therapy, it is reasonable to re-treat using the same drug regimen. For those patients with early relapse or refractory MM,

consideration should be given to treatment with bortezomib or

lenalidomide-containing regimens. In a comparison with dexamethasone alone, patients receiving bortezomib had a longer

time to disease progression (6.2 months vs. 3.5 months) and

longer OS, leading to a recommendation to halt the dexamethasone arm and allow those patients to receive single-agent

bortezomib.135 Bortezomib may be combined with pegylated

liposomal doxorubicin, resulting in prolonged time to disease

progression as compared with bortezomib alone (9.3 months vs.

6.5 months).158 Common toxicities of the combination regimen

include neutropenia, thrombocytopenia, diarrhea, and fatigue.

Although bortezomib alone may be better tolerated than the

combination with pegylated liposomal doxorubicin, the combination is more efficacious.

In addition to demonstrating efficacy as initial therapy of

patients with MM, the combination of lenalidomide and dexamethasone has also been evaluated in patients with relapsed

or refractory disease. Two pivotal phase III trials evaluating

the combination versus dexamethasone alone demonstrated significant benefit of the combination with regard to OR (60%

vs. 21.9%), CR rate (15% vs. 2%), time to disease progression

(13.4 months vs. 4.6 months), duration of response (15.8 months

vs. 7 months), and OS.159

The NCCN considers bortezomib alone or in combination

with pegylated liposomal doxorubicin and the combination of

lenalidomide and dexamethasone as the preferred regimens for

the management of patients with relapsed or refractory MM.133

LYMPHOMA

Epidemiology, Pathophysiology,

and Etiology

The lymphomas are a heterogeneous group of hematologic

malignancies that originate in lymphoid tissues and arise from

malignant transformation of lymphocytes (B cells, T cells, or

natural killer cells). A lymphoma may arise within single or multiple lymph nodes or in extranodal sites involving the lymphoid

tissue of the gastrointestinal tract, CNS, or other sites. The two

major types of lymphomas are non–Hodgkin lymphoma (NHL)

and Hodgkin lymphoma (HL) and it is estimated that these hematologic malignancies account for greater than 70,000 new cases

2190Section 17 Neoplastic Disorders

annually, with eight times as many patients affected by NHL

compared with HL.160 In women, the incidence rate of HL has

been rising compared with men, who have maintained a stable

rate of disease for the past several decades.160 NHL occurs at all

ages, but risk increases with age, and individuals are commonly

diagnosed in their 60s. HL can occur at any age, although 43.8%

of cases occur in patients younger than 34 years of age, and 27.7%

occur in patients older than 55 years.

NHL represents a spectrum of diseases marked by different

pathological features, natural history, response to treatment, and

prognosis. NHL is divided into categories based on cell of origin

(B [80%–85%], T [15%–20%], or natural killer [rare]), histology

(low, intermediate, or high grade), immunophenotypic characteristics, cytogenetic abnormalities, and natural history. Table

92-9 gives the World Health Organization classification of Non–

Hodgkin lymphomas. NHL is further categorized as indolent

or aggressive. Indolent NHLs generally carry a good prognosis,

with a median survival of 10 years; however, it is not curable

in advanced stages. Aggressive NHL has a much shorter natural history than indolent NHL, but it is cured in 30% to 60% of

patients.

HL is classified into two distinct diseases, classical HL and

lymphocyte-predominant HL. Classical HL accounts for 95% of

all HL and is further divided into four subtypes, with the most

common subtype being nodular sclerosis, representing about

two-thirds of cases. HL is highly curable, with 75% to 80% of

patients achieving long-term remission.

The etiology of NHL is unknown, although genetics, environmental and occupational exposures, viral disease (human

immunodeficiency virus [HIV], CMV, hepatitis C virus), and

immune suppression have been proposed to be associated in

some studies. Other studies have shown a higher risk of NHL

in individuals with close family members with NHL. There is

also a possible genetic predisposition to HL. Jews and individuals

TABLE 92-9

World Health Organization Classification of Non–Hodgkin’s Lymphoma

Precursor B- and T-Cell Neoplasms

Precursor B-lymphoblastic leukemia/lymphoma

Precursor T-lymphoblastic leukemia/lymphoma

Mature B-Cell Neoplasmsa

Chronic lymphocytic leukemia/small lymphocytic lymphoma

B-cell prolymphocytic leukemia

Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia ¨

Splenic marginal zone B-cell lymphoma

Hairy cell leukemia

Splenic B-cell lymphoma/leukemia, unclassifiable

Splenic diffuse red pulp small B-cell lymphoma

Hairy cell leukemia-variant

Plasma cell neoplasms

Monoclonal gammopathy of undetermined significance (MGUS)

