Editors: Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry M.

Title: Hematology in Clinical Practice, 4th Edition

Copyright ©2005 McGraw-Hill
> Table of Contents > Part II - White Blood Cell Disorders > Chapter 23 - Hodgkin's Disease

Chapter 23
Hodgkin's Disease
Hodgkin's disease is a distinct type of lymphoma that in many ways offers a paradigm for the
diagnosis and treatment of hematologic malignancies. Accurate diagnosis and staging are
critically important for successful treatment. The concept of staging is nowhere more clearly
illustrated than in Hodgkin's disease. Clinical staging of the Hodgkin's disease patient
provides both a strong predictor of prognosis and a foundation for the selection of a specific
treatment regimen. In addition, treatment of Hodgkin's disease is based on solid principles of
radiobiology and chemotherapy that serve as a model for all other treatment regimens.
Because of this solid theoretical base, treatment of Hodgkin's disease has become very
successful. Gone untreated, 90% of patients with Hodgkin's disease die within 2–3 years,
whereas 80% or more are now curable with modern therapy. Therefore, Hodgkin's disease is
one of the best examples of a malignancy that can be cured if diagnosed and managed well.
However, despite our well-developed understanding of the clinical course, staging, and
treatment of this disease, its cause remains unknown. Even the origin of the malignant cell is
a source of controversy.

DIAGNOSIS & CLASSIFICATION

Like other lymphomas, Hodgkin's disease usually presents as an enlargement of the lymphoid
organs, frequently accompanied by systemic symptoms such as fever, weight loss, fatigue,
and so on. It is unique in several respects, however. Unlike the non-Hodgkin's lymphomas,
the tumor masses largely comprise normal reactive T cells and are usually CD4 predominant,
not a clone of malignant lymphocytes.

REED-STERNBERG CELLS & LYMPHOCYTIC/HISTIOCYTIC CELLS

The putative malignant cell is the Reed-Sternberg cell, a large, frequently binucleate cell that
more closely resembles a macrophage-like cell than a lymphocyte (see Color Plates 62 and
63). The relative number of the Reed-Sternberg cells may vary from very high to very low,
but always make up < 2% of the apparent tumor load. In some cases only a very careful
search will reveal the presence of these cells, without which the diagnosis cannot be made
with certainty. The majority of cells found in the lesion are a diverse population of
lymphocytes, eosinophils, and other reactive cells that, although they may represent by far
most of the cells in the lesion, are thought to be passive or at least secondary to the malignant
process.
Reed-Sternberg cells have been difficult to study because they are present in small numbers
and are difficult to separate from the surrounding infiltrate of reactive cells. Therefore, only
very few cell lines have been established. Immunophenotyping studies of isolated Reed-
Sternberg cells do suggest that they are primarily monoclonal B cells derived from germinal
center cells, although a small percentage (< 2%) appear to be from T cell precursors. At the
same time, they lack many of the surface antigens typical of B and T cells, expressing instead
a number of unusual antigens (eg, CD30, CD15, CD70, TARC, IRF4). In addition, despite Ig
gene arrangements compatible with their B-cell origin, Reed-Sternberg cells do not transcribe
Ig. An overexpression of CCR7 is of interest as a possible reason behind the localization of
Reed-Sternberg cells to lymph nodes and spleen. The elaboration of several cytokines and
their receptors (tumor necrosis factor, nuclear factor-κB, Th2 cytokines, and IL-13) appear to
be responsible for many of the clinical characteristics, including the B symptoms, fibroblast
proliferation in nodular sclerosis, eosinophil infiltration, and abnormal immune response
typical of Hodgkin's disease.
Despite many years of study, the mechanism by which Reed-Sternberg cells arise and their
precise role in the malignant process remain obscure. As with other lymphomas, there
appears to be a primary failure in the normal apoptotic process, not an increase in
proliferation. In classical Hodgkin's lymphomas, Epstein-Barr virus (EBV) can be isolated
from the Reed-Sternberg cell in approximately 50% of cases and the incidence of Hodgkin's
disease in patients with a past history of infectious mononucleosis appears to be increased.
However, an etiologic role for EBV infection has not been proved.
Because of the limitations of immunologic and genetic studies in this disease, diagnosis of
Hodgkin's disease still depends on the pathologic interpretation of biopsy material.
Diagnostic certainty requires the identification of Reed-Sternberg cells or, in the case of
nodular lymphocyte predominant disease, “popcorn― or L&H cells (lymphocytic or
histiocytic cells [or both] of Lukes-Butler classification) set in a diverse population of B and
T lymphocytes, eosinophils, and other reactive cells (see Color Plate 64). The predominant
infiltrating cell in Hodgkin's nodes is a CD4+ regulatory T cell that is present in two
forms—one that secretes IL-10 (an immunosuppressive cytokine), and a second that
suppresses immune cells through cell-cell contact. The presence of these cells has
implications for protecting Reed-Sternberg cells from immune destruction and producing a
generalized immunosuppression. The overall histologic pattern of the tumor has a strong
association with clinical course and can fall into one of five categories (Table 23-1).

