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REVIEW ARTICLE
Prognostic Factorsin Aggressive Non-Hodgkin’sLymphoma:
Who Has “High-Risk” Disease?
By Margaret A . Shipp
to the Ann Arbor
MBINATION CHEMOTHERAPY has transformed ized and advanced stage disease according
classification (Table 1).L2-28Theseclinicalcharacteristics
aggressive non-Hodgkin’s lymphoma (NHL) from a
were thought to reflect three basic features:(1) the tumor’s
fatal diseaseto one that is now often curable.
I Complete response rates of
60%to 80%and predicted 5-year survivals of growth and invasive potential (lactate dehydrogenase [LDH],
stage, masssize, number of nodal and extranodal sites ofdisgreater than 55% have been obtained with
current regimens
e
a
s
e
, bone marrow [BM] involvement); (2) the patient’s rein
pilot
single-institution
However,
many
of
these
sponse to the tumor (performance status, B symptoms); and
regimens(MACOP-B,m-BACOD,ProMace-CytaBOM)
(3) the patient’s ability to tolerate intensive therapy (perforproved to be no more effective than standarddose CHOP in
mance status,BM involvement, age) (Table1).
recent randomized cooperative group
~ t u d i e s ,raising
~ , ~ the
disappointing possibility
that the favorable pilot results were The prognostic significanceof age deserves special mention. As expected, age at diagnosis was more commonly
caused in part by patient selection. This dilemma has refoidentified as a prognostic factor in studies
that included large
cused our attention on the need to compare treatment reginumbers of older patients.’8.22.24.26.27,29~31
In an early Southmens in comparablepatient subgroups and to identify pawest Oncology Group Trial, elderly patients who received
tients with different long-term prognoses to individualize
automatic dose reductions becauseof age had significantly
therapy.
lower complete response ratesthan elderly patients who reThe identification of “high-” or “low-risk” patients with
aggressive NHL would haveimportant therapeutic implica- ceived fulldose therapy.29 In a subsequent Nebraska Lymphoma Group trial, elderly patients treated with full-dose
tions. “High-risk” patients who are not effectively treated
therapy had complete response rates and therapy-related
with current regimens are most likely to benefit from new
toxicities that were comparable with those of younger paexperimental approaches whereas“low-risk’’ patients may
tients; however, fewer elderly patients survived 5 years bedo well withstandard therapy and incur substantialtoxicity
cause this group had an increased incidence of death beif they are treated with experimental regimens.
As noted, the
of elderly
identification of different patient risk groups will alsoaid in causeofunrelatedcauses.3oAdditionalseries
patients from Canadaand Denmark had higher death rates
the design and interpretation of therapeutic trials.
caused by both the lymphoma itself and the toxicity of the
This review summarizes recent efforts to develop cliniadministered ~hemotherapy.*~*”
These studies highlight
the
cally based pretreatment prognostic factor modelsto identendency to treat elderly patients withlower doses of chetify patients with aggressive NHL who have different risks
for death from their disease. Treatment-related prognostic motherapy to reduce treatment-related toxicity while emphasizing the fact that older patients benefit from full-dose
factors will also be discussed. In addition, the review will
therapy.
highlight more recently described cellular and molecular
features that may be directly associated with the biologic
DEVELOPMENT OF APREDICTIVE MODEL BASED ON
heterogeneity of aggressive NHL.
c“
CLINICALPRETREATMENTPROGNOSTICFACTORS
IDENTIFICATION OFCLINICALPROGNOSTIC
FACTORS
Early prognostic factor models. Manyinvestigators
have identified the clinical pretreatment variables associated with survivalin univariate analysesof their own series
of patients with aggressiveNHL.’2-28 Features
that retained
independent significance in multivariate analyses of survival were often used to develop prognostic factor models
node
Currently, patients with aggressive NHL are staged with
the Ann Arbor classificationthat was originally developed
for Hodgkin’s disease.” This classification schemaemphasizes the distribution of nodal disease sites because Hodgkin’s disease commonly spreads via contiguous lymph
groups.lo Because the patterns of disease spread in Hodgkin’s and NHL are somewhat different, it is not surprising
From the Department
ofMedicine. Dana Farber Cancer
Institute
that the Ann Arbor classification is less accurate in idenand Harvard Medical School, Boston,
MA.