Plasma cell myeloma

Solitary plasmacytoma of bone

Extraosseous plasmacytoma

Monoclonal immunoglobulin deposition diseases

Extranodal marginal zone B-cell lymphoma (MALT lymphoma)

Nodal marginal zone B-cell lymphoma

Follicular lymphoma

Primary cutaneous follicle center lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma (DLBCL)

T-cell/histiocyte-rich large B-cell lymphoma

Primary DLBCL of the central nervous system

Primary cutaneous DLBCL, leg type

EBV-positive DLBCL of the elderly

DLBCL associated with chronic inflammation

Lymphomatoid granulomatosis

Primary mediastinal (thymic) large B-cell lymphoma

Intravascular large B-cell lymphoma

ALK-positive large B-cell lymphoma

Plasmablastic lymphoma

Large B-cell lymphoma arising in HHV8-associated multicentric

Castleman disease

Burkitt lymphoma/leukemia

B-cell lymphoma, unclassifiable, with features intermediate

between DLBCL and Burkitt lymphoma

B-cell lymphoma, unclassifiable, with features intermediate between

DLBCL and classic Hodgkin lymphoma

Mature T-Cell and NK Cell Neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Chronic lymphoproliferative disorder of NK cells

Aggressive NK cell leukemia

Systemic EBV-positive T-cell lymphoproliferative diseases of childhood

Hydroa vacciniformelike lymphoma

Adult T-cell leukemia/lymphoma

Extranodal NK/T-cell lymphoma, nasal type

Enteropathy-type T-cell lymphoma

Hepatosplenic T-cell lymphoma

Subcutaneous panniculitislike T-cell lymphoma

Mycosis fungoides

Sezary syndrome ´

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders:

Primary cutaneous anaplastic large cell lymphoma

Lymphomatoid papulosis

Primary cutaneous peripheral T-cell lymphomas, rare subtypes

Primary cutaneous gamma-delta T-cell lymphoma

Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic

T-cell lymphoma

Primary cutaneous CD4-positive small/medium T-cell lymphoma

Peripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic T-cell lymphoma

Anaplastic large cell lymphoma, ALK-positive

Anaplastic large cell lymphoma, ALK-negative

Immunodeficiency-Associated Lymphoproliferative Disorders

Lymphoproliferative diseases associated with primary immune

disorders

Lymphomas associated with HIV infection

Posttransplant lymphoproliferative disorders (PTLD)

Plasmacytic hyperplasia and infectious mononucleosis−like PTLD

Polymorphic PTLD

Monomorphic PTLD

Classic Hodgkin lymphoma type PTLD

Other iatrogenic immunodeficiency-associated lymphoproliferative

disorders

MALT, mucosa-associated lymphoid tissue; ALK, anaplastic lymphoma kinase; HHV8, human herpesvirus-8; NK, natural killer; EBV, Epstein-Barr virus; HIV, human

immunodeficiency virus.

aB- and T/NK-cell neoplasms are grouped according to major clinical presentations (predominantly disseminated/leukemic, primary extranodal, predominantly nodal).

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.

2191Adult Hematologic Malignancies Chapter 92

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. Presentation can involve one or more lymph nodes and, sometimes, extralymphatic 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 associated 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 lymphadenopathy 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 complain 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, performance 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 prednisone [CVP], or bendamustine) plus rituximab.

HL is highly responsive to treatment, with up to 95% of

patients achieving complete remission with initial treatment. Initial treatment may include radiation, combination chemotherapy, or combined chemotherapy and radiation. The standard of

care for patients with HL is doxorubicin, bleomycin, vinblastine,

and dacarbazine (ABVD) owing to its demonstrated superiority 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 number 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 associated with serious long-term effects; therefore, minimization of

late toxicities is an extremely important consideration in selection 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 examination 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 marrow 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 annually, 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).