Types of Hodgkin's Disease

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is characterized
histologically by a vague nodular pattern, rich in lymphocytes, containing a distinctive
morphologic variant of the Reed-Sternberg cell, the so-called L&H, or “popcorn― cell.
These cells are surrounded by a collar of CD57+ T cells and large numbers of small
polyclonal B cells. The phenotype of the “popcorn― cell resembles that of a B
lymphocyte (CD15 and CD30-, CD19, 20, 22, and 45+). This form is relatively indolent and
slow to spread, often resembling a low-grade non-Hodgkin's lymphoma.
The more common histologic types (classical Hodgkin's lymphoma) are nodular sclerosis,
mixed cellularity, lymphocyte-depleted, and, the newly proposed, lymphocyte-rich classical
Hodgkin's lymphoma. They share the common feature of the presence of classical or lacunar
type Reed-Sternberg cells, both of which are monoclonal B cells with a distinct
immunophenotype, CD15 and 30+, CD20 and 45-. Nodular sclerosis Hodgkin's disease is
further characterized by variable amounts of collagenous connective tissue separating nodules
of lymphocytes containing lacunar-type Reed-Sternberg cells. Depending on the number and
degree of atypia of the Reed-Sternberg cells, nodular sclerosis Hodgkin's lymphomas can be
subclassified as grade 1 or 2. Grade 1 disease, which makes up 75–85% of cases, has the
best prognosis. Mixed cellularity and lymphocyte-depleted Hodgkin's disease, the other two
histopathologic forms, carry the worst prognosis. They are characterized by fewer
lymphocytes and relatively more classical bilobed Reed-Sternberg cells with prominent
eosinophilic nucleoli. In some cases the predominant cells are difficult to distinguish from
other poorly differentiated lymphomas or sarcomas.

CLINICAL FEATURES
The most common presentation of a Hodgkin's disease patient is the appearance of a painless
or only slightly tender, rubbery swelling of a superficial lymph node or group of nodes in a
young adult. The tendency of Hodgkin's disease to first appear in a single node group in an
otherwise healthy individual can make it difficult to distinguish from the lymphadenopathy
associated with an infectious process. Nodes that are slightly tender are even more of a
problem because tender nodes often accompany acute infections. In addition, Hodgkin's
nodes can on occasion wax and wane in the same way as those associated with an infectious
process. The diagnosis is obviously easier when the mass is large, presents in more than one
area, and is associated with systemic symptoms (B symptoms) such as night sweats, fever,
weight loss, pruritus, or fatigue.
The most common areas of involvement in young patients are the cervical, axillary, and
mediastinal nodes. Extension to subdiaphragmatic nodes is seen in less than one-quarter of
these patients if they seek medical attention without delay. Moreover, they are unlikely to
have any involvement of liver, spleen, or other organs. Systemic symptoms are present in less
than one-third of patients. Hodgkin's disease has an age-dependent incidence with a peak in
young adults and another peak in the elderly. Unusual presentations, such as disease limited
to the spleen or an extranodal site, are more common in the elderly. Moreover, whereas
lymphocyte predominant and nodular sclerosis Hodgkin's disease are common in the younger
age group, mixed cellularity and lymphocyte-depleted Hodgkin's disease are more often seen
in patients 30 years or older.

