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with first-degree relatives with HL have a higher risk of disease.
Other evidence suggests an association with prior Epstein-Barr
virus infections and BCL2 translocations.
Clinical Presentation and Diagnosis
Presentation of fast-growing, aggressive NHL, such as diffuse
large B-cell (DLBC) lymphoma is variable; most patients present
with lymphadenopathy and extranodal involvement. Presenta-
tion can involve one or more lymph nodes and, sometimes, extra-
lymphatic organs. The most common extranodal sites include the
gastrointestinal tract, skin, bone marrow, sinuses, or CNS. Fever
(>38◦ C), night sweats, and weight loss (>10% of body weight in
6 months) are defined as B symptoms and are generally associ-
ated with more advanced or aggressive disease. Approximately
one-third of patients with aggressive lymphomas will report
B- symptoms.161 Excisional or incisional lymph node biopsy, bone
marrow biopsy, morphology, and immunophenotyping are used
to confirm and classify an NHL diagnosis. Patients with indolent
NHLs such as follicular or marginal zone lymphoma typically
present with slow-growing, painless, generalized lymphadenopa-
thy that can be either transient or persistent.
Individuals with HL will also present with lymphadenopathy
typically in a contiguous pattern, whereas lymph nodes are more
likely to present in a noncontiguous pattern in NHL. Extranodal
lymphoid involvement in HL is less common than in NHL. In
more than 90% of individuals the disease is located above the
diaphragm at the time of initial diagnosis. They may also com-
plain of B symptoms, fatigue, pruritus, cough, loss of appetite,
and abdominal discomfort. The diagnosis of classic HL is made
by the presence of Reed-Sternberg cells in a lymph node biopsy.
Treatment
Aggressive and highly aggressive B-cell NHLs are potentially
curable. Patients with localized, nonbulky (<10 cm) stage I or
II DLBC lymphoma without B symptoms are typically treated
with rituximab, cyclophosphamide, doxorubicin, vincristine, and
prednisone (R-CHOP) for three to six cycles with or without
radiotherapy. For patients with advanced disease (bulky stage II
or stage III or IV disease), R-CHOP for six cycles is the standard
of care. Patients with stage III or IV aggressive NHL should also
be encouraged to participate in clinical trials.
Indolent NHLs such as follicular lymphoma typically progress
slowly; the disease may wax and wane, and median survival is 8
to 12 years after diagnosis.161 Depending on the extent of disease,
patient symptoms, and age, treatment may take a wait and watch
approach, radiation alone, rituximab, or combination systemic
chemotherapy. If treated, localized disease (defined as nonbulky
stage I or II) generally includes radiation with or without systemic
therapy. Approximately half of patients with localized disease
will remain lymphomafree at 10 years with radiation therapy
alone, and the addition of chemotherapy has not been shown
to improve OS.93,161 If treated, advanced disease (bulky stage
II, stage III, or stage IV) is individualized based on age, perfor-
mance status, comorbid disease states, disease progression, and
future transplant possibility. Treatment is controversial because
observation alone is associated with a 5-year survival of more
than 75%.162 Treatment of advanced disease usually consists of
chemotherapy (cyclophosphamide, doxorubicin, vincristine, and
prednisone [CHOP], cyclophosphamide, vincristine, and pred-
nisone [CVP], or bendamustine) plus rituximab.
HL is highly responsive to treatment, with up to 95% of
patients achieving complete remission with initial treatment. Ini-
tial treatment may include radiation, combination chemother-
apy, or combined chemotherapy and radiation. The standard of
November 20, 2011 13:49
care for patients with HL is doxorubicin, bleomycin, vinblastine, 2191
and dacarbazine (ABVD) owing to its demonstrated superior-
ity over other combination chemotherapy regimens,93 although
other regimens such as Stanford V are used. HL has an excellent
prognosis, with 75% to 80% of newly diagnosed adult patients
achieving long-term remission. Prognosis depends on a num-
ber of factors, including the presence of systemic symptoms,
disease stage, and the presence of bulky masses. In patients who
relapse, the disease remains highly responsive to therapy. Patients
with relapsed disease have two main treatment options: salvage
chemotherapy with or without radiation therapy, or high-dose
chemotherapy with stem cell support. HL treatment can be asso-
ciated with serious long-term effects; therefore, minimization of
late toxicities is an extremely important consideration in selec-
tion of a treatment regimen.
Non–Hodgkin Lymphoma
CLINICAL PRESENTATION
CASE 92-6
QUESTION 1: R.G., a 49-year-old woman, presents with
complaints of swollen lymph nodes and occasional fevers
and night sweats during the past month. Physical examina-
tion reveals marked cervical, supraclavicular, and inguinal
lymphadenopathy. Laboratory values are normal with the
exception of a mild anemia (Hgb, 11 g/dL) and an elevated
LDH. HIV and hepatitis B surface antibody and antigen are
negative. Excisional biopsy of a supraclavicular lymph node
and immunophenotyping confirms a diagnosis of DLBC non–
Hodgkin lymphoma (NHL). Flow cytometry is positive for
CD10, CD19, and CD20 surface markers. Her bone mar-
row biopsy is negative for lymphoma. How common is NHL,
and what are R.G.’s signs and symptoms, and what is her
stage?
Approximately 65,000 new cases of NHL are diagnosed annu-
ally, making it the sixth most common new cancer in both
men and women in the United States.160 More than 80% of
NHLs are B-cell neoplasms, with follicular and DLBC lymphoma
as the most common subtypes, accounting for 31% and 22%,
respectively163 (Table 92-10). Chapter 92
Hundreds of lymph nodes can be found throughout the body,
and they are designed to process antigens present in the lym-
phatic system. Each one consists of a capsule, cortex, medulla,
and sinuses, with anatomical and functional compartments, such
as follicular (germinal) centers, follicular mantle, and interfollic-
Adult Hematologic Malignancies
ular and medullary areas (Fig. 92-1). The growth pattern of lym-
phoma is described as follicular when malignant B cells take over
normal germinal centers of lymph follicles. When the normal
architecture of the lymph node is replaced by a uniform popula-
tion of neoplastic lymphocytes, the growth pattern is described
as diffuse. Morphologic features of the lymph node, such as cell
type, size, and appearance, are important because they establish
the specific subtype of lymphoma and are helpful in determining
the best treatment.164
CELLULAR CLASSIFICATION OF NON–HODGKIN
LYMPHOMA
Historically, the main classification systems used for NHLs
were the Working Formulation classification and the Revised
European–American Lymphoma (REAL) classification. The
Working Formulation classification classified NHLs into three
broad groups (low, intermediate, and high grade) based on the
morphology and clinical behavior of the disease; the REAL classi-
fication included morphology, immunophenotype, cytogenetics,
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2192
TA B L E 9 2 - 1 0
Presenting Clinical Features of the Common Non–Hodgkin Lymphomas