Submitted August 31, 1993; accepted November23, 1993.
tifyingprognosticsubgroups of patients withaggressive
Supported in part by an American Cancer
Society Junior Faculty
NHL.” For this reason, investigators have attempted to
Award.
identify clinical prognostic factors
that would formthe basis
Address reprint requests to Margaret A . Shipp, MD, Department
of a new classification for aggressive NHL that would be
o
f
Medicine, Dana Farber Cancer Institute and Harvard Medical
more reflective ofthe unique biology ofthis disease.
School, 44 BinneySt, Boston, MA 02115.
In previous analyses of relatively small numbers of paThe publication costsof this article weredejiayed in part by page
tients with aggressive NHL, a varietyof pretreatment clinicharge payment. This article musttherefore be hereby marked
cal characteristics were consistently associated with sur“advertisement” in accordance with18 U.S.C.section I734 solelyto
vival: ageat diagnosis; systemic (B) symptoms; performance indicate thisfact.
status; serum LDH; number of nodal and extranodal sites
0 I994 by TheAmerican Society ofHematology.
of disease; tumor bulk; and the distinction between local0006-4971/94/8305-0033$3.00/0
B/&,
Vol83, No 5 (March l), 1994:pp 1 165-1173
1165
rformance
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1166
MARGARET A. SHlPP
Table 1. Association Between Host/Tumor Characteristics and
Clinical Prognostic Features
in Aggressive NHL
relative risk (low-risk [L], low-intermediate [L-l], high-intermediate [H-I], or high [H] risk) were identified (Table
333).
HostITurnorCharacteristlcs
Clinical ProanostE Factors
In 2,03 l patients of all ages,a model (International Index)
Tumor’s growth and invasive potential SerumLDH
based
on age, stage, serum LDH, performance status, and
No. of nodaland extranodal
number of extranodal disease sites identified four risk
sites of disease
groups with predicted 5-year survivals of 73%, 51%, 43%,
Mass size
Stage according to Ann Arbor
and 26%,respectively (Tables 2 and 3A).33 Becauseyounger
classification
and older patients had significantly different outcomes and
BM involvement
patients 260 years were more likely to be candidates for intensive experimental regimens, an age-adjusted model for
Patient’s response to the tumor
Systemic B symptoms
patients 560 years of age (age-adjusted International Index)
Performancestatus
was also de~eloped.’~
In 1,274 younger patients, the clinical
Patient‘s ability to tolerate intensive
Age at diagnosis
features that were independently associated with survival intherapy
cluded stage, LDH, and performance status (Table 2). An
BM involvement
age-adjusted model based on these three features (Table 2 )
identified four risk groups of patients 260 years of age with
predicted 5-year survivals of 83%, 69%, 46%,and 32% (Tapredictive for an individual patient’s risk for death.19-22,24-27 ble 3B).”
Although the specific clinical features used in these prognosTo determine whether younger patients had better outtic factor models differed, all models incorporated paramecomes because they presented with less extensive disease,
ters of disease volume and extent of tumor involvement at
the clinical characteristics of patients I and >60 years of age
presentation. For example, an early prognostic factor model
were compared (Table4). Equal percentages of younger and
in patients treated with either M- or m-BACOD was based
olderpatients
presented with advanced stage disease,
on pretreatment performance status, largest mass size, and
multiple extranodal sites of involvement, elevated serum
’~
early progLDH, and nonambulatory performance status (Table 4),
number of extranodal sites ~ f d i s e a s e .Another
nostic factor model in patients treated with CHOP-bleo
suggesting that the disease at diagnosis was similar in the
used “tumor burden” (the number of extranodal and extentwo age groups.
sive nodal sites of disease) and serum LDH.20 A similar
To more specifically compare outcomes in younger and
prognostic factor model in patients treated with the LNHolder patients, patients older than 60 years were also ana84 regimen incorporated tumor size, numbers of extranodal
lyzed according to theage-adjusted International Index (Tasites of disease, collapsed Ann Arbor stage, and serum
ble 3C). Similar numbers of younger and older patients fell
into each of the four risk groups (Table 3, B and C). AlLDH.” In each model, an individual patient’s risk was rethough patients older than 60 years of agehad complete related to the numberof adverse factors present at diagnosis.
The above-mentioned models were similarly predictive for
sponse (CR) rates that were similar or only slightly lower
than those of patients 560 years, the older patients were
outcome in a large series of uniformly treated patients, suggesting that the models used slightly different parameters to
identify similar patient subgroups.32
Table 2. Prognostic Factors for Survival
in
The International Index. To develop a widely accepted
International Index Patients
prognostic factor model for patients with aggressive NHL,
Relative Risk
PValue
16 single institutions and cooperative groups in the United
States, Europe, and Canadarecently participated in the InA. Patients of all ages
ternational Non-Hodgkin’s Lymphoma Prognostic Factors
Age ( ~ 6years
0 v >60 years)
1.96
<.001
Project.33In this project, patients with aggressive NHL who
1.00
1.85
1
LDH (snl v >nl)
Performance status (0.