Table 23-1. Histologic classification of Hodgkin's disease.

REAL Histologic Description Frequency

Classification
Nodular/lymphocyte
predominant
Lymphocyte-rich classical
HL
Nodular sclerosis
Mixed cellularity
Lymphocyte-depleted
Nodular pattern with “popcorn― cells 4–5%
Abundant mature lymphocytes, a few classical Reed- 5–10%
Sternberg cells
Prominent fibrosis, mature lymphocytes, and Reed- 60–80%
Sternberg cells present
Both mature lymphocytes and Reed-Sternberg cells 15–30%
Predominantly large, poorly differentiated cells < 1%

The incidence of Hodgkin's disease has been linked to several factors, including environment,
social status, infectious agents, and genetic propensity. It is slightly more common in men
and has occurred as clustered cases in families, communities, and schools. It is also more
common in developed countries. Patients who have had infectious mononucleosis or have a
positive test for prior EBV infection have a threefold increased risk for developing the
disease. There is also an increased incidence in individuals with occupational chemical
exposures or immune deficiency states. These associations suggest an infectious cause, as
well as a component of genetic susceptibility, which appears to be much more striking in
Hodgkin's disease than in other lymphomas. Recent studies of identical twins have reinforced
the fact that there is a genetic propensity to this disease with some yet undefined
environmental or infectious process superimposed.

STAGING
Accurate staging is extremely important. The natural history of the disease suggests that it
arises in a single site and then spreads from that site in an orderly and more or less
predictable pattern from one lymphoid (usually nodal) site to contiguous lymphoid sites and
from lymphoid sites to contiguous nonlymphoid sites. It is difficult to prove that this is
always the case, and in some cases it clearly is not, but it is a useful concept that has led to a
very successful strategy of staging and treatment. Thus, the primary objective of staging is to
determine the current location of all the disease in the patient in order to plan a treatment that
will address each of the involved areas and all contiguous sites of possible spread.
The staging of Hodgkin's disease is conceptually simple. One determines the location and
extent of the disease, and then assigns a stage as outlined in Table 23-2. This staging does
require a careful evaluation of the patient, including a full history, detailed physical
examination, and several radiologic and laboratory studies.

History & Physical Examination

The history should document the timing and characteristics of the onset of the disease and
the presence of systemic (B) symptoms, including weight loss, night sweats, low-grade fever,
pruritus, and fatigue. On physical examination, all portions of the lymphoid organs should be
carefully examined (Figure 23-1). Special attention should be paid to the lymphoid regions
of the oral pharynx (Waldeyer's ring), the popliteal and epitrochlear regions, the subclavicular
regions, as well as the more common axillary, anterior and posterior cervical, and inguinal
regions.

Biopsy
A biopsy of the principal tumor mass or accessible enlarged node should be done, and the
results reviewed with an experienced hematopathologist. It is not uncommon for the
diagnosis of Hodgkin's disease to be confused or delayed by inadequate biopsy or too casual
examination of a biopsy specimen. It is also common to find lymph nodes containing overt
Hodgkin's disease located adjacent to nodes that show only reactive hyperplasia. Therefore,
biopsy specimens from more than one node should be taken if available. The presence of
hepatomegaly suggests extension of the disease outside of the lymphatic system. Infiltration
of the skin can result in generalized pruritus, appearance of subcutaneous nodular tumors, or
in its most severe form, exfoliative dermatitis.

Table 23-2. Staging system for Hodgkin's disease.