International
Prognostic
GI Index %
Stage %
Fre- Age Extranodal Bone Marrow B-Symp- Involve- Elevated
quency % (yrs) 1 2 3 4 Involvement % Involvement % toms % ment % LDH % 0/1 2/3 4/5

Diffuse 31 64 25 29 13 33 71 16 33 18 53 35 46 9
Large
B-Cell
Follicular 22 59 18 15 16 51 64 42 28 3 30 45 48 7

Source: J Clin Oncology, 1998, Aug 16 (8):2780. Uses Revised European & American Lymphoma Classification.

and clinical groupings—indolent, aggressive, and highly aggres-
sive lymphomas. The WHO updated the REAL classification,
recognizing three categories of lymphoid malignancies based on
morphology and cell lineage.93,165 Currently, the WHO classifica-
tion is the primary system for categorizing lymphoid neoplasms.
Lymphomas are common hematologic cancers in adults, and
R.G. has one of the more common types. R.G. has swollen lymph
nodes and occasional fevers and night sweats, which are highly
consistent with NHL. Immunophenotyping of her lymph nodes
confirms DLBC lymphoma. She is classified as having an aggres-
sive, mature B-cell neoplasm.
disease, and greater than two extranodal involved sites are asso-
ciated with poorer survival.
Flow cytometry for R.G. is positive for surface markers CD10,
CD19, and CD20, which is consistent with DLBC lymphoma, a
type of aggressive lymphoma. Based on the Ann Arbor Stag-
ing System, R.G. has advanced stage IIIB disease because of the
presence of lymph nodes on both sides of her diaphragm and B
symptoms (fever and night sweats). R.G. has an elevated LDH
and advanced stage disease, which are associated with lower sur-
vival rate. Patients with stage IIIB disease are generally treated
with systemic chemotherapy.

