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CHAPTER 98 trial testing whether a novel infusional regimen consisting of dose-adjusted

DIFFUSE LARGE B-CELL rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxoru-
bicin (DA-R-EPOCH) is superior to standard R-CHOP has been completed, but
LYMPHOMA AND RELATED the results not yet reported as of this writing. High-dose chemotherapy with
autologous stem cell transplantation may be curative for patients with DLBCL
DISEASES that relapses after treatment with frontline chemotherapy.

Stephen D. Smith and Oliver W. Press* DEFINITION AND HISTORY

Diffuse large B-cell lymphomas (DLBCLs) comprise a heterogeneous
group of aggressive malignancies of large, transformed B cells which
SUMMARY cause diffuse effacement of the normal lymph node structure. DLBCL
has masqueraded under a variety of colorful but misleading monikers
Diffuse large B-cell lymphomas (DLBCLs) comprise a heterogeneous group of in early lymphoma classification systems, including “reticulum cell sar-
aggressive malignancies of large, transformed B lymphocytes. DLBCL is the coma,” and “diffuse histiocytic lymphoma,” as described in an excellent
most common lymphoma in the world and accounts for approximately 25 to recent review of the history of the lymphomas. Distinct disease enti-
1
30 percent of lymphoma cases in the United States. The incidence increases ties are distinguished based on morphologic, biologic, and clinical fea-
with age, with a median age at presentation in the sixth decade. The disease tures as established by an international panel of experts on behalf of the
2
typically presents as a rapidly growing mass that may involve either lymph World Health Organization (WHO, Table 98–1). The disease can arise
node or extranodal sites, and often is associated with systemic symptoms. de novo or may transform from an indolent lymphoma, such as small
lymphocytic lymphoma or follicular lymphoma.
Approximately 50 to 60 percent of patients will present with advanced stage,
disseminated disease. DLBCL is curable with combination chemotherapy. For
localized disease, either three cycles of rituximab, cyclophosphamide, doxo- EPIDEMIOLOGY
rubicin, vincristine, and prednisone (R-CHOP) plus involved-field radiation DLBCL is the most common B-cell lymphoid neoplasm in the United
therapy or six cycles of (R-CHOP) is recommended, whereas for advanced States and Europe and accounts for approximately 28 percent of all mature
stage DLBCL, six cycles of R-CHOP is appropriate. A large phase III intergroup B-cell lymphomas. Incidence varies by ethnicity, with Americans of
3,4
European descent being more likely to develop DLBCL than Americans
of African descent. Like most other lymphomas, there is a male pre-
dominance. The disease most commonly presents in late middle-aged
and older persons with a median age at diagnosis of approximately 65
years. Because lymphoma incidence rates increased dramatically from
Acronyms and Abbreviations: ABC, activated B-cell–like; ACVBP, doxorubicin the 1940s to the 1990s, numerous exogenous factors have been exam-
(Adriamycin), cyclophosphamide, vindesine, bleomycin, prednisone; allo-HSCT, ined to ascertain if one or more play a role in pathogenesis of the disease,
allogeneic hematopoietic stem cell transplantation; ASCT, autologous stem cell including herbicides (e.g., phenoxyacids), pesticides (e.g., organochlo-
transplantation; BEAM, high-dose carmustine, etoposide, cytarabine, and melpha- rines), organic solvents (e.g., toluene, benzene), dark hair dyes, body
lan; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete mass index, tobacco use, alcohol use, and inflammatory states. At this
remission; CytaBOM, cytarabine, bleomycin, vincristine, methotrexate (with leu- time, no inhalant, exposure, or ingestant has been unequivocally proven
covorin rescue); DFS, disease-free survival; DLBCL, diffuse large B-cell lymphoma; to increase the relative risk of DLBCL. 5
EBV, Epstein-Barr virus; EFS, event-free survival; EPOCH, etoposide, prednisone,
vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, methylprednisolone,
cytarabine, cisplatin; FDG, 18-fluorodeoxyglucose; GCB, germinal center B-cell–like; ETIOLOGY AND PATHOGENESIS
GELA, Group d’Etude des Lymphomes de l’Adulte; GVHD, graft-versus-host disease; DLBCL is a molecularly heterogeneous disease with multiple complex
ICE, ifosfamide, carboplatin, etoposide; IFRT, involved-field radiation therapy; Ig, chromosomal translocations and genetic abnormalities as identified by
immunoglobulin; LDH, lactate dehydrogenase; MACOP-B, high-dose methotrexate, cytogenetics, gene expression profiling, and whole-genome sequenc-
doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; m-BACOD, mod- ing. The disease is derived from B cells whose immunoglobulin (Ig)
erate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, genes have undergone somatic mutation in the lymph node germinal
dexamethasone; MOPP, mechlorethamine, vincristine, procarbazine, prednisone; OS, center. Approximately 40 percent of cases in immunocompetent hosts
6
overall survival; PFS, progression-free survival; ProMACE, prednisone, methotrexate, and approximately 20 percent of HIV-related cases display BCL6 rear-
doxorubicin, cyclophosphamide, etoposide; PTLD, posttransplantation lymphopro- rangements. Chromosomal translocations involving band 3q27 lead
7–9
liferative disorder; R-CHOP, rituximab plus CHOP; R-EPOCH, rituximab plus EPOCH; to a truncated BCL6 gene within its 5′ flanking region. Such trunca-
R-ICE, rituximab plus ICE; VACOP-B, vincristine, doxorubicin, cyclophosphamide, tions commonly occur within the first exon or first intron, leading to
etoposide, prednisone, and bleomycin; WHO, World Health Organization. complete removal or truncation of the promoter sequences; the coding
sequence is left intact. In a small number of cases, the breakpoint is
10
not located in the immediate proximity of the BCL6 gene. Increased
* This chapter contains elements from the chapter in the 8th edition of Williams expression of BCL6 occurs from a process termed promoter substitution
Hematology written by Michael Boyiadzis and Kenneth A. Foon. by which heterologous promoters are juxtaposed to the BCL6 coding

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