Stage Description Example

I Involvement of a single lymphoid region or a
single nonlymphoid site (IE)
II Involvement of two or more regions on the same
side of the diaphragm
III Involvement of two or more regions on both sides
of the diaphragm
IV Spread of disease from lymphoid sites to
nonlymphoid organs, involvement of more than
one nonlymphoid organ
B Each stage is further modified as B by the
presence of fever, weight loss, or night sweats
Nodes on one side of the neck only
Nodes in the neck and chest
Nodes in the neck and
retroperitoneum or the spleen
Nodes in the chest and infiltration of
the marrow and lung
Nodes in the retroperitoneum and
groin with fever and night sweats
(IIB)

Radiologic Studies
with bulky mediastinal disease. To more accurately detect lymph node involvement of the
mediastinum and abdominal nodes, a computed tomography (CT) scan of both thorax and
abdomen should be performed. The CT scan is sensitive to lymph node enlargement or tissue
invasion in the mediastinum, lung, and upper abdomen. To fully evaluate retroperitoneal
nodes of the lower abdomen, bipedal lymphangiography can be performed. This technique
will detect disease in nodes of near normal size that may be missed by CT scanning alone.
Lymphangiography is unnecessary if the CT scan shows definite tumor involving the
retroperitoneal nodes. It is also contraindicated in patients with extensive chest involvement
owing to possible respiratory compromise. In selected patients, a magnetic resonance image
(MRI) may be valuable in defining disease, especially disease involving nonlymphoid organs
or residual disease in treated areas. A technetium scan may help define bony involvement in
patients who complain of bone pain.

Laboratory Studies
The laboratory evaluation of the Hodgkin's disease patient should include a complete blood
count, tests of renal and liver function (including alkaline phosphatase and lactic
dehydrogenase [LDH] levels), a serum calcium, and bilateral iliac crest marrow aspirates and
biopsies. These tests are especially important in evaluating disease extension outside of the
lymphatic system. When anemia is present, studies of iron supply should be ordered to
determine whether it is secondary to the inflammatory nature of the disease or results from
marrow infiltration by tumor. A marrow biopsy may be helpful in the latter case. Even
though the classic histologic patterns seen in lymph node biopsies are not reproduced in
the marrow, it may be possible to identify Reed-Sternberg cells. Typically these cells are the
size of a small megakaryocyte and contain two bean-shaped nuclei, each with a single large
nucleolus. In some cases, Reed-Sternberg cells cannot be identified, but the normal marrow
structure is disrupted by small non caseating granulomata or patchy fibrous tissue.
Abnormalities of the granulocyte and lymphocyte counts may be observed. Some patients
present with an eosinophilia or monocytosis, whereas others have an absolute lymphopenia.
The latter is a bad prognostic sign and may be associated with lymphocyte-depleted
Hodgkin's disease and a loss in skin test responsiveness (anergy). Older patients presenting
with splenic disease can demonstrate thrombocytopenia or an autoimmune hemolytic anemia.
In contrast to the non-Hodgkin's lymphomas, immunologic and gene rearrangement studies
of blood cells cannot be used to either make the diagnosis or confirm the spread of the
disease. All of the peripheral blood changes are reactive in nature.
Patients with abnormal liver chemistries or a suspicious lesion on CT should have a guided
needle biopsy of the lesion or laparoscopic liver biopsy.