STAGING AND PROGNOSIS TREATMENT

Staging is important for the selection of therapy. The Ann Arbor
Staging System (Table 92-11) is used to stage lymphoma based on
the results of the bone marrow biopsy, distribution, and number
of involved sites; presence or absence of extranodal involvement;
and presenting constitutional symptoms. In general, stage I or II
is referred to as limited disease, whereas stage III or IV is consid-
ered advanced disease. Because of the wide range of outcomes in
patients with lymphoma, even within histologic subtypes, factors
that predict both response to treatment and outcomes are used
to determine overall prognosis and need for aggressive therapy.
The International Prognostic Index was designed to determine
Section 17
AGGRESSIVE NON–HODGKIN LYMPHOMA
CASE 92-6, QUESTION 2: R.G. consults with a hematolo-
gist and elects to receive combination chemotherapy con-
sisting of cyclophosphamide, doxorubicin, vincristine, and
prednisone with rituximab (R-CHOP) every 21 days for six
cycles. She will then be referred to a radiation oncologist
to determine whether she will receive additional benefit
from radiation therapy. Is R-CHOP considered standard ini-
tial therapy? What are the adverse effects that might occur
in R.G.?

predictors of response and survival for aggressive lymphomas.

Performance status greater than 2, age greater than 60 years,
serum LDH above the upper limit of normal, advanced stage
TA B L E 9 2 - 1 1
Ann Arbor Staging System