Hundreds of lymph nodes can be found throughout the body,

and they are designed to process antigens present in the lymphatic system. Each one consists of a capsule, cortex, medulla,

and sinuses, with anatomical and functional compartments, such

as follicular (germinal) centers, follicular mantle, and interfollicular and medullary areas (Fig. 92-1). The growth pattern of lymphoma 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 population 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 classification included morphology, immunophenotype, cytogenetics,

2192Section 17 Neoplastic Disorders

TABLE 92-10

Presenting Clinical Features of the Common Non–Hodgkin Lymphomas

International

Prognostic

Index %

0/1 2/3 4/5

GI

Fre- Age Extranodal Bone Marrow B-Symp- Involve- Elevated

quency % (yrs) Involvement % Involvement % toms % ment % LDH %

Stage %

1234

Diffuse

Large

B-Cell

31 64 25 29 13 33 71 16 33 18 53 35 46 9

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 aggressive lymphomas. The WHO updated the REAL classification,

recognizing three categories of lymphoid malignancies based on

morphology and cell lineage.93,165 Currently, the WHO classification 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 aggressive, mature B-cell neoplasm.

STAGING AND PROGNOSIS

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 considered 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

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

Mantle cell

Marginal zone

Follicular

Burkitt

Anaplastic

large cell

F

S

PC

MC

Small B cell

CLL/small lymphocytic

Waldenström

Peripheral T cell

Cutaneous T cell

FIGURE 92-1 Sites of origin of malignant lymphomas in a lymph

node according to anatomical and functional compartments of the

immune system. CLL, chronic lymphocytic leukemia; F, follicles, or

germinal centers; MC, medullary cords; PC, paracortex, or

interfollicular areas; S, sinuses.

disease, and greater than two extranodal involved sites are associated 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 Staging 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 survival rate. Patients with stage IIIB disease are generally treated

with systemic chemotherapy.

TREATMENT

AGGRESSIVE NON–HODGKIN LYMPHOMA

CASE 92-6, QUESTION 2: R.G. consults with a hematologist and elects to receive combination chemotherapy consisting 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 initial therapy? What are the adverse effects that might occur

in R.G.?

TABLE 92-11

Ann Arbor Staging System

Stage Descriptiona

I Involvement of a single lymph node region or a single

extralymphatic organ or site (IE)

II Involvement of two or more lymph node regions on the

same side of the diaphragm (II) or localized

involvement of an extralymphatic organ or site (IIE)

III Involvement of lymph node regions on both sides of the

diaphragm (III) or localized involvement of an

extralymphatic organ or site (IIIE) or spleen (IIIS) or

both (IIISE)

IV Diffuse or disseminated involvement of one or more

extralymphatic organs with or without associated

lymph node involvement. Bone marrow and liver

involvement are always stage IV

a

Identification of the presence or absence of symptoms should be noted with

each stage designation: A, asymptomatic; B, fever, sweats, weight loss greater

than 10% of body weight.

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.

2193Adult Hematologic Malignancies Chapter 92

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 radiation. 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’Etude 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 antigen CD20. Although the exact mechanism is unknown, rituximab 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 myelosuppression 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 neutropenia (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 performed 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 variety of dosing schedules. An infusion-related complex consisting

of fever, chills, and rigors may occur during rituximab infusion,

necessitating premedication with acetaminophen and diphenhydramine. Other less common infusion-related symptoms include

nausea, urticaria, pruritus, bronchospasm, angioedema, and

hypotension. These reactions generally occur within 30 minutes 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 number 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 prevent hepatitis reactivation.172

Safety precautions associated with the chemotherapy medications included in the CHOP regimen include documentation

of a normal cardiac ejection fraction (EF) before administration of doxorubicin and peripheral neuropathy assessments at

baseline and throughout treatment owing to the administration

of vincristine. Because of the increased risk of fetal abnormalities 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 neutropenia.

R-CHOP would be considered standard treatment for R.G.

because she has advanced stage IIIB disease. She should have

baseline evaluation of EF and routine assessments for peripheral neuropathy attributable to vincristine. Supportive-care treatments 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 therapy 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 autologous 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–crossresistant 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 conventional therapy and demonstrated chemosensitive disease at

relapse have the best outcome from autologous HCT. Allogeneic

HCT may be considered in those not considered good candidates 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 lymphoma, progresses very rapidly and commonly metastasizes to

the CNS.164 The majority of adult patients can be cured with an

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 intensive chemotherapy. The hyperfractionated cyclophosphamide,

vincristine, doxorubicin, and dexamethasone regimen, alternating with high-dose methotrexate and cytarabine, has a CR rate

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-thecounter aluminum hydroxide and famotidine. He was otherwise 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 lymphoma. Laboratory values are normal. CT scans of the

2194Section 17 Neoplastic Disorders

chest, abdomen, and pelvis showed axillary and mediastinal 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 develops 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 rituximab with a CR rate of 15% and OR rate of 64%, which

may be extended by maintenance rituximab.174 No improvement 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 without rituximab, or oral alkylating agents such as chlorambucil or

cyclophosphamide.93,177 A recently available option is bendamustine, 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 recommends treatment with a rituximab-containing regimen unless

contraindicated, although definitive evidence supporting a survival 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 rituximab alone. His daughter read on a lymphoma website

that radioimmunotherapy and transplantation are potential treatments. She asks whether these options would be

appropriate for D.J.