Staging Laparotomy
A staging laparotomy may be indicated in patients with clinical stage I or II disease,
especially in patients with mediastinal disease. It is in this group of patients where successful
treatment may be accomplished with radiotherapy limited to the areas of clinical disease and
adjacent lymphoid areas. Undetected disease outside the treated areas will certainly result in
relapse, however. The staging laparotomy allows the detection of occult abdominal node or
organ involvement. One-third to one-half of patients who appear to have clinical stage I or II
disease will be reclassified following staging laparotomy as stage III or IV. At the same time,
patients with stage IA disease limited to one site, the neck or mediastinum, and those with
stage I or IIA disease and lymphocyte predominant histology should be treated without a
staging laparotomy. There is a definite morbidity associated with staging laparotomy,
including an increased risk of postsplenectomy sepsis in children and young adults. In
children less than 5 years of age, splenectomy is contraindicated because of an increased risk
of recurrent septicemia. Moreover, in these patients, salvage chemotherapy for recurrence is
so effective that long-term survival is not compromised.
A well-performed staging laparotomy should include a biopsy of all of the abdominal node
groups regardless of their size or appearance, splenectomy, and both a wedge biopsy and
multiple needle biopsies of the liver. Every attempt should be made to locate and take a
biopsy of any lymph node that appears suspicious on the lymphangiogram. Biopsy sites
should be marked with clips. A flat plate of the abdomen during surgery can help ensure that
all suspicious nodes are successfully identified. Adult patients should always be immunized
preoperatively with Haemophilus and polyvalent pneumococcal vaccines. Moreover, the
staging workup should have been exhaustive enough to assure the clinician that the
laparotomy is absolutely necessary. For example, no patient should go to surgery who has not
had studies of liver chemistries, blood and marrow evaluation, CT/MRI scans of the
abdomen, and, if possible, bipedal lymphangiography. If disease can be shown to be present
on both sides of the diaphragm or involve the liver or marrow, the patient can be staged
clinically and does not need surgery.

Prognosis
The patient's prognosis and subsequent management are determined largely by the stage of
the disease. The number of node sites involved and the spread to nonlymphoid organs are the
strongest prognostic indicators. If a patient has disease isolated to a single node group, even
an adverse histology will not significantly change the relatively good prognosis or the
selection of therapy. There are, however, observations that do have an impact on prognosis.
The most important of these is the presence of B symptoms, especially when fever and
significant weight loss are both present. Other factors that suggest a poor prognosis include
bulky mediastinal tumor, a high LDH level, nonlymphoid organ involvement, severe marrow
disease, and a poor response to initial radiotherapy or chemotherapy.

THERAPY & CLINICAL COURSE

The several possible combinations of histology, B symptoms, location of disease, and
prognostic factors together with varying regimens of either radiotherapy or chemotherapy
make it difficult to propose a rigid logic tree for the treatment of Hodgkin's disease.
Nevertheless, there are some clear basic principles that guide the choice of therapy. It is well
established that both radiotherapy and chemotherapy can cure Hodgkin's disease. The
therapeutic goal, therefore, is to provide the highest cure rate in the shortest period with the
least morbidity. This goal should be achievable in almost all patients with stage I or II disease
and in a sizable majority of those with more advanced stage III or IV disease. Treatment
failure most often results from either inaccurate staging or a suboptimal radiotherapy/
chemotherapy regimen.

Stages IA & IIA: Favorable Disease

Stages IA and IIA disease have traditionally been treated with high-energy radiation
delivered to the involved areas and the adjacent uninvolved areas (extended field radiation).
Involved areas receive a tumoricidal dose of 40 Gy, whereas adjacent uninvolved areas are
given 30–36 Gy. Standard radiation ports include the mantle for patients with disease
limited to the neck and the inverted Y for patients with disease limited to the lower
abdominal or inguinal nodes (Figure 23-2). Additional treatment to the mediastinum and
periaortic nodes is required for patients with mediastinal or upper abdominal involvement.
Since up to 20% of stage IA and IIA patients treated in this fashion will relapse, attempts are
underway to better predict favorable outcome and plan therapy accordingly. Risk factors for
early relapse include: a large mediastinal mass, age > 50 years, an elevated ESR, and
involvement of 4 or more nodal areas. Favorable indicators include: young age, lymphocyte
predominant histology, and disease limited to nodes above the diaphragm. Based on these
factors, patients with stage IA/IIA supradiaphragmatic disease with lymphocyte predominant
histology and no risk factors do the best and may be treated with local radiation only. All
others have a somewhat less favorable prognosis and are candidates for mantle radiation or
ABVD chemotherapy and radiation limited to the involved nodal field(s). However, this is
not the final answer. Because this approach may still involve innappropriate treatment for a
number of patients, it is hoped that gene-profiling, in the future, will better discriminate
between favorable and less favorable disease.