1 v 2-4)
1 .80
<.001
were treated with a doxorubicin-containing combination
1.001
1.47
Stage (l/llv III/IV)
chemotherapy regimen between 1982 and 1987 wereevaluExtranodal involvement
ated for pretreatment clinical features predictive for overall
(<l site v z 1 site)
1.48
<.001
survival and relapse-free survival. Clinical features that were
B. Patients s60 yrs of age
independently associated with survival included age, LDH,
2.17
<.001
Stage (l/ll v III/IV)
performance status, stage, and number ofextranodal disease
<.001
1.95
LDH (snl v >nl)
sites (Table 2). These features were incorporated into a
1.81
1.001
Performance status (0.1 v 2-4)
model that identified groups of patients with different risks
The subset of factors that retained independent prognosticsignififor death (Table 3).33Because the relative risk associated
cance for overall survival in International Index
patients of all ages (A) and
with each of the clinical features was comparable (Table 2),
patients I60 years of age (B) are shown. The only factor that retained
an individual patient’s relative risk for death was deterindependent prognostic significancein patients of all ages (A) but not in
mined by adding the number of adverse prognostic factors
patients I60 years of age (B) was the number of extranodal sites of
present at diagnosis (Table 3). The relative risk for death in
disease (patients 5 60years of age: s 1 site v > 1 site, relative risk 1.20.
patients with each possible number of adverse prognostic
P = .134).
Abbreviation: nl, normal.
factors was determined and groups of patients with similar
~~
~
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ORS
PROGNOSTIC
Table 3. Development of a PrognosticFactor Model:The International index and Age-Adjusted index
Survival (%)
RFS OF CRs (%)
Risk Group
Risk
Distribution
Factors
of Cases (%)
A. International Index (patients of all ages)
0.1
Low
2
Low-intermediate (LI)
22
3
High-intermediate
(HI)
4.5
High (H) 16
(L)
79
35
27
CR .
Rate (%)
2-yr
2-yr
Rate
5-yr
Rate Rate
5-yr
Rate
87
67
43
55
44
66
54
59
58
70
50
49
40
84
66
73
51
34
26
92
78
69
46
57
32
46
88
79
59
62
37
86
66
53
58
90
83
80
71
56
36
68
64
60
45
41
21 37
56
44
37
B. Age-Adjusted Index Appliedto Patients S 60 yrs of Age
(L)
L)
1167
Low
Low-intermediate (LI)
High-intermediate (HI)
High 14
(H)
46
0
l
2
3
22
74
32
32
61
C. Age-Adjusted Index Appliedto Patients> 60 yrs of Age
75
910
18
Low
Low-intermediate (LI)
35
High-intermediate
(HI)
High 16
(H)
1
2
3
31
47
48
31
Adapted from information appearing The
in New EnglandJo~rnalofMedicine.3~
lapse
from
CR
were
also
ide~~tified.’~
As in earlier
much lesslikely to maintain their completeremissions
age were the feas t ~ d i e s ~stage,
~ - serum
~ ~ ~LDH,
~ ~ ,and
~ ~
(compare RFS of CRs, Table3, B and C).33The age-related
tures most closely correlated with the durability of CR.33
differences in relapse rates, which were most striking in lowEach ofthe clinical features associated
with an increased risk
and low-intermediate-risk patients (Table 3, B and C),
for relapse from CR was also associated with a decreased
translated into significant age-related differences
in survival
likelihood of achieving an initial remission,33 suggesting
1). In contrast, high-intermediatein these risk groups (Fig
that the achievement and durability of a CRare related paand high-risk patients Iand >60 years of age had more
rameters that should be considered together in approaches
1).
comparable long-term survivals (Fig
to “high-risk” patients.