D.J.’s disease is typical of indolent NHLs in that they respond to

therapy, but the disease eventually recurs and is generally incurable. Because these lymphomas are generally chemotherapysensitive, relapsed disease can be treated with the same modalities as first-line treatment. Retreatment with rituximab has been

found to be efficacious without additional toxicities.179 Radioimmunoconjugates are monoclonal antibodies that target CD20-

positive lymphoma cells. These antibodies are linked to radioisotopes, 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

[

131I]-tositumomab and yttrium-90 [90Y]-ibritumomab tiuxetan

have been developed to treat follicular lymphomas. Both contain anti-CD20 antibodies with β-emitting radioisotopes. [131I]-

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 hematologic 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 [131I]-

tositumomab should also receive a saturated solution of potassium 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 counseled 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 duration 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 sclerosing 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 diagnosed patients, the tumor is staged to assist in treatment selection. 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, including 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 further 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 lymphadenopathy, 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

2195Adult Hematologic Malignancies Chapter 92

TABLE 92-12

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 lymphocyte count less than 600 cells/μL.172,184 J.R. has three of these

prognostic factors (age >45 years, male, stage IV disease), totaling 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 therapy) are commonly used to treat early and advanced-stage

disease owing to the increased risk of heart disease, pulmonary toxicity, and secondary malignancies associated with

radiation. Multiple combination chemotherapy regimens have

been developed for HL, including ABVD; mechlorethamine,

vincristine, procarbazine, and prednisone (MOPP); bleomycin,

etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); and the Stanford V regimen (mechlorethamine, doxorubicin, etoposide, vincristine, vinblastine, 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, including 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 survival 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 Stanford V followed by radiation. For patients like J.R. with stage IVB

(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 radiation 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 nodular 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 remission 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 lymphocytepredominant HL, rituximab combination chemotherapy (such

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

two cycles beyond documentation of complete remission. Late

effects of HL therapy are a major concern, particularly secondary

malignancies, cardiovascular disease, hypothyroidism, and fertility issues.189 Safety precautions associated with the chemotherapy 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 cardiotoxicity 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 abnormal pulmonary function tests or chest radiographs. If pulmonary

changes occur, bleomycin should be discontinued from further treatment; deletion does not appear to reduce long-term

survival.190 Patients receiving ABVD are at high risk for neutropenia 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

2196Section 17 Neoplastic Disorders

recommends against dose reductions or delays based on neutropenia 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 including secondary malignancies, hypothyroidism, and increased risk

of cardiovascular disease.

RELAPSED DISEASE

CASE 92-8, QUESTION 3: J.R. achieved a complete remission and received a total of six cycles of full-dose ABVD. Two

years after completion of chemotherapy, a routine followup radiograph of the chest revealed enlarged lymph nodes,

which were subsequently biopsied and found to be recurrent 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. Prognostic 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 performance status permit.192 Most patients will be treated with

high-dose chemotherapy and autologous HCT. Before undergoing transplantation, most patients will receive cytoreductive therapy depending on what initial therapy was given. Regimens such

as ESHAP, DHAP, or ICE are often considered, along with others, 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 better 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 autologous 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.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

and websites for this chapter, with the corresponding reference number in this chapter found in parentheses after the

reference.

Key References

Burnett A et al. Therapeutic advances in acute myeloid leukemia

[published correction appears in J Clin Oncol. 2011;29:2293]. J Clin

Oncol. 2011;29:487. (17)

Cervantes F et al. Practical management of patients with chronic

myeloid leukemia. Cancer. 2011 Mar 16.