Stage Descriptiona
Neoplastic Disorders

Mantle cell Anaplastic

large cell
Marginal zone I Involvement of a single lymph node region or a single
extralymphatic organ or site (IE)
S II Involvement of two or more lymph node regions on the
Follicular same side of the diaphragm (II) or localized
Burkitt involvement of an extralymphatic organ or site (IIE)
III Involvement of lymph node regions on both sides of the
F
diaphragm (III) or localized involvement of an
extralymphatic organ or site (IIIE) or spleen (IIIS) or
MC
both (IIISE)
IV Diffuse or disseminated involvement of one or more
PC extralymphatic organs with or without associated
lymph node involvement. Bone marrow and liver
Small B cell
Peripheral T cell involvement are always stage IV
CLL/small lymphocytic
Waldenström Cutaneous T cell a
Identification of the presence or absence of symptoms should be noted with
each stage designation: A, asymptomatic; B, fever, sweats, weight loss greater
FIGURE 92-1 Sites of origin of malignant lymphomas in a lymph than 10% of body weight.
node according to anatomical and functional compartments of the Reprinted with permission from DeVita VT et al, eds. DeVita, Hellman, and
immune system. CLL, chronic lymphocytic leukemia; F, follicles, or Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, PA:
germinal centers; MC, medullary cords; PC, paracortex, or Lippincott Williams & Wilkins; 2011.
interfollicular areas; S, sinuses.
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Aggressive lymphomas are potentially curable. Patients with
nonbulky, localized stage I or II DLBC lymphoma are typically
treated with R-CHOP for three to six cycles with or without radia-
tion. For individuals with advanced disease, defined as bulky stage
II or stage III or IV disease, six cycles of R-CHOP are commonly
used.93 However, patients with advanced disease should also be
considered for a clinical trial.
The Groups d’Étude des Lymphomas de l’Adult compared
the 5-year follow-up of CHOP with R-CHOP in newly diagnosed
DLBC lymphoma patients 60 to 80 years of age. Rituximab is a
chimeric human monoclonal antibody to the B-cell surface anti-
gen CD20. Although the exact mechanism is unknown, ritux-
imab is believed to induce lysis through complement-mediated
destruction, antibody-dependent cytotoxicity, and induction of
apoptosis working in synergy with chemotherapy.166 Eventfree
survival, PFS, DFS, and OS were all higher in the R-CHOP arm.
No additional significant long-term toxicity was apparent.167
Because these results have been confirmed in both young and
elderly patients, R-CHOP has become the standard of care in the
United States.168,169,170
The effect of dose intensity (reduction of treatment interval
from 3 weeks to 2 weeks) on response was investigated in a study
comparing R-CHOP every 14 days (RCHOP-14) with traditional
R-CHOP every 21 days (RCHOP-21). Growth factor support with
G-CSF was required in the every 14-day arm to prevent myelo-
suppression and treatment delay. A total of 1,048 patients were
randomly assigned to one of the two treatment arms, and 82%
of patients receiving RCHOP-21 completed the study compared
with 89% of patients receiving RCHOP-14. Grades III and IV
toxicities were similar in both arms, with a slightly higher neu-
tropenia (57%) and infection rate (22%) in the patients receiving
RCHOP-21 compared with those receiving RCHOP-14 at 31%
and 17%, respectively.171 Although final analysis was not per-
formed regarding OS, radiological response rates were the same
in both arms at 47%, and the authors concluded that RCHOP-14
can be given as safely and effectively as RCHOP-21.171 However,
RCHOP-21 remains the most commonly used regimen.
The standard dose of rituximab is 375 mg/m2 given IV in a vari-
ety of dosing schedules. An infusion-related complex consisting
of fever, chills, and rigors may occur during rituximab infusion,
necessitating premedication with acetaminophen and diphenhy-
dramine. Other less common infusion-related symptoms include
nausea, urticaria, pruritus, bronchospasm, angioedema, and
hypotension. These reactions generally occur within 30 min-
utes to 2 hours from the start of the infusion (typically, the first
dose) and resolve if the infusion is slowed or interrupted. Another
less common side effect associated with rituximab is tumor lysis
syndrome, which occurs mostly in patients with a high num-
ber of circulating CD20-positive cells. Before rituximab therapy,
hepatitis B surface antigen and hepatitis B core antibody testing
should be performed, and patients testing positive should receive
empiric antiviral therapy during chemotherapy treatment to pre-
vent hepatitis reactivation.172
Safety precautions associated with the chemotherapy medi-
cations included in the CHOP regimen include documentation
of a normal cardiac ejection fraction (EF) before administra-
tion of doxorubicin and peripheral neuropathy assessments at
baseline and throughout treatment owing to the administration
of vincristine. Because of the increased risk of fetal abnormali-
ties associated with cyclophosphamide in particular, a pregnancy
test should be done before chemotherapy initiation. Antiemetics
should be given before chemotherapy administration to prevent
nausea or vomiting, and a bowel regimen should be initiated to
prevent constipation. Prophylaxis with a CSF after chemotherapy
should be considered in patients at high risk for febrile neutro-
