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Overview of Prognostic Factors in Non-Hodgkin’s Lymphoma

Overview of Prognostic Factors in Non-Hodgkin’s Lymphoma

ABSTRACT: The non-Hodgkin’s lymphomas are a biologically heterogeneous group of diseases with varying clinical presentations and outcomes. A number of studies have identified variables that carried independent prognostic significance. Although several staging systems had evolved that incorporated these prognostic variables, they were still unable to predict outcome. Ideally, the object of a staging system is to predict the likelihood of treatment response, time to progression or disease-free survival, and overall survival, and to provide a way to compare the outcome of similar groups of patients among various clinical trials. The need for such a system led to the creation of prognostic models such as the M. D. Anderson Tumor Score and, more recently, the International Prognostic Index. These prognostic models may identify those patients at highest risk for treatment failure, thereby identifying those patients who may require different therapeutic approaches. [ONCOLOGY 12(Suppl 8):17-24, 1998]

Introduction

There are many clinically important prognostic factors in
non-Hodgkin’s lymphoma, though only a few have consistently been
shown to correlate with prognosis and outcome in multivariate
analyses. These prognostic parameters (Table
1
) have been incorporated into various proposed staging systems,
such as the M. D. Anderson Tumor Score and the International
Prognostic Index (IPI).[1,2] Unlike in Hodgkin’s disease, the
Ann Arbor staging system is of limited use in predicting outcome in
patients with non-Hodgkin’s lymphoma, primarily due to its
inability to estimate tumor burden. The Ann Arbor staging system
becomes more useful when used in combination with other parameters
that estimate tumor burden and which might also reflect, directly or
indirectly, the tumor’s biologic features.

Surrogate parameters for tumor burden include an elevated
beta-2-microglobulin (ß2M), bulky disease, and the number of
extranodal sites .[3-5] Bulky disease in the M. D. Anderson Tumor
Score System is defined as any peripheral lymph node or mass ³
7 cm, a T3 or T4 lesion (by the TNM system) in the sinus cavity or
nasopharynx, or > two-thirds infiltration of the stomach, liver,
or other extranodal sites that are difficult to measure. Such
estimates of tumor burden, when combined with serum lactic
dehydrogenase (LDH) levels and used as a prognostic model, have
proven useful in predicting 5-year survival. For example, patients
with poor-risk disease as defined by extensive nodal and/or
extranodal disease and elevated LDH levels had a 5-year survival of
20%, in comparison with 87% for those good-risk patients with less
extensive disease and normal LDH levels.[5]

Beta-2-microglobulin seems to correlate with tumor burden as well,
and is an independently significant and easily measured prognostic
parameter.[5] The ß2M level has been used together with LDH to
identify patients with a poor prognosis; in combination with an
elevated serum LDH, an elevated ß2M correlates with an inferior
time to treatment failure and survival among patients with aggressive
non-Hodgkin’s lymphoma, regardless of Ann Arbor stage.[6]

Swan et al correlated these variables to identify a distinct
high-risk group of patients with large-cell lymphoma whose 2-year
survival was 19% compared with a 2-year survival of 100% in a
low-risk group of patients.[6] In this system, an intermediate
prognostic category was observed and consisted of cases with either
ß2M or LDH elevation, but not both. This intermediate category
is considered undesirable for treatment planning because it is much
easier to design or select treatment for patients with either a very
favorable or a very unfavorable prognosis, but is more difficult for
patients with an intermediate prognosis. The former could be treated
with conventional regimens whereas the unfavorable group could be
entered on experimental programs.

Estimates of tumor burden have proven to be significant in
multivariate analyses and have found their way into some of the more
recent staging systems. Ann Arbor stage, an increased ß2M and
LDH, the presence of constitutional “B” symptoms and bulky
disease were incorporated into a staging system known as the M. D.
Anderson Tumor Score.[7] One point is assigned for each adverse
prognostic feature with the sum representing a “tumor
score.” An estimate of tumor burden, the tumor score, correlates
with response rates (Table 2).

In a study of 144 patients who were uniformly treated with the CHOP
regimen (cyclophosphamide [Cytoxan, Neosar], doxorubicin
[Adriamycin], vincristine [Oncovin], and prednisone), those patients
with a tumor score of 0 to 2 had a time to treatment failure rate of
83% compared to 24% for those patients with a tumor score of 3 or
more.[7] This system incorporated tumor-dependent variables that had
been found to be significant in multivariate analyses, were easily
reproducible, and correlated with outcome. A major advantage of this
system is the definition of only two prognostic categories with no
intermediate categories.

