
42. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric
anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half
of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:
2825-2833.
43. Maloney DG, Press OW. Newer treatments for non-Hodgkin’s lymphoma:
monoclonal antibodies. Oncology (Williston Park). 1998;12(10, suppl8):63-76.
1096 Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
44. Czuczman MS. CHOP plus rituximab chemoimmunotherapy of indolent
B-cell lymphoma. Semin Oncol. 1999;26(5, suppl 14):88-96.
45. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab
compared with CVP as first-line treatment for advanced follicular lymphoma.
Blood. 2005;105:1417-1423.
46. Hainsworth JD, Litchy S, Burris HA III, et al. Rituximab as first-line and
maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J
Clin Oncol. 2002;20:4261-4267.
47. Friedberg JW, Neuberg D, Gribben JG, et al. Combination immunotherapy
with rituximab and interleukin 2 in patients with relapsed or refractory follicular
non-Hodgkin’s lymphoma. Br J Haematol. 2002;117:828-834.
48. Davis TA, Maloney DG, Grillo-Lopez AJ, et al. Combination immuno-
therapy of relapsed or refractory low-grade or follicular non-Hodgkin’s lym-
phoma with rituximab and interferon-alpha-2a. Clin Cancer Res. 2000;6:2644-
2652.
49. Ansell SM, Witzig TE, Kurtin PJ, et al. Phase 1 study of interleukin-12 in
combination with rituximab in patients with B-cell non-Hodgkin lymphoma.
Blood. 2002;99:67-74.
50. Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with
iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin
lymphoma: updated results and long-term follow-up of the University of
Michigan experience. Blood. 2000;96:1259-1266.
51. Witzig TE, White CA, Gordon LI, et al. Final results of a randomized
controlled study of the zevalin radioimmunotherapy regimen versus a standard
course of rituximab immunotherapy for B-cell NHL [abstract]. Blood. 2000;
96:831a. Abstract 3591.
52. Tsang R, Gospodarowicz M, Pintilie M, et al. Localized extranodal
marginal zone B-cell lymphoma: clinical outcome with radiation therapy [ab-
stract]. Int J Radiat Oncol Biol Phys. 2002;54(suppl 1):142.
53. Yahalom J, Portlock CS, Gonzales M, et al. H pylori-independent MALT
lymphoma of the stomach: excellent outcome with radiation alone [abstract].
Blood. 2002;11(pt 1):160a. Abstract 600.
54. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared
with chemotherapy plus radiotherapy for localized intermediate- and high-
grade non-Hodgkin’s lymphoma. N Engl J Med. 1998;339:21-26.
55. Miller TP, LeBlanc M, Spier C, Chase E, Fischer RI, Southwest Oncol-
ogy Group. CHOP alone compared to CHOP plus radiotherapy for early stage
aggressive non-Hodgkin’s lymphomas: update of the Southwest Oncology
Group (SWOG) randomized trial [abstract]. Blood. 2001;98(pt 1):724a-725a.
Abstract 3024.
56. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without
radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma:
Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004;22:
3032-3038.
57. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radio-
therapy for localized aggressive lymphoma. N Engl J Med. 2005;352:1197-1205.
58. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard
regimen (CHOP) with three intensive chemotherapy regimens for advanced
non-Hodgkin’s lymphoma. N Engl J Med. 1993;328:1002-1006.
59. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab
compared with CHOP alone in elderly patients with diffuse large-B-cell lym-
phoma. N Engl J Med. 2002;346:235-242.
60. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-
CHOP study in the treatment of elderly patients with diffuse large B-cell
lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin
Oncol. 2005;23:4117-4126.
61. Habermann TM, Weller E, Morrison VA, et al. Phase III trial of
rituximab-CHOP (R-CHOP) vs. CHOP with a second randomization to main-
tenance rituximab (MR) or observation in patients 60 years of age and older
with diffuse large B-cell lymphoma (DLBCL) [abstract]. Blood. 2003;102:6A.
Abstract 8.
62. Pfreundschuh M, Truemper L, Gill D, et al. First analysis of the com-
pleted mabthera international (MlnT) trial in young patients with low-risk
diffuse large B-cell lymphoma (DLBCL): addition of rituximab to a CHOP-
like regimen significantly improves outcome of all patients with the identifica-
tion of a very favorable subgroup with IPI=O and no bulky disease [abstract].
Blood. 2004;104:48A. Abstract 62.
63. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined
CHOP plus rituximab therapy dramatically improved outcome of diffuse large
• www.mayoclinicproceedings.com

B-cell lymphoma in British Columbia. J Clin Oncol. June 13, 2005 [Epub
ahead of print].
64. Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-
dose methotrexate/cytarabine followed by stem-cell transplantation: an active
regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16:3803-
3809.
65. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myelo-
ablative radiochemotherapy followed by autologous stem cell transplantation
in first remission significantly prolongs progression-free survival in mantle cell
lymphoma: results of a prospective randomized trial of the European MCL
Network. Blood. 2005;105:2677-2684.
66. Sweetenham JW, Santini G, Qian W, et al. High-dose therapy and
autologous stem-cell transplantation versus conventional-dose consolidation/
maintenance therapy as postremission therapy for adult patients with lympho-
blastic lymphoma: results of a randomized trial of the European Group for
Blood and Marrow Transplantation and the United Kingdom Lymphoma
Group. J Clin Oncol. 2001;19:2927-2936.
67. Mead GM, Sydes MR, Walewski J, et al, UKLG LY06 Collaborators. An
international evaluation of CODOX-M and CODOX-M alternating with IVAC
in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group
LY06 study [published correction appears in Ann Oncol. 2002;13:1961]. Ann
Oncol. 2002;13:1264-1274.
68. Lee EJ, Petroni GR, Schiffer CA, et al. Brief-duration high-intensity
chemotherapy for patient with small noncleaved-cell lymphoma or FAB L3
The Symposium on Oncology Practice: Hematological Malignancies
will continue in the September issue.
Mayo Clin Proc. • August 2005;80(8):1087-1097
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT
acute lymphocytic leukemia: results of cancer and leukemia group B study
9251. J Clin Oncol. 2001;19:4014-4022.
69. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves
progression-free survival and survival in relapsed follicular non-Hodgkin’s
lymphoma: results from the randomized European CUP trial. J Clin Oncol.
2003;21:3918-3927.
70. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow trans-
plantation as compared with salvage chemotherapy in relapses of chemotherapy-
sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333:1540-1545.
71. Micallef IN, Lillington DM, Apostolidis J, et al. Therapy-related myelo-
dysplasia and secondary acute myelogenous leukemia after high-dose therapy
with autologous hematopoietic progenitor-cell support for lymphoid malignan-
cies. J Clin Oncol. 2000;18:947-955.
72. Howe R, Micallef IN, Inwards DJ, et al. Secondary myelodysplastic
syndrome and acute myelogenous leukemia are significant complications fol-
lowing autologous stem cell transplantation for lymphoma. Bone Marrow
Transplant. 2003;32:317-324.
73. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of
graft-versus-malignancy using fludarabine-based nonablative chemotherapy
and allogeneic blood progenitor-cell transplantation as treatment for lymphoid
malignancies. J Clin Oncol. 1998;16:2817-2824.
74. Branson K, Chopra R, Kottaridis PD, et al. Role of nonmyeloablative
allogeneic stem-cell transplantation after failure of autologous transplantation in
patients with lymphoproliferative malignancies. J Clin Oncol. 2002;20:4022-4031.
• www.mayoclinicproceedings.com 1097