2. Indolent lymphomas
Aggressive lymphomas
Highly aggressive lymphomas
• Chronic lymphocytic
leukemia (CLL)/small
lymphocytic lymphoma
(SLL)
• Follicular Grade I, II, III§
lymphoma
• Lymphoplasmacytic
lymphoma
• Splenic/nodal marginal
zone B-cell lymphoma
• Mantle cell lymphoma
• Diffuse large B-cell
lymphoma (DLBCL)
• Follicular Grade III§
lymphoma
• Burkitt lymphoma • Lymphoblastic lymphoma
Non-Hodgkin’s Lymphoma
How common is NHL?
Non-Hodgkin’s lymphoma (NHL) is a commonly occurring
hematologic malignancy and is among the top ten most
common cancers in the United States. Currently, NHL ranks
as the fourth most common cancer in women and the fifth
in men. In the United States, an estimated 58,870 people
will be newly diagnosed with NHL in 2006.1,2
Classification of NHL
NHL is pathologically diverse. It includes many subtypes, each
with distinct epidemiologies, etiologies, and morphologic,
immunophenotypic, and clinical features. NHL can be
categorized into specific groups, depending on the different
characteristics of the cancerous cells. The purpose of further
classifying NHL is to describe the disease characteristics and
develop appropriate treatment strategies for each type of
lymphoma for a better prognosis. The WHO/REAL* classification
divides B-cell NHL into 3 clinically relevant categories:3
• Indolent lymphoma†
• Aggressive lymphoma‡
• Highly aggressive lymphoma
WHO/REAL classification of
B-cell lymphomas3,4
Indolent NHL
Indolent NHL is a more slow-growing lymphoma and is
considered a chronic disease. Indolent NHL has a relatively
good prognosis and is treatable and manageable over
time, with a median survival as long as 10 years. However,
although it’s manageable, it cannot be cured and patients
in the advanced clinical stage may eventually relapse despite
responding well to therapy. Successive retreatments may
result in prolonged duration of responses.5,6
Aggressive NHL
Aggressive NHL grows rapidly and typically has a shorter
natural history if not treated. However, most people with this
lymphoma respond very well to treatment. In general, overall
survival at 5 years is approximately 50% to 60%, and of
patients with aggressive NHL, 30% to 60% can be cured.5
Highly aggressive NHL
Highly aggressive NHL is often a high-stage disease at
presentation. Like aggressive NHL, highly aggressive
lymphoma is considered curable, but is rapidly fatal if
untreated, or if patient is unresponsive to therapy.3
*World Health Organization/Revised European-American Lymphoma.
†RITUXAN®
(Rituximab) is indicated for the first-line treatment of diffuse
large B-cell, CD20+, non-Hodgkin’s lymphoma (DLBCL) in combination
with CHOP or other anthracycline-based chemotherapy regimens.
‡RITUXAN is indicated for relapsed or refractory, low-grade or follicular,
CD20+, B-cell non-Hodgkin’s lymphoma.
§Follicular lymphomas of Grade III in some patients may behave more
like one of the aggressive lymphomas, and can be further subdivided.
3. Risk Group IPI Scores 5-Year
Survival
Complete
Response Rate
Low 0 83% 92%
Low/
Intermediate
1 69% 78%
High/
Intermediate
2 46% 57%
High 3 32% 46%
Staging NHL
Ann Arbor staging classification
The Ann Arbor staging system determines the extent of disease
in patients with NHL. It is based primarily on the distribution of
lymphatic involvement with respect to the diaphragm and the
presence of extralymphatic organ involvement.1
International Prognostic Index (IPI) for
aggressive NHL7
The IPI is a prognostic indicator for patients with diffuse large
B-cell, non-Hodgkin’s lymphoma (DLBCL) and other aggressive
lymphomas. The IPI predicts the risk of disease recurrence
and overall treatment outcome by taking into account
several factors.
Five adverse prognostic factors7
• Age >60 years
• Ann Arbor Stage III/IV
• More than one extranodal site
• Serum lactate dehydrogenase
(LDH) level >normal
• Performance status ≥2
Prognostic index by risk group7
One point is given for each of the previously listed
characteristics present in the patient.
Age-Adjusted Prognostic Index
by risk groups (≤60 years of age)7
Because younger and older patients have different prognoses,
an age-adjusted model is used for patients ≤60 years. For this
score, each of the prognostic factors listed previously, with the
exception of age and number of extranodal sites, is given
one point.