penia.
November 20, 2011 13:49
R-CHOP would be considered standard treatment for R.G. 2193
because she has advanced stage IIIB disease. She should have
baseline evaluation of EF and routine assessments for periph-
eral neuropathy attributable to vincristine. Supportive-care treat-
ments of antiemetics, stool softener, and possibly filgrastim to
prevent fever and neutropenia will be needed for R.G.
CASE 92-6, QUESTION 3: R.G. has a CR to R-CHOP ther-
apy demonstrated by restaging studies performed after her
third and sixth cycles of treatment, and did not receive
radiation therapy after R-CHOP. Every 3 months, she has
a follow-up examination for disease recurrence. At her
15-month follow-up visit, she has radiographic evidence of
disease recurrence in her abdomen. What treatment options
are available to R.G. at this time?
High-dose chemotherapy immediately followed by autolo-
gous HCT should be considered for patients who relapse after
conventional chemotherapy. Salvage chemotherapy regimens
are administered before HCT to ensure the disease is sensitive
to additional cytotoxic therapy. Regimens use non–cross-
resistant agents such as ifosfamide, carboplatin, and etoposide
(ICE) with or without rituximab; dexamethasone, cytarabine,
and cisplatin (DHAP) with or without rituximab; and etoposide,
methylprednisolone, cytarabine, and cisplatin (ESHAP) with or
without rituximab. Patients who previously responded to con-
ventional therapy and demonstrated chemosensitive disease at
relapse have the best outcome from autologous HCT. Allogeneic
HCT may be considered in those not considered good candi-
dates for autologous HCT.93 R.G. received three cycles of R-ICE
chemotherapy, to which her disease was highly responsive, and
then a sufficient number of her stem cells were collected for
autologous HCT.
CASE 92-6, QUESTION 4: How does treatment differ for
highly aggressive NHL?
Highly aggressive NHL, such as lymphoblastic or Burkitt lym-
phoma, progresses very rapidly and commonly metastasizes to
the CNS.164 The majority of adult patients can be cured with an
Chapter 92
aggressive combination therapy. Regimens such as R-CHOP may
not be intensive enough to prevent progression between cycles
of therapy. Therefore, regimens similar to those for ALL are used
because they provide more continuous exposure to more inten-
sive chemotherapy. The hyperfractionated cyclophosphamide,
vincristine, doxorubicin, and dexamethasone regimen, alternat-
ing with high-dose methotrexate and cytarabine, has a CR rate
Adult Hematologic Malignancies
of 91%.173 These regimens must include CNS prophylaxis with
intrathecal methotrexate or cytarabine.164 These patients are at
increased risk for TLS and should be treated with allopurinol,
vigorous IV hydration, and electrolytes.
INDOLENT LYMPHOMA
Clinical Presentation
CASE 92-7
QUESTION 1: D.J. is a 64-year-old healthy man who
presents to his physician complaining of low-grade fevers
and a constant “bloated feeling,” despite taking over-the-
counter aluminum hydroxide and famotidine. He was oth-
erwise asymptomatic, denying recent weight loss or night
sweats. On physical examination, axillary adenopathy was
found. An excisional biopsy and pathological examination
revealed follicular B-cell lymphoma, a type of indolent lym-
phoma. Laboratory values are normal. CT scans of the
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2194
chest, abdomen, and pelvis showed axillary and mediasti-
nal lymphadenopathy. D.J. has stage II disease, with a low
follicular lymphoma International Prognostic Index score
of 2, for which he receives radiation therapy alone. D.J.
remains asymptomatic for 3 years. However, now he devel-
ops abdominal and splenic lymphadenopathy, night sweats,
and weight loss during a 2-month period. What treatment
options are available for D.J.?
Recurrent, chemotherapy-sensitive disease is common for the
indolent NHLs. Chemotherapy options include single-agent rit-
uximab with a CR rate of 15% and OR rate of 64%, which
may be extended by maintenance rituximab.174 No improve-
ment in OS has been reported. Rituximab, in combination with
chemotherapy regimens such as CHOP or CVP, achieves higher
CR rates and extends the duration of response.175,176 Other
options include purine analogs alone or in combination, such
as fludarabine, mitoxantrone, and dexamethasone with or with-
out rituximab, or oral alkylating agents such as chlorambucil or
cyclophosphamide.93,177 A recently available option is bendamus-
tine, which is commonly combined with rituximab (BR). The OR
rate and OS were similar to R-CHOP, but the BR patients had
significantly longer PFS.178 The NCCN Practice Guideline rec-
ommends treatment with a rituximab-containing regimen unless
contraindicated, although definitive evidence supporting a sur-
vival advantage is lacking.93 An echocardiogram reports D.J.’s
EF as 40%. Therefore, a non–anthracycline-containing regimen
(R-CVP) was selected to minimize cardiotoxicity because D.J.
will be at higher risk.
CASE 92-7, QUESTION 2: D.J. is now 6 years out from his
initial diagnosis. His disease was stable for 2 years after
response to treatment with R-CVP. However, his most recent
CT scan shows progression of his disease. The decision
is made to administer more therapy, this time using rit-
uximab alone. His daughter read on a lymphoma website