The previously described correlation between outcome
and chemotherapy
elderly
in
dose
prompts
Although the International Index and earlier prognostic
speculation that certain patients older than 60 years of age
factor models were specifically developed to predict outmay have had less durable CRs because they received less come in patients with aggressive NHL, such models may
intensive treatment. In addition, older patients may have
also be usefulin lymphoma patients with more indolent hishad blunted host immune responses to their disease. As we
tologies. For example, the model developed by Coiffier et
also predicted survival in a smaller series of follicular
reduce the toxicity of chemotherapy with hematopoietic
lymphoma patientq3*and the International Index predicted
growth factors, prophylactic antibiotics, and platelet support, it will be easier to treat older patients with full-dose
survival in a larger series of similarpatients (Fig 239).Furregimens and to explore additional approachesto maintainthermore, the International Index also predicted survival
ing CRs in
this age group.
and relapse from CR in a recently described series of paIn both the International Index and the age-adjusted intients with low-grade (small lymphocytic, follicular small
dex, the increased risk for death resulted from both a lower cleaved, and follicular mixed) lymphoma.@
CR rate and a higher rate of relapse from CR (Table 3).33
TREATMENT-RELATED PROGNOSTIC FACTORS
Because patients with an increased risk of relapse might be
It is important to distinguish pretreatment clinical feacandidates for intensive experimental “consolidation”
thertures that can be used to determine upfront therapy from
cell or autologous BM s u p
apy with peripheral blood stem
parameters that are more directly associated with response
the pretreatment clinical features predictive refor
to treatment. Although treatment-related parameters caninduction therapy,
not be used to guide decisions regarding
they provide important prognostic information regarding
Table 4. Clinical Characteristics of Patients s
the chemosensitivityof an individual patient’s disease.
and >60 Years of Age
Time to CR. In 1986, Armitageet a14’ identified the
s60 yrs (%)
r60 yrs (%)
time required to achieve CR as an important prognostic
64
68
Advanced stage(lll/lV)
variable in aggressive NHL. In their series, only40% of paElevated serum LDH
39
41
tients who required morethan 5 cycles ofstandard therapy
19
19
Non-ambulatory performance status
(2-4)
to achieve CR remained disease free whereas 80% of pa> 1 Extranodal disease site
30
30
tients who needed 1 3 cycles of therapy to achieve CR re-
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1168
MARGARET A . SHIPP
Fig 1. Overallsurvival of younger ( ~ 6 years)
0
andolder (>60 years) patients according to the
(A) Low
(L)-risk
age-adjusted International
patients; (B) low-intermediate (L-l)-risk patients;
(C) high-intermediate (H-l)-risk patients; (D) high
(H)-risk patients.
mained disease free at 2 years.41Engelhard et aI4’ subsequently identified timetoCR
asthe most important
prognostic determinant of overall survival in their series of
548 patients with aggressive NHL. These data clearly correlate rapid responses with more favorable outcome^.^^^^'
However, it is difficult to evaluate time to CRusing standard radiographic techniques because patients with bulky
tumors frequently have residual abnormalities of uncertain
significance on plain films and CT/MRIscans. For thisreason, Kaplan et a143used gallium-67 citrate (Ga-67) imaging
to distinguish between residual viable tumor andscar tissue
and toassess early responses to therapy in patients with aggressive NHL. Patients with gallium-avid tumors were reevaluated after 4 to 6 cycles oftherapy and at completion
the
of their regimen.43Only 24% of the patients who had persistent gallium uptake midtreatment achieved long-term responses, whereas 70% of patients who were gallium-negative
80
0
I 1 L
I
1
I
4
I
l
I
1
8
I
12
I
after 4 to 6 cycles maintained durableC R S . In
~ ~more recent
studies in which “high-risk” patients with aggressive NHL
were imaged with Ga-67 after 2 of 4 planned cycles of highdose induction therapy, patients with negative postcycle 2
gallium scans were significantly more likely to have durable
complete remission^.^^ Our own experience suggests that
gallium scans provide the most useful information when
they are performed with “double dose” (8 to 10 mCi) radioisotope and 72- to 96-hour views and interpreted in conjunction with standard radiographic studies by a committed
radi~logist.~~
Doseintensityand
schedule. As noted, early studies
highlighted significant differences in survival rates of elderly
patients who were treated with “full-dose’’ or “dose-reduced” induction therapy.29.30The doses of cyclophosphamide and doxorubicin administered inthe first 12 weeks of
therapy were also the factors most closely associated with
survival in 1 15 patients with aggressive NHL treated with
CHOP, M-BACOD, or MACOP-B at Stanford U n i v e r ~ i t y . ~ ~
Similar patients who received reduced doses of cyclophosphamide on the LNH-84 regimen also had decreased CR
rates and increased rates of relapse from CR.’ These data
suggest that there may be a minimum dose of therapy required to achieve optimal results in aggressive NHL and
that certain patients may benefit from dose escalation of the
most active drugs in thisdisease.44
In additional ongoing studies, Wilson etSparanoet
and others are evaluating whether a change from a bolus to infusional schedule of administration reduces the development of resistance to several of the agents commonly
used to treat aggressive NHL.