Stage I Lymphoma in one lymph node region
Stage II
Lymphoma in two or more lymph node regions on the
same side of the diaphragm
Stage III
Lymphoma in lymph node regions on both sides of
the diaphragm
Stage IV
Lymphoma in one or more extralymphatic organs with
or without associated lymph node involvement (diffuse
or disseminated)
Risk Group IPI Scores 5-Year
Survival
Complete
Response Rate
Low 0–1 73% 87%
Low/
Intermediate 2 51% 67%
High/
Intermediate
3 43% 55%
High 4–5 26% 44%
4. Follicular Lymphoma International Prognostic
Index (FLIPI)8
The FLIPI is similar to the IPI but applies to patients with follicular
NHL, a type of indolent NHL. The FLIPI can be used to help
predict the success of therapy in follicular NHL patients.
Five adverse prognostic factors8
• Age >60 years
• Ann Arbor Stage III/IV
• Hemoglobin level <12 g/dL
• Number of nodal areas >4*
• Serum LDH level >normal
Prognostic index by risk group8
One point is given for each of the previously listed
characteristics present in the patient.
FLIPI: measurable lymph node areas8
Nodal Areas
Right
Cervical
Preauricular
Upper Cervical
Median or Lower
Postcervical
Superclavicular
Mediastinal
Paratracheal
Mediastinal Hilar
Axillary
Axillary
Epitrochlear
Epitrochlear
Para-Aortic
Para-Aortic
Common Iliac
External Iliac
Inguinal
Inguinal
Femoral
Popliteal
Popliteal
Left
Cervical
Preauricular
Upper Cervical
Median or Lower
Postcervical
Superclavicular
Axillary
Axillary
Epitrochlear
Epitrochlear
Mesenteric
Splenic Hilar
Portal
Celiac
Mesenteric
Inguinal
Inguinal
Femoral
Popliteal
Popliteal
FPO
Risk Group
Number of
Factors
5-Year
Survival
10-Year
Survival
Low 0–1 91% 71%
Intermediate 2 78% 51%
High ≥3 53% 36%
Use the figure as a reference for the location of lymph node areas.
Please note that each box represents one nodal area per the FLIPI.
*The spleen is considered an extranodal site and not a nodal area
5. NCCN* guidelines for DLBCL9
*National Comprehensive Cancer Network.
Treatment Options
Nonbulky
(<10 cm)
Adverse
risk factors
present:
• Elevated
LDH
• Stage II
• Age >60 years
• Performance
Status ≥2
Adverse
risk factors
not present
Induction
therapy
Induction
therapy
Induction
therapy
CHOP
6–8 cycles
+ RITUXAN
± RT
CHOP
+ RITUXAN
x 3 cycles
+ RT
Bulky
(≥10 cm)
CHOP 6–8 cycles
+ RITUXAN
CHOP
6–8 cycles
+ RITUXAN®
(Rituximab)
+ Loco-
regional
radiation
therapy
(RT)
CHOP
+ RITUXAN
x 3 cycles
+ RT
CHOP
+ RITUXAN
6–8 cycles
when RT
contra-
indicated
CHOP 6–8 cycles
+ RITUXAN
or
Clinical trial
SStage I, II
Stage III, IV + age-adjusted IPI ≥60 years
Low/
low-intermediate
risk (aaIPI 0–1)
High-intermediate/
high risk
(aaIPI ≥2)
NCCN* guidelines for follicular NHL9
No indication Indication present
Clinical trial
or
Single-agent or
combination therapy
or
RT
No response
or progressive
disease
N
Stage II
Bulky abdominal
disease
Stage III, IV
Indications for treatment:
• Candidate for clinical trial
• Symptoms
• Threatened end-organ function
• Cytopenia secondary to lymphoma
• Bulky disease
• Steady progression
• Patient preference
Observe
S
Stage I, II
6. RITUXAN®
(Rituximab) for
the Treatment of NHL
Targeted therapy of RITUXAN
RITUXAN is indicated for the first-line treatment of diffuse
large B-cell, CD20+, non-Hodgkin’s lymphoma (DLBCL)
in combination with CHOP or other anthracycline-based
chemotherapy regimens, and for the treatment of relapsed
or refractory, low-grade or follicular, CD20+, B-cell NHL.
RITUXAN is an FDA-approved genetically engineered
chimeric murine/human antibody that binds specifically to
the CD20 antigen on normal and malignant B lymphocytes.10
RITUXAN works with the human immune system and induces
B-cell lysis through several proposed mechanisms, based on
in vitro data, including complement-dependent cytotoxicity
(CDC) and antibody-dependent cell-mediated cytotoxicity
(ADCC). RITUXAN has been shown to induce apoptosis in the
B-cell lymphoma line. RITUXAN is highly specific and targets the
CD20+ B cells. Also, most stem cells in the bone marrow lack
the CD20 antigen, allowing healthy B cells to regenerate after
treatment and return to normal levels within twelve months.10,11
RITUXAN proposed mechanisms of action11
FPO
7. *GELA: Groupe d’Etude des Lymphomes de l’Adulte.