that radioimmunotherapy and transplantation are poten-
tial treatments. She asks whether these options would be
appropriate for D.J.
Section 17
D.J.’s disease is typical of indolent NHLs in that they respond to
therapy, but the disease eventually recurs and is generally incur-
able. Because these lymphomas are generally chemotherapy-
sensitive, relapsed disease can be treated with the same modali-
ties as first-line treatment. Retreatment with rituximab has been
found to be efficacious without additional toxicities.179 Radioim-
Neoplastic Disorders
munoconjugates are monoclonal antibodies that target CD20-
positive lymphoma cells. These antibodies are linked to radioiso-
topes, enabling delivery of local radiation therapy. Although
radioimmunotherapy may be used as a first-line therapy, it is most
often used in the setting of relapsed disease.180,181 Both iodine-131
[131 I]-tositumomab and yttrium-90 [90 Y]-ibritumomab tiuxetan
have been developed to treat follicular lymphomas. Both con-
tain anti-CD20 antibodies with β-emitting radioisotopes. [131 I]-
Tositumomab also emits gamma irradiation.
Patients are candidates for radioimmunoconjugates if they
have less than 25% bone marrow involvement and platelet counts
greater than 100 × 103/μL because of the significant hemato-
logic toxicity associated with radioimmunotherapy. Response
rates are higher than those seen with rituximab therapy alone.
However, because of complicated administration procedures that
are required for these agents and high cost, this treatment has
not been widely used clinically. To protect the thyroid from
the adverse effects of radioactive iodine, patients receiving [131 I]-
tositumomab should also receive a saturated solution of potas-
November 20, 2011 13:49
sium iodide (two drops PO three times a day) at least 24 hours
before the first dose is administered and then continued for
14 days after therapy. Because low-level radiation exposure
is a concern, patients receiving either agent should be coun-
seled to properly dispose of body fluids, carefully attend to
personal hygiene, and limit their social contact for up to
7 days after administration. Hematologic toxicity can occur
7 to 9 weeks after administration, with a median dura-
tion of neutropenia and thrombocytopenia of approximately
3 weeks.180
High-dose chemotherapy followed by autologous HCT has a
higher PFS and OS than standard therapy (R-CHOP or other).182
Patients in second remission should be referred for transplant
evaluation, but HCT requires careful patient selection because of
the high risk of morbidity and mortality.183 D.J. is not a transplant
candidate because of his advanced age and EF and will continue
to receive conventional therapies.
Hodgkin Lymphoma
CLINICAL PRESENTATION AND PROGNOSIS
CASE 92-8
QUESTION 1: J.R. is a 55-year-old man with complaints
of painless swelling around his collarbone, fever, night
sweats, cough, and an unintentional 20-pound weight loss
in the past 6 months. Radiography of the chest revealed a
small mediastinal mass, and a CT scan of the neck, chest,
abdomen, and pelvis confirmed cervical and mediastinal
lymph node enlargement, as well as multiple enlarged
lymph nodes in the perisplenic and inguinal areas. A bone
marrow biopsy was positive for lymphoma cells. Excisional
biopsy of the cervical lymph node revealed nodular scle-
rosing HL with Reed-Sternberg cells. Laboratory values are
normal. HIV and hepatitis B surface antibody and antigen
are negative. Is this a typical presentation for HL? What is
J.R.’s stage and prognosis?
Presentation of HL can be limited to a single lymph node or to
an extralymphatic organ or site, or it can involve multiple lymph
nodes and extralymphatic organs. In general, the more extensive
the involvement, the higher the stage of disease. In newly diag-
nosed patients, the tumor is staged to assist in treatment selec-
tion. The international staging classification is the Cotswolds
classification which is a modification of the Ann Arbor Staging
System. The Cotswolds staging classification is shown in Table
92-12.172 Several factors unfavorably impact prognosis, includ-
ing older age, certain histology (mixed cellularity or lymphocyte
depleted), high erythrocyte sedimentation rate, presence of B
symptoms and bulky mediastinal disease increasing number of
nodal sites and extranodal lesions. Therefore, HL is usually fur-
ther classified into three groups based on stage and symptoms;
early stage favorable (stage I or II with no unfavorable factors), early
stage unfavorable (stage I or II with any unfavorable factors such
as large mediastinal adenopathy, B symptoms, numerous sites
of disease, or significantly elevated erythrocyte sedimentation
rate), and advanced stage disease (stage III or IV).
J.R.’s symptoms are those typical of HL, mainly lymph-
adenopathy, fever, night sweats, and weight loss. He also has
bone marrow involvement and mediastinal mass. J.R. has diffuse
or disseminated involvement of one or more extranodal organs
with lymph node involvement and B symptoms; therefore, he
has stage IVB (advanced stage) disease.
HL is one of the few malignancies that is typically curable,
even in the advanced stages. An analysis of 5,000 patients with
advanced-stage HL identified seven prognostic factors, each of
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TA B L E 9 2 - 1 2
Cotswolds Staging Classification For Hodgkin Lymphoma