I
16
Years
Fig 2. The age-adjusted International Index also predicts overall
survival inpatientswith follicular lymphoma.The predicted survival
of 148 follicular lymphomapatients stratified accordingto the ageadjusted International Index is shown.= Risk groups
are defined as
3, low (L), low-intermediate(L-l), high-intermediindicated in Table
ate (H-l), and high(H).
CELLULAR AND MOLECULARFEATURESASSOCIATED
WITH PROGNOSIS IN AGGRESSIVE LYMPHOMA
It is important to recognize that the clinical features incorporated into predictive models in aggressive NHL are, in
part, surrogate variables for the biologic heterogeneity of
this disease. For example, it is the biologic features associated with having an elevated serum LDH rather than the
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1169
PROGNOSTICFACTORSINAGGRESSIVENHL
elevated LDH itself that adversely affects a patient’s outcome. In recent years, cellular and molecular features including tumor cell proliferation, immunophenotype, adhesion molecule expression, and karyotypic abnormalities
have been linked to survival in aggressive NHL.
Tumor cell prolifeation. Several methods including
flow cytometric DNA assessment4*and tritiated thymidine
uptake49have been used to evaluate tumor cell proliferation
and to correlate this parameter with long-term survival in
patients with aggressive NHL. Tumorcell proliferation has
also been evaluated in aggressive NHL using the nuclear
proliferation antigen, Ki-67.50In patient groups that were
similar in age, stage, tumor burden, LDH, therapy, and CR
rate, the percentage of Ki-67+ cells was closely correlated
with median survival (>60% Ki-67’ cells, median survival
of 8 months v <60% Ki-67’ cells, median survival of 39
months, P = .003) and was an independent factor in multivariate analy~is.~’
Ki-67 expression was similarly associated
with survival in B-lineage diffuse small cell lymphoma^.^'
IMMUNOPHENOTYPIC CHARACTERISTICS
B- versus T-cellphenotype. Although the majority of aggressive NHLs areof B-cell origin, up to -20% of these tumors have a T-cell phenotype. Controversy remains regarding the prognostic significance of immunophenotype in this
disease. To date, morphologic distinctions between diffuse
large cell and B- and/or T-cell immunoblastic lymphomas
have not been associated with significant differences in out~ o m e . ~ Similarly,
’,~~
the distinction between B- and T-cell
disease had no prognostic significance in a recent series of
patients with aggressive NHL from Stanford.54 However,
Coiffier et a155and Slymen et a156recently reported that patients with T-cell aggressive NHL relapsed from CR more
frequently than patients with B-cell disease (eg, T-cell v Bcell, 43% v 29% relapse from CR, P < .OO l 5 5 ) .
Majorhistocompatibility
complex (MHC) molecules.
Patients with drug-induced or infection-associated immunodeficiency clearly have an increased risk of developing aggressive NHL.57-59Because “tumor antigens” may be recognized in association with MHC molecules, several
investigators have postulated that the absence of MHC-encoded recognition structures could limithost tumor immunosurveillance in this disease.m%6’
In a small series of large
cell lymphoma patients stratified for clinical characteristics,
Miller et a1@found thatpatients whose tumors lacked HLADR had significantly shorter mediansurvivals than patients
with HLA-DR+ tumors (0.5 years v 2.8 years, P = .003).
Although a similar trend was noted ina subsequent Eastern
Cooperative Oncology Group study, the differences in survivals of patients with HLA-DR- and HLA-DR’ tumors
did not achieve statistical significance.62
Investigators at University of Arizona followed up on
their earlier observations6’ by correlating tumor expression
of class I and class I1 MHC determinantswith the numbers
of CD8’ T-tumor infiltrating lymphocytes (TIL) in patients
with aggressive NHL.61 Sixty-eight percent of the tumors
with low CD8+ T-TIL counts
were missing one or more class
I or class I1 HLA determinants, whereas only 20%oftumors
with high CD8+ T-TIL were missing similar MHC determi-
-/+
+/+
+/+/+
*O
0
t
1
2
3
4
5
Years
Fig 3. Lymphocyte homing receptor staining intensity is correlated with overall survival in 7 7 patients with intermediate-grade
lymphoma.= The predicted 5-year survivals for patients with f ,
, and
lymphocyte homing receptor staining intensity
are shown. Reproduced fromthe Journal of Clinical investigation,
1991, volume87, page 1835, by copyright permissionof the American society for Clinical Investigation.”