Stages I & II: Unfavorable Disease

Patients with stage I or II disease and one or more risk factors (B symptoms, age > 50 years,
elevated ESR, > 4 node regions involved, subdiaphragmatic disease, large mediastinal mass)
have a relapse rate that can approach 50%. They are clearly candidates for combined
chemotherapy/radiotherapy (4 or more courses of ABVD and radiation [30 Gy] to involved
nodal areas). Stage IIB patients with extranodal disease or a large mediastinal mass are at an
even greater risk of relapse and should be treated similar to stage III and IV patients with
polychemotherapy (see the following).
The presence of a large mediastinal tumor represents a special challenge. Even with
combined modality therapy with radiation to the mediastinal mass, a residual mediastinal
abnormality is seen in 60–90% of patients. Whether this is residual tumor or unresolved
scar tissue can only be distinguished by watching and waiting. If, after therapy, the residual
mass is stable and the patient has no B symptoms, it can be assumed to be a scar. If the mass
increases in size, however, or the patient has a recurrence of B symptoms, the presence of
resistant tumor is more likely. A gallium scan may be helpful to distinguish the two
possibilities. If there is avid uptake of the gallium by the mass, it is likely that the disease is
recurring. In very young patients, regeneration of the thymus can also result in high gallium
uptake and mimic recurrent disease.

Side Effects & Complications of Radiation Therapy

Side effects of radiation therapy include nausea and fatigue, especially in patients receiving
abdominal radiation. Transient hair loss over the areas of radiation is expected. Patients who
receive mantle radiation may develop parotitis after the first or second treatment. When
multiple areas are irradiated, marrow depression can occur. Generally, it is observed near the
end of a prolonged course of therapy and is relatively mild with white blood cell counts of 1 -
2000/µL and platelet counts not below 50,000/µL. Neutropenia leading to sepsis is very
unusual, and recovery from marrow depression occurs spontaneously without the need for
growth factor treatment.
Long-term complications of radiation therapy include decreased salivary flow and
hypothyroidism in patients who have received mantle therapy, pulmonary or cardiac
complications if the mediastinal port is not well plotted, and loss of marrow reserve in those
patients who receive extensive irradiation. The most important late complication of
radiotherapy is the development of a second malignancy. The risk of post-therapy leukemia,
non-Hodgkin's lymphoma, or tumors involving the genitourinary tract, lung, skin, or colon
has been reported by some investigators to be as high as 10% during the first decade after
treatment.

Stages III & IV

Stages III and IV patients should be treated with intense multidrug chemotherapy. The
chemotherapy of Hodgkin's disease is particularly interesting because it was the first
successful application of multiagent chemotherapy where several different drugs were chosen
for their partial effectiveness against the disease and for their nonoverlapping toxicities.
Table 23-3 outlines some of the chemotherapeutic regimens currently used for Hodgkin's
disease. The MOPP protocol (nitrogen mustard–vincristine-procarbazine-prednisone) was
the first but is now less widely used. Newer combinations have a better response rate and and
less toxicity. In particular, the ABVD regimen (Adriamycin-bleomycin-vinblastine-DTIC) is
more effective and does not appear to carry the increased risk of secondary leukemia
associated with MOPP. The combination of MOPP with ABVD also has been used to provide
two different non–cross-resistant regimens for patients who relapse after MOPP or whose
disease is resistant to initial therapy. Stanford V and BEACOPP have been developed as
shorter-duration protocols with reduced toxicity.
The key to effective chemotherapy is to give full doses on a tight schedule. Dose reductions
and delays must be avoided if at all possible. In those patients who develop myelosuppression
after each cycle of drugs, it is important to try to continue with the maximum dose of drug
and to use a growth factor such as granulocyte colony-stimulating factor (G-CSF) to
overcome the myelosuppression. Chemotherapy, such as ABVD or MOPP, is carried out over
6–12 monthly cycles according to the tumor response. Radiologic studies of areas of
known disease should be carried out after the fourth and sixth cycles. In those patients who
respond rapidly and completely, therapy can be discontinued after the sixth cycle. If the
disease is slow to respond or persists, up to 12 cycles of therapy should be given.
The response rate to the ABVD regimen in patients with stages III and IV disease is better
than 80% with a 60% disease-free survival at 5 years. A combined MOPP/ABVD regimen
may give as high as a 90% response rate with 75% disease-free survival at 5 years. The
combined regimen can place the patient at a disadvantage, however, for subsequent salvage
therapy. Stanford V and BEACOPP protocols combined with targeted radiation therapy give
response rates approaching 100% with better than 90% disease-free survival at 5 years.
Maintenance chemotherapy is not recommended because it does not improve disease-free
survival and can lead to an increased incidence of second malignancy. Maintenance therapy
with interferon may be an exception, offering improved disease-free survival without the risk
of second malignancy.