Stage Description

I Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring) or involvement of a single
extralymphatic site (IE).
II Involvement of two or more lymph node regions on the same side of the diaphragm (hilar nodes, when involved on both sides, constitute
stage II disease); localized contiguous involvement of only one extranodal organ or site and lymph node region(s) on the same side of
the diaphragm (IIE). The number of anatomic regions involved should be indicated by a subscript (e.g., II3).
III Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen
(IIIS) or by localized contiguous involvement of only one extranodal organ site (IIIE) or both (IIISE).
III1 With or without involvement of splenic, hilar, celiac, or portal nodes.
III2 With involvement of para-aortic, iliac, and mesenteric nodes.
IV Diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without associated lymph node involvement.
Designations Applicable to Any Disease Stage

A No symptoms.
B Fever (temperature, >38◦ C), drenching night sweats, unexplained loss of >10% body weight within the preceding 6 months.
X Bulky disease (a widening of the mediastinum by more than one-third or the presence of a nodal mass with a maximal dimension >10 cm).
E Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.
CS Clinical stage.
PS Pathologic stage (as determined by laparotomy).

Reprinted with permission from DeVita VT et al, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams
& Wilkins; 2011.

which show an annual reduction in survival by 7% to 8% yearly.
These adverse prognostic factors include age older than 45 years,
serum albumin level less than 4 g/dL, Hgb less than 10.5 g/dL,
male sex, stage IV disease, WBC greater than 15,000 cells/μL,
and lymphocyte count less than 8% of total WBC count or lym-
phocyte count less than 600 cells/μL.172,184 J.R. has three of these
prognostic factors (age >45 years, male, stage IV disease), total-
ing an annual reduction in survival of 23%.
TREATMENT
CASE 92-8, QUESTION 2: J.R. is scheduled to begin
chemotherapy with the ABVD regimen. His EF is 60%. Is
this the optimal initial treatment? What information should
be included in his medication counseling?
Chemotherapy regimens (with or without radiation ther-
apy) are commonly used to treat early and advanced-stage
disease owing to the increased risk of heart disease, pul-
monary toxicity, and secondary malignancies associated with
radiation. Multiple combination chemotherapy regimens have
(advanced) disease, chemotherapy is always used and ABVD or
Stanford V is recommended, and radiation may be administered
in certain individuals. J.R. will receive treatment with up to six
cycles of ABVD. If he has a complete remission after six cycles,
no further therapy will be given. J.R will likely not receive radia-
tion because he does not have a bulky mediastinal mass on initial
presentation.
Traditionally, patients with any of the histologic subtypes of
HL have been treated in a similar fashion. One exception is nodu-
lar lymphocyte-predominant HL, which consistently expresses
CD20 antigen. A small phase 2 study of 22 treated and untreated
patients showed an OR rate of 100% with a complete remis-
sion rate of 41% to rituximab 375 mg/m2 weekly for four
doses.188 Based on this and several other studies demonstrating
rituximab’s benefit in patients with CD20-positive lymphocyte-
predominant HL, rituximab combination chemotherapy (such Chapter 92
as ABVD, CHOP), with or without radiation, is now considered
standard of care.172
HL is a chemotherapy-sensitive disease, and administration of
full doses given on schedule is critical. Cycles of ABVD are given
every 28 days, and all patients should continue treatment for
Adult Hematologic Malignancies

