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1616 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1617

alternate approaches in high-risk subsets. The superiority of escalated suggest an important interplay between characteristics of Hodgkin and
BEACOPP was seen across the spectrum of the international prognostic Reed-Sternberg cells and the inflammatory environment.
score, but approximately 30 percent of high-risk (four to seven factors)
patients experience treatment failure. Alternately, the improvement
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in progression-free survival with BEACOPP over ABVD in an Italian COMPLICATIONS OF TREATMENT
169
study was limited to higher-risk patients. Age has been a consistent The treatment of Hodgkin lymphoma is associated with important
adverse prognostic marker regardless of tumor burden, but recent gains acute and chronic side effects. Although the acute complications of che-
eliminate this adverse factor up to approximately age 55 years. 208,209 motherapy and radiotherapy may be troublesome, they are relatively
Although less-intensive treatment may explain inferior results in a sub- easily managed. Late-treatment effects in the form of sterility, second
set of patients, results in older patients are worse, even when the inten- malignancy, and cardiopulmonary disease are more serious and are
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sity of therapy is controlled. The BEACOPP regimen was associated known to contribute to shortened longevity for cured patients. 145,152,233,234
with unacceptable toxicity and demonstrated no advance over ABVD Excess mortality from second malignancies and cardiac disease increase
for patients older than age 65 years. 210 with time and are currently the leading causes of death for cHL patients.
Normal results from FDG-PET imaging at the completion of treat- As treatment has evolved, the risks of radiation-related complications
ment confers a high negative predictive value, ranging from 81 to 100 has lessened but long latency periods and uncertainty regarding associ-
percent. The positive predictive value at the end of chemotherapy ations with lower doses make it difficult to predict individual risks. Rec-
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is more variable and is related to disease extent and use of radiother- ognition and understanding of these problems helps to shape primary
apy. 176,211,212 There is great interest in FDG-PET imaging after one to treatment choice and facilitate optimal followup for survivors.
three cycles of chemotherapy, as several studies indicate that negative Acute leukemia and myelodysplasia were the initial second
results predict treatment success whereas positive results predict a high malignancies to be observed after successful treatment for Hodgkin
likelihood of treatment failure. 95,96,98,99 Numerous ongoing phase III clin- lymphoma with MOPP chemotherapy. The risk following MOPP
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ical trials are designed to alter treatment based on early PET results with was proportional to the cumulative dose of alkylating agents and was
100
a goal of achieving high cure rates and minimizing toxicity. PET sta- associated with recurring abnormalities of chromosomes 5 and 7. 235–237
tus prior to autologous transplantation has also emerged as a dominant Actuarial risks of approximately 5 percent with relative risks in excess of
prognostic factor. 213 100 have been reported over a 7- to 10-year period with alkylating agent-
Adverse prognostic factors identified for patients with relapsed based therapies. The risk of secondary leukemia is greater in patients
cHL undergoing autologous stem cell transplantation include (1) dura- older than age 35 years. Prognosis for secondary leukemia is poor with
238
tion of first complete remission less than 1 year, (2) failure to achieve a survivals of less than 1 year. The risk of acute leukemia is significantly
141
second complete remission with salvage chemotherapy prior to trans- less after ABVD chemotherapy, although it is not absent. A large inter-
plantation, (3) presence of B symptoms or extranodal sites of disease national study observed a significant reduction in excess absolute risk
involvement, and (4) persistence of FDG-avidity on PET imaging prior after 1984, presumably as a consequence of change in primary therapy.
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to transplant. 213–215 However, acute leukemia may complicate Hodgkin lymphoma treatment
Patients with primary progressive Hodgkin lymphoma have the with higher doses of etoposide and doxorubicin, such as in the BEA-
least-favorable prognosis. Fortunately, newer treatment approaches COPP regimen. 143,165,168 This form of leukemia tends to occur earlier and
have reduced the proportion of patients in this category. be associated with balanced translocations of chromosome 11. Patients
Clinical prognostic factors are surrogates for the underlying cel- who have received second-line therapies and autologous transplantation
lular and molecular biology of Hodgkin lymphoma. Serum levels of are at highest risk for myelodysplasia and secondary leukemia.
cytokines, including soluble CD30, a probable marker of tumor bur- There is an increased relative risk of non-Hodgkin lymphomas
den, and IL-10, a measure of immunosuppression related to the micro- after treatment for Hodgkin lymphoma. 239,240 These are diffuse, aggres-
environment, are associated with adverse prognosis independent of sive B-cell lymphomas that may occur early or late after treatment.
clinical features. The chemokine CCL17, secreted by Hodgkin and There is no clear relationship to the type of primary treatment. The
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Reed-Sternberg cells, is elevated in patients’ sera and is being studied incidence of secondary lymphoma in a series of 5406 patients treated
as a marker of response. 217,218 Multiple, but not all, investigators found on GHSG protocols was 0.9 percent; prognosis was worse if lymphoma
BCL-2 expression to be of prognostic significance. 219–222 CD20 expres- developed within 3 months of primary therapy. Although prognosis
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sion by Hodgkin and Reed-Sternberg cells has been associated with was relatively poor in this series, the data antedated the routine use of
less-favorable outcomes in some, but not all, series. 223,224 Lack of HLA rituximab in treatment regimens. It is not clear how non-Hodgkin lym-
class II expression, which may allow immune escape of Hodgkin and phomas relate to treatment-related immunodeficiency, predisposition
Reed-Sternberg cells, was found to be an independent prognostic to B-cell malignancy, or a shared common cell of origin. Marginal zone
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factor. The prognostic significance of EBV association varies with age, lymphomas with identical B-cell receptor genes also have been identi-
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conferring an adverse outcome in older individuals. 226,227 Furthermore, fied. Diffuse large B-cell lymphoma and its variants are most frequent
single nucleotide polymorphisms in HLA-A2 have been associated in nodular lymphocyte-predominant Hodgkin lymphoma, where they
52
with risk of EBV-positive Hodgkin lymphoma. A number of studies have been found to be genetically related. 243
have focused on the inflammatory microenvironment of Hodgkin lym- An increased risk of solid cancers after treatment for Hodgkin lym-
phoma. Increased numbers of T-regulatory cells have correlated with phoma has long been recognized, and with time, these have emerged to
favorable outcomes and decreased numbers of markers for cytotoxic T account for 75 to 80 percent of all cases of second malignancy. 145,152,239
cells have correlated with adverse outcomes in several series. 228–230 Simi- The risk is related to radiotherapy exposure, with tumors occurring in
larly, heavy infiltration of cHL with macrophages (detected by immuno- or at the edges of the radiation field. The most common solid tumors are
histocytochemical staining for CD68), is associated with poor outcome, breast, lung, and gastrointestinal malignancies. The latency for devel-
presumably because of secretion of immunosuppressive cytokines. oping second cancers is an important consideration, as these typically
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Finally, a 23-gene expression signature that can be assessed in formalin- develop after at least 10 years and continue to pose excess risk for as
fixed paraffin embedded tissue biopsies has been shown to have major long as 30 years after treatment. Breast cancer is increased in women
prognostic power in patients with cHL. Together, these findings treated before age 30 years and is markedly increased in children and
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