Table 23-3. Typical chemotherapeutic regimens for Hodgkin's disease.

Regimen Dose and Schedule

MOPP Repeat every 28 days for 6 months
Nitrogen mustard 6 mg/m2 IV, days 1 and 8
Vincristine 1.4 mg/m2 IV, days 1 and 8
Procarbazine 100 mg/m2 PO, days 1–14
Prednisone 40 mg/m2 PO, days 1–14
ABVD Repeat every 28 days for 6 months
Adriamycin 25 mg/m2 IV, days 1 and 15
Bleomycin 10 mg/m2 IV, days 1 and 15
Vinblastine 10 mg/m2 IV, days 1 and 15
DTIC 375 mg/m2 IV, days 1 and 15
Stanford V Repeat every 12 weeks
Mechlorethamine 6 mg/m2 IV, wks 1, 5, and 9
Adriamycin 25 mg/m2 IV, wks 1, 3, 5, 9, and 11
Vinblastine 6 mg/m2 IV, wks 1, 3, 5, 9, and 11
Bleomycin 1.4 mg/m2 IV, wks 2, 4, 6, 8, 10, and 12
Etoposide 5 mg/m2 IV, wks 2, 4, 6, 8, 10, and 12
Prednisone 40 mg PO, OD, wks 1–10
G-CSF As required
BEACOPP Repeat every 14–21 days
 Bleomycin 10 mg/m2 IV, day 8
Etoposide 100 mg/m2 IV, days 1–3
Adriamycin 25 mg/m2 IV, day 1
Cyclophosphomide 650 mg/m2 IV, day 1
Oncovin (vincristine) 1.4 mg/m2 IV, day 8
Procarbazine 100 mg/m2 PO, days 1–7
Prednisone 40 mg PO OD, days 1–14
G-CSF As required

Stages IB - IIB & IIIA

Patients with stages IB–IIB and IIIA disease may be managed with varying regimens of
radiotherapy and chemotherapy. The stage IB–IIB patient with only a single systemic
symptom can be treated with radiotherapy alone with the expectation of a better than 80% 10-
year survival. However, in patients with several B symptoms the response is so poor that
multidrug chemotherapy should be used from the beginning, just as with stage III and IV
patients.
Stage I or II patients with mediastinal node involvement also need to be carefully evaluated
for subdiaphragmatic disease, including in selected patients, an exploratory laparotomy with
splenectomy. A third or more turn out to have stage IIIA disease; therefore, they can be
candidates for multidrug chemotherapy. Patients who have surgically proven disease limited
to upper abdominal nodes or the spleen generally have a more favorable prognosis than those
with lower abdominal and iliac node involvement. In either case, multidrug chemotherapy or
a combined modality approach using three or four cycles of chemotherapy followed by total
nodal or involved field irradiation should be used. Because of the morbidity associated with
surgical staging, especially the risk to children and young adults of postsplenectomy sepsis,
some centers manage stage II patients with radiation alone and allow those with stage III
disease to demonstrate their subdiaphragmatic disease by treatment failure. They can then be
rescued with chemotherapy.