Coiffier et al prospectively applied several of these prognostic
systems from various single institutions to patients receiving the
LNH-84 regimen and identified groups of good- and poor-risk patients.
(The LNH-84 regimen includes doxorubicin, cyclophosphamide, vindesine
[Eldisone, Enisone], bleomycin [Blenoxane], prednisone, and
methotrexate.) Although the ability of each system to predict
prognosis was roughly equivalent, a commonly accepted definition of
tumor burden remained elusive.[8] Serum LDH levels and Ann Arbor
stage remained the most important variables, although ß2M was
not included as a variable. Coiffier then proposed a prognostic index
based on LDH and three measurements of tumor burden (tumor size, the
number of extranodal sites, and Ann Arbor stage). Other prognostic
variables such as serum albumin levels and bone marrow involvement
did not seem to add to the prognostic capability beyond the
aforementioned variables.[9]

The International Non-Hodgkin’s Lymphoma Prognostic Factors
Project also reviewed pretreatment clinical prognostic factors in
order to develop a system that might correlate with future outcome
for newly diagnosed patients with non-Hodgkin’s lymphoma. The
resulting International Prognostic Index (IPI) has proven to be
particularly useful in predicting outcome, and is widely used. Both
prospective and retrospective analyses of other data have confirmed
the utility of this prognostic model.[10]

The IPI incorporates advanced age (defined as greater than 60 years
old), advanced stage (Ann Arbor III or IV), elevated LDH, poor
performance status, and greater than one extranodal disease site. For
example, patients with only one or fewer adverse prognostic features
are classified as being low risk, with a complete response rate of
87%, and a 5-year overall survival rate of 73%. Patients with
low-intermediate and high-intermediate risk have complete response
rates of 67% and 55%, and 5-year survival rates of 51% and 43%,
respectively. Patients with high risk disease have a projected
complete response rate of only 44%, with a 5-year survival rate of
26%. Variations of the IPI scale, such as an age-adjusted IPI score,
have also been found to be quite sensitive.[2]

The IPI has proven useful in predicting outcome in patients with both
aggressive and low-grade lymphoma and has even proven to be useful
among patients with mantle cell lymphoma.[11] Both the M.D. Anderson
tumor score and the IPI are shown in Table
2
and Table 3 along with
projected response rates and survival estimates. The only drawback of
the IPI is the fact that there are a large number of cases that fit
into the intermediate risk categories, making treatment selection problematic.

Other Relevant Prognostic Factors

Bone Marrow and Central Nervous System Involvement

Patients with lymphoma involving the bone marrow, testes, or
those with a lymphoblastic or Burkitt’s lymphoma are at greatest
risk for central nervous system (CNS) involvement. Given the poor
prognosis of CNS or lepto-meningeal lymphoma, it is important to
search for central nervous system involvement in such patients at
presentation and to incorporate CNS prophylaxis into the treatment
plan whenever indicated. Similarly, bone marrow involvement is
considered to be an adverse feature and may occur in approximately
10% of all patients with histologically aggressive non-Hodgkin’s
lymphoma at the initial staging evaluation. While bone marrow
involvement has been shown to be prognostically important, it does
not significantly add to the utility of existing prognostic models
such as the IPI, and is therefore not generally included.

The presence of divergent histology in the marrow is an interesting
phenomenon with prognostic ramifications.[12] Robertson et al
described 50 patients with diffuse large-cell lymphoma of lymph nodes
and evidence of bone marrow involvement. Forty-eight percent had
large-cell lymphoma, 38% had small cleaved-cell lymphoma, and 14% had
mixed histology in the marrow. Those with large-cell lymphoma in the
bone marrow had a low complete remission rate (16.7%), a high risk of
CNS involvement (33%), and a poor 5-year overall survival (12%).
Those with small-cleaved-cell lymphoma in the bone marrow had a
higher complete remission rate (89.4%), a lower rate of CNS
involvement (5%), and a better 5-year survival rate (79%). However,
those patients with small-cleaved-cell lymphoma in the marrow had a
continuous rate of relapse with a progression-free survival of only
30% at 5 years and 15% at 8 years, reminiscent of the situation with
indolent non-Hodgkin’s lymphoma.[12]

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