RITUXAN®
(Rituximab) plus chemotherapy
for front-line DLBCL
For patients with DLBCL, RITUXAN plus chemotherapy can
significantly improve treatment responses when compared
with chemotherapy alone. Recent studies show that
RITUXAN+CHOP improved overall survival benefits in patients
across diverse subpopulations, including a wide range of ages,
concomitant conditions, and IPI scores. In the GELA* Study
(LNH 98-5) of 399 elderly patients, 8 cycles of RITUXAN+CHOP
improved overall survival by 47% (based on a hazard ratio of
0.68) and decreased the risk of death by 32% at 5 years
median follow-up when compared with CHOP alone.10
RITUXAN+CHOP yields significant overall survival benefits and
is the first new combination to extend DLBCL survival since
the 1970s.10,12
Immunostaining of DLBCL shows larger than normal neoplastic
cells with prominent central nucleolus and abundant cytoplasm.
FPO
RITUXAN as monotherapy for
relapsed/refractory, follicular NHL
RITUXAN is effective as a single agent for the treatment of
relapsed or refractory, follicular NHL. In a pivotal trial of 166
patients who received RITUXAN weekly for 4 doses, 48% of
patients demonstrated overall response. In another study,
57% of patients achieved overall response with 8-week
dosing. RITUXAN also proved to be effective in retreatment,
demonstrating more durable responses. Early and repeated
use of RITUXAN can prolong progression-free periods and
may allow patients to be more symptom-free.10
FPO
Immunostaining of follicular lymphoma shows its typical
nodular appearance.
8. SAFETY SUMMARY
WARNINGS: Fatal Infusion Reactions: Deaths within
24 hours of RITUXAN infusion have been reported. These fatal
reactions followed an infusion reaction complex which included
hypoxia, pulmonary infiltrates, acute respiratory distress
syndrome, myocardial infarction, ventricular fibrillation, or
cardiogenic shock. Approximately 80% of fatal infusion
reactions occurred in association with the first infusion. Patients
who develop severe infusion reactions should have RITUXAN
infusion discontinued and receive medical treatment.
Tumor Lysis Syndrome (TLS): Acute renal failure requiring
dialysis with instances of fatal outcome has been reported in
the setting of TLS following treatment with RITUXAN.
Severe Mucocutaneous Reactions: Severe
mucocutaneous reactions, some with fatal outcome, have
been reported in association with RITUXAN treatment.10
The following serious adverse reactions, some with fatal
outcomes, have been reported in patients treated with
RITUXAN: severe or fatal infusion reactions, tumor lysis
syndrome, severe mucocutaneous reactions, hepatitis B
reactivation with fulminant hepatitis, other viral infections,
hypersensitivity reactions, cardiac arrhythmias, renal toxicity,
bowel obstruction and perforation.10
RITUXAN®
(Rituximab)
Important Safety
Information
RITUXAN as Monotherapy: In clinical trials of patients
administered RITUXAN as a single agent in relapsed or
refractory, low-grade or follicular, CD20+, B-cell, non-Hodgkin's
lymphoma, the most common adverse events were part of an
infusion-related symptom complex, commonly consisting of
fever, chills/rigors, nausea, pruritus, angioedema, asthenia,
hypotension, headache, bronchospasm, throat irritation, rhinitis,
urticaria, rash, vomiting, myalgia, dizziness, and hypertension.
Pulmonary events were reported in 38% of patients, and 31%
reported infectious events. Grade 3 and 4 cytopenias included
lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia
(3%), and thrombocytopenia (2%). Administration of RITUXAN
weekly for 8 doses resulted in higher rates of Grade 3 and 4
adverse events overall (70%) compared with administration
weekly for 4 doses (57%).10
RITUXAN in Combination With Chemotherapy: The following
adverse events, regardless of severity, were reported more
frequently (≥5%) in patients age ≥60 years receiving R-CHOP as
compared to CHOP alone for DLBCL: cardiac disorder (29% vs
21%), pyrexia (56% vs 46%), chills (13% vs 4%), and lung
disorder (31% vs 24%). Supraventricular arrhythmias or
tachycardia accounted for most of the difference in cardiac
disorders, with 4.5% vs 1.0% incidences for R-CHOP and CHOP,
respectively. The following Grade 3 or 4 adverse events were
reported more frequently among patients in the R-CHOP arm
compared with those in the CHOP arm: thrombocytopenia (9%
vs 7%) and lung disorder (6% vs 3%). Other severe adverse
events reported more commonly among patients receiving
R-CHOP in one or more studies were viral infection,
neutropenia, and anemia.10