Salvage Therapy
Patients must be carefully monitored after successful initial treatment. Relapse can occur at
any time, even in stages IA and IIA patients, including late relapses in up to 15% of these
patients. Patients with more advanced disease will relapse sooner and more frequently
(Figure 23-3). There is still an excellent chance, however, to achieve a second remission and
prolonged periods of disease-free survival. If the patient relapses more than 12 months after
initial therapy, re-treatment with the same regimen will be successful 70–80% of the time
and will result in a sustained remission. If relapse occurs sooner than 12 months, a different
chemotherapy regimen should be instituted. For example, a MOPP-treated patient should be
changed to the ABVD regimen. A response is seen about 50% of the time, with success
depending a great deal on the presence of such factors as B symptoms, bulky disease, and
adverse histologies.
All patients with relapsed Hodgkin's disease should be considered for high-dose
chemotherapy followed by autologous marrow transplantation. Those with more responsive
disease, lack of B symptoms, and a longer duration of remission are more likely to achieve
long-term survival after this form of salvage therapy, but even unfavorable prognosis patients
can benefit. A typical autologous transplant/chemotherapy regimen is described in Chapter
22. High-dose chemotherapy regimens commonly used to prepare Hodgkin's disease patients
include some combination of cyclophosphamide, BCNU, etoposide, cytarabine, and
melphalan with or without total body irradiation. This approach has the potential of providing
a better chance for long-term disease-free survival: 55–65% of patients appear to be
disease-free after 5+ years. The success rate is greatly influenced by patient selection,
however. Older patients, patients who have been exposed to a large number of chemotherapy
drugs with or without irradiation, and those who have poorly responsive tumor also tend to
fail to respond to autologous marrow transplantation. Another distressing drawback of an
autologous transplant is a reported incidence of secondary acute myeloid
leukemia/myelodysplasia of 9–15% after 5–7 years.
Other possible salvage therapies for patients who are not candidates for or who fail
autologous transplantation include single-agent vinblastine; combination chemotherapy with
drugs such as etoposide, ifosfamide, and cisplatin; or immunotherapy. Anti-CD20
(Rituxamib) has shown some efficacy in patients with lymphocyte predominant Hodgkin's
disease.
Complications of chemotherapy, the combined modalities of chemotherapy and radiotherapy,
and autologous marrow transplantation include vital organ damage and prolonged
immunosuppression. Radiation pneumonitis and pericarditis, together with drug-induced
chronic restrictive pulmonary disease and myocardiopathy, increase in frequency with
exposure to intensive chemotherapy/radiotherapy. The risk of a second malignancy is also
present. This situation is most dramatic for those patients who receive combined modality
therapy at an early age or who receive an autologous transplant as salvage therapy. Another
risk for the young patient is gonadal dysfunction following chemotherapy. Even a few
treatment cycles with MOPP or MOPP/ABVD combinations will result in azoospermia in
males secondary to irreversible damage to the testes. ABVD therapy has been recommended
in young males because of its lower incidence of testicular damage. Young males should be
offered sperm storage prior to beginning chemotherapy if they wish to ensure their ability to
have children. Young women have less difficulty with ovarian failure following
chemotherapy. Less than one-quarter of young women will become infertile, but more than
80% of women over the age of 30 will immediately enter menopause. Chemotherapy and
radiotherapy in the treatment of Hodgkin's disease in young women have not been associated
with teratogenicity.
Hodgkin's disease patients must be looked on as immunosuppressed individuals throughout
their lives. Even with successful treatment, cellular immunity may not return to normal.
Furthermore, most Hodgkin's disease patients will experience an episode of herpes zoster
and may be at risk for disseminated vaccinia if exposed to a child with chickenpox. Patients
who have had splenectomy are considered at risk for infections with encapsulated organisms,
especially Streptococcus pneumoniae and Haemophilus. Up to 10% of young patients who
have a splenectomy for the diagnosis of Hodgkin's disease will experience at least one life-
threatening episode of pneumococcal sepsis during the first 10 years after staging. It is
essential that these patients be immunized to polyvalent pneumococcal vaccine prior to their
staging and receive a periodic booster. If they experience an episode of sepsis, prophylaxis
with oral antibiotics should be considered.
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