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Chapter 82 Diagnosis and Treatment of Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma 1311

TABLE Staging Evaluation for Diffuse Large B-Cell Lymphoma TABLE Ann Arbor Staging System for Lymphomas
82.2 82.3
All Patients As Clinically Indicated Stage a Cotswold Modification of Arbor Classification
History and physical examination Other viral studies I Involvement of a single LN region or lymphoid structure
CBC and chemistry (including LDH) CT or MRI of the head II Involvement of two or more LN regions on the same side of
HIV and hepatitis B and C serology Body PET scan the diaphragm (the mediastinum is considered a single site,
but the hilar LNs are considered bilaterally); the number of
Chest radiograph Additional imaging
atomic sites should be indicated by a subscript (e.g., II 3 )
CT scan of the chest, abdomen, CSF evaluation by cytology or III Involvement of LN regions on both sides of the diaphragm:
and pelvis flow cytometry
III 1 (with or without involvement of splenic hilar, celiac, or
BM aspirate and biopsy Other tests indicated by results portal nodes) and III 2 (with involvement of paraaortic, iliac,
of staging and mesenteric nodes
BM, Bone marrow; CBC, complete blood count; CSF, cerebrospinal fluid; CT, IV Involvement of one or more extranodal sites in addition to a
computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance site for which the designation E has been used
imaging; PET, positron emission tomography.
a All cases are subclassified to indicate the absence (A) or presence (B) of the
systemic symptoms of significant fever (>38.0°C [100.4°F]), night sweats, and
unexplained weight loss exceeding 10% of normal body weight within the
Intrathecal Prophylaxis in Diffuse Large B-Cell Lymphoma previous 6 months. The clinical stage (CS) denotes the stage as determined by
all diagnostic examinations and a single diagnostic biopsy only. In the Ann
Arbor classification, the term pathologic stage (PS) is used if a second biopsy of
In DLBCL, the role of intrathecal prophylaxis to prevent CNS recurrence any kind has been obtained, whether the result was negative or positive. In the
is controversial and poorly studied, and there are several different Cotswold modification, the PS is determined by laparotomy; X designates bulky
approaches. Our approach is as follows. All patients at risk for CNS disease (widening of the mediastinum by more than one-third or the presence
disease undergo a lumbar puncture at diagnosis, and CSF is checked of a nodal mass >10 cm), and E designates involvement of a single extranodal
by cytology and flow cytometry; if the results are positive, patients site that is contiguous or proximal to the known nodal site.
receive active treatment of the CNS. We administer intrathecal prophy- LN, Lymph node.
laxis to all patients who fulfill either of the following criteria:
1. Two or more extranodal sites of disease involvement and an
elevated LDH level.
2. Certain extranodal sites of involvement that have been associated
with an increased risk of CNS spread such as BM and testis. TABLE Revised International Prognostic Index (R-IPI) a
We use intrathecal methotrexate at a dose of 12 mg. We commence 82.4
prophylaxis on cycle 3 day 1 and administer it on days 1 and 5 of No. of IPI Factors IPI Score Outcome Overall Survival (%)
cycles 3 through 6.
0 0 Very good 94
1–2 1–2 Good 79
sites such as the testis and BM are associated with an increased risk 3, 4, or 5 3–5 Poor 55
of CNS disease, and intrathecal prophylaxis should be considered a One point is given for the presence of each of the following characteristics: age
(see box on Intrathecal Prophylaxis in Diffuse Large B-Cell older than 60 years, elevated serum LDH level, ECOG performance status ≥2,
Lymphoma). Ann Arbor stage III or IV, and more than two extranodal sites.
DLBCL is staged according to the Ann Arbor staging system (Table ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index;
82.3), which was originally developed for Hodgkin lymphoma (HL). LDH, lactate dehydrogenase
From Sehn LH, Berry B, Chhanabhai M, et al: The revised International
However, because of the heterogeneity and hematogenous pattern of Prognostic Index is a better predictor of outcome than the standard IPI for
dissemination in NHL, in contrast to contiguous LN spread with HL, patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood
the staging system has more limited value. At the same time, important 109:1857, 2007.
modifications to the Ann Arbor staging system made at the Cotswold
Conference have made it more applicable to NHL. 5

DLBCL, overall survival is different in each group and in many
Prognosis studies superior in patients with the GCB compared with the ABC
subtype. Using gene expression profiling, a molecular prognostic
To identify prognostic factors in NHL, an international project to model of survival, independent of the IPI, has been developed for
correlate clinical variables and outcome in 2031 patients with R-CHOP–treated DLBCL. In routine clinical practice, it has not
untreated aggressive lymphoma was undertaken. The following been feasible to perform gene expression profiling and immunohis-
parameters were associated with inferior outcome: age older than 60 tochemistry algorithms to predict cell of origin have been used up
years, Ann Arbor stage III or IV disease, serum LDH level above until now. While these have been somewhat helpful, they have
normal range, Eastern Co-operative Oncology Group (ECOG) per- demonstrated varying degrees of concordance with microarray results,
formance status of two or higher, and involvement of two or more limiting their usefulness. Therefore novel assays to more accurately
extranodal sites. A clinical prognostic model, termed the International predict cell of origin are needed and in that regard, the recent 20-gene
Prognostic Index (IPI), was developed using these five factors. In this predictor assay developed by the Lymphoma and Leukemia Molecular
model, one point was allocated for each feature and nicely stratified Profiling Project (LLMPP) is promising and potentially widely
patients into four groups with 5-year survivals of 73%, 51%, 43%, applicable (Fig. 82.4).
and 26% for zero or one, two, three, and four or five risk factors, This increased understanding of the heterogeneous biology of
respectively, with CHOP-based treatment. Based on this model, the DLBCL has led to the investigation of strategies and novel agents
IPI has become the standard in DLBCL for assessing clinical prog- that have selective activity within molecular subtypes and sets the
nosis and treatment stratification within and comparison between stage for an era of precision medicine in DLBCL therapeutics, where
5
clinical trials. Recently, a revised prognostic model for R-CHOP, therapy can be ascribed based on molecular phenotype. This offers
termed Revised-IPI, was published (Table 82.4). 6 the chance of improving the curability of DLBCL, particularly in the
Although not yet routinely performed in aggressive NHL, gene activated B-cell subtype where standard approaches are inadequate
expression profiling is emerging as an important prognostic tool. In for the majority of patients.