Dimopoulos MA et al. Long-term follow-up on overall survival

from the MM-009 and MM-010 phase III trials of lenalidomide

plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147. (158)

Hallek M. Chronic lymphocytic leukemia for the clinician. Ann

Oncol. 2011; 22(Suppl 4):iv54. (112)

Kindler T et al. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116:5089. (67)

Kyle R et al. American Society of Clinical Oncology 2007 clinical practice guidelines update on the role of bisphosphonates in

multiple myeloma. J Clin Oncol. 2007;25:2464. (152)

Marcucci G et al Molecular genetics of adult acute myeloid

leukemia: prognostic and therapeutic implications [published

correction appears in J Clin Oncol. 2011;29:1798]. J Clin Oncol.

2011;29:475. (16)

Munshi NC, Anderson KC. Plasma cell neoplasms. In: DeVita

VT et al, eds. Cancer: Principles and Practice of Oncology. 8th ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2008:2305.

(121)

Ng AK et al. Long-term complications of lymphoma and its treatment. J Clin Oncol. 2011;29:1885. (188)

Palumbo A, Anderson K. Multiple myeloma. N Engl J Med.

2011;364:1046. (125)

Palumbo A et al. Oral melphalan, prednisone, and thalidomide compared with melphalan and prednisone alone in elderly

patients with multiple myeloma: randomised controlled trial.

Lancet. 2006;367:825. (142)

Pollyea DA, et al. Acute myeloid leukaemia in the elderly: a

review. Br J Haematol. 2011;152:524. (49)

Rathore B, Kadin ME. Hodgkin’s lymphoma therapy: past,

present, and future. Expert Opin Pharmacother. 2010;11:2891.

Richardson P et al. Bortezomib or high-dose dexamethasone

for relapsed multiple myeloma. N Engl J Med. 2005;352:2487.

(135)

Richardson P et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679. (140)

Rosti G, et al. Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase. Crit

Rev Oncol Hematol. [Epub ahead of print]

Riches JC et al. Chronic lymphocytic leukemia: an update on

biology and treatment. Curr Oncol Rep. 2011 Jul 20. [Epub ahead

of print].

Sawas A et al. New therapeutic targets and drugs in nonHodgkin’s lymphoma. Curr Opin Hematol. 2011;18:280.

Key Websites

American Society of Hematology. Hematology. Education Program

Book. 2010. http://www.asheducationbook.org.

The National Comprehensive Cancer Network. NCCN Guidelines for Treatment of Cancer. Non–Hodgkin’s Lymphomas. Version 3.2011. http://www.nccn.org.

Breast Cancer 93

Kellie L. Jones

CORE PRINCIPLES

CHAPTER CASES

1 Mammography and clinical breast examinations are important screening modalities

for breast cancer.

Case 93-1 (Question 1)

2 Prevention can include both surgery (prophylactic mastectomy) and

chemoprevention. Tamoxifen and raloxifene are two agents approved for breast

cancer prevention.

Case 93-1 (Question 2)

3 Breast cancer is the most common cancer diagnosed in American women. Many

risk factors have been associated with the development of breast cancer; however,

the two most common risk factors are sex and age.

Case 93-2 (Question 1),

Case 93-3 (Question 1)

4 A painless mass is a common presenting symptom for patients. To diagnose the

disease and determine the histology, a mammogram and biopsy are performed.

Staging is also performed to determine the extent of disease.

Case 93-3 (Questions 2–4)

5 Tumor-specific prognostic factors are evaluated such as hormonal status (estrogen

and progesterone receptor status) and human epidermal growth factor receptor 2

(HER2) status. The results help guide treatment selection.

Case 93-3 (Question 5)

6 Local and systemic treatment can include surgery, radiation, hormonal therapy,

chemotherapy, or biologic therapy.

Case 93-3 (Questions 6–9)

7 Early-stage disease is highly curable. In the adjuvant setting (after surgery), patients

will receive hormonal therapy (if estrogen receptor/progesterone receptor-positive)

or possibly chemotherapy, depending on the size of the disease and the presence

of positive axillary lymph nodes.

Case 93-3 (Questions 7–9)

8 Adjuvant chemotherapy can include anthracyclines, cyclophosphamide, and

taxanes. Biologic therapy such as trastuzumab can be incorporated if the patient

has HER2-positive disease.

Case 93-3 (Questions 6–8)

9 Metastatic disease is considered incurable. Decisions regarding therapy will

depend on the hormonal status of the tumor, toxicities from previous treatment, or

other pre-existing comorbidities. Therapies could include systemic therapy

(hormonal therapy, chemotherapy, or biologic therapy) or local treatment (radiation

therapy or surgery).