been developed for HL, including ABVD; mechlorethamine,
vincristine, procarbazine, and prednisone (MOPP); bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine, procar-
bazine, and prednisone (BEACOPP); and the Stanford V regi-
men (mechlorethamine, doxorubicin, etoposide, vincristine, vin-
blastine, bleomycin, and prednisone). In direct comparison with
MOPP, ABVD has been shown to have an improved OS and
a lower risk of both short- and long-term toxicities, includ-
ing myelosuppression, infertility, and secondary leukemias;
therefore, ABVD is the preferred treatment compared with
MOPP.185–187 Although promising results have been obtained
with BEACOPP and Stanford V, they have not been compared
with ABVD in well-designed, long-term studies evaluating sur-
vival and toxicity.
NCCN guidelines recommend that patients with stage IA
through IIA (favorable disease) receive ABVD with radiation or
the Stanford V regimen with radiation.172 Individuals with stage I
to II (unfavorable disease) receive ABVD chemotherapy or Stan-
ford V followed by radiation. For patients like J.R. with stage IVB
two cycles beyond documentation of complete remission. Late
effects of HL therapy are a major concern, particularly secondary
malignancies, cardiovascular disease, hypothyroidism, and fertil-
ity issues.189 Safety precautions associated with the chemother-
apy medications included in the ABVD regimen include
documentation of a normal cardiac EF before administration of
doxorubicin and pulmonary function testing at baseline owing
to risk of bleomycin-induced lung injury. Treatment-related car-
diotoxicity is usually observed 5 to 10 years after completion
of treatment, and therefore long-term follow-up is important.
Patients should be monitored for pulmonary symptoms or abnor-
mal pulmonary function tests or chest radiographs. If pulmonary
changes occur, bleomycin should be discontinued from fur-
ther treatment; deletion does not appear to reduce long-term
survival.190 Patients receiving ABVD are at high risk for neutrope-
nia because of the administration of dacarbazine and vinblastine,
and patients will be at increased risk of infections. Prophylaxis
or treatment of neutropenia using a CSF has not been shown to
improve OS or event-free survival in HL patients.191 The NCCN
P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in
LWBK915-92 LWW-KodaKimble-educational
2196 recommends against dose reductions or delays based on neu-
tropenia and does not recommend the use of growth factors
routinely.172
In conclusion, J.R. has classical HL, and ABVD is considered a
first-choice regimen, especially because he has normal EF before
treatment. Pulmonary function should be monitored during the
course of therapy. Because he is 55 years of age, it is unlikely that
fertility is a major concern; however, he still should be warned.
He will be at risk for acute toxicities such as nausea and vomiting,
neutropenia, and infections, as well as long-term toxicities includ-
ing secondary malignancies, hypothyroidism, and increased risk
of cardiovascular disease.
RELAPSED DISEASE
CASE 92-8, QUESTION 3: J.R. achieved a complete remis-
sion and received a total of six cycles of full-dose ABVD. Two
years after completion of chemotherapy, a routine follow-
up radiograph of the chest revealed enlarged lymph nodes,
which were subsequently biopsied and found to be recur-
rent disease. What treatment should J.R. receive?
Patients with relapsed HL have two main treatment options:
high-dose chemotherapy with autologous stem cell support or
salvage chemotherapy with or without radiation therapy. Prog-
nostic and patient-specific factors may assist in determining
which avenue is optimal. Patients whose recurrence occurs less
than 1 year after initial therapy and who have stage III or IV
disease at relapse need more aggressive therapy if age and per-
formance status permit.192 Most patients will be treated with
high-dose chemotherapy and autologous HCT. Before undergo-
ing transplantation, most patients will receive cytoreductive ther-
apy depending on what initial therapy was given. Regimens such
as ESHAP, DHAP, or ICE are often considered, along with oth-
ers, although the optimal regimen is not known. DFS for patients
who relapse 1 year or later after initial therapy and are treated
with salvage chemotherapy is 45% at 20 years.193 Patients who
undergo high-dose chemotherapy and autologous HCT have
an improved eventfree survival and PFS, but no difference in OS
from those who receive conventional chemotherapy alone.194,195
Freedom from treatment failure at 3 years was significantly bet-
Section 17
ter for patients given high-dose chemotherapy and autologous
stem cell transplantation (55%) than for those given conventional
chemotherapy (34%; p = 0.019).195 J.R. will be referred for autol-
ogous HCT; however, he will receive a salvage regimen before
transplantation. Harvesting of autologous stem cells will need to
be coordinated around his pretransplant salvage chemotherapy.
Neoplastic Disorders
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