++
+++
nants (P= .0004), prompting speculation that the loss of
tumor MHC molecules might result in low T-TILs.~’Decreased numbers ofhost tumor
T-TILSwere also linked with
shortened survival in B-lineage diffuse small cell lymphoma~.~’
p2 Microglobulin is a small extracellular protein that is
noncovalently associated with (Y chain of the class I MHC
gene; the protein is also detectable in serum. Swan et a163
have correlated elevated serum p2 microglobulin levels with
high tumor burdens and shortened survival in patientswith
aggressive NHL. Although increased serum 62 microglobulin levels have not yet been linked to decreased lymphoma
cell surface p2 microglobulin or deficient antitumor responses, serum p2 microglobulin is an easily measured parameter that has been incorporated into a predictive serologic classification system for aggressive NHL.63
Adhesion molecule expression. The lymphocytehoming receptor (LHR, Hermes antigen, CD44) facilitates the
binding of lymphocytes to high endothelial venules and permits the extravagation of lymphocytes into nodal areas.64In
early studies, LHR-negative aggressive lymphomas were
less likely to disseminate than lymphomas with increased
LHR expression (Fig 3).65-68In additional studies, Horst et
a169found that 5 1% of patients with CD44hi% lymphomas
but only 12%of patients with CD44”” lymphomas presented
with advanced stage disease.Not surprisingly, patients whose
tumors had increasedlevelsof CD44 expressionalso had
shorter survival^.^"^^ These data prompt speculation that this
adhesion molecule may promote the dissemination of aggressive lymphomas. In fact, an aggressive lymphoma cell line
transfected with the “hematopoietic” CD44 isoform metastasized more frequently in nude mice than CD44- parental
cells.” Additional preliminary studies suggest that extranodal
and advanced-stage aggressiveNHLs also express CD44 vari-
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1170
MARGARET A. SHlPP
ples but was not altered in other lymphoid malignancies
ants including an isoformassociatedwiththemetastatic
spread of epithelial
malignan~ies.~'
such as follicular, Burkitts,and small lymphocytic lymphoThe lymphocyte function-associatedantigen, LFA- 1 (CD
mas and acute and chronic lymphocytic leukemias.Io2bel-6
transcripts were identified in mature B cells but not pre-B
l 1a/ 18) has also been implicated in lymphocyte adhesion
cells, plasma cells,Tcells,
and migration.@Although the absence of LFA-1 was linked
or other hematopoietic cell
with shortened survival in an early study of a smallnumber
types,'02 prompting speculation that bel-6 may be a protoof patients with aggressive NHL,72this adhesion molecule
oncogene that functions to control normal B-cell differenwas not correlated with clinical behavior in additional larger
tiation and specifically contributes to the pathogenesis of
~eries.~~.~~
diffuse large cell lymphoma. For these reasons, lesions in
Karyotypicabnormalities. Several chromosomal abnorbel-6may also have prognostic significance in aggressive
malities have been identified in aggressive NHL, although
NHL.
there is no single karyotypic abnormality that is ahallmark
SUMMARY
for this disease. After early conflicting
report^,^^,'^ Cowan et
a176 showedthat DNA ploidydid not have predictive value.
As the above-mentioned cellular and molecular parameKaryotypic abnormalities in genera177,78and specific deleters and newly identified biologic features are evaluated in
tions and abnormalities of the short arm of chromosome 17
larger numbers of patients with aggressive NHL, the bioand 7 have been associated with adverse
outcomes in aggreslogic heterogeneity ofthis disease will bebetter appreciated.
sive NHL79,'0; abnormalities involving chromosomes 1, 2,
With a more complete understanding of the disease, it is
3,6, 1 1, 12, 14, and 18 have also beend e s ~ r i b e d . ~ ~ , ~ ' , ' ' , ~ ~likely that we will substitute biologic variables for clinical
A substantial percentage (up to30%)of aggressiveNHLs
surrogate features in ourprognostic factor models and target
also have the (t[ 14; 18][q32;q21]) characteristic chromothese biologic variables for
therapy in specific subsets of pasomal translocation of follicularlymphomas.8',82This chrotients. In the meantime, widely accepted clinical models
mosomal translocation results in inappropriately elevated
such as the International Index and the age-adjusted index
levels of the 18q2 l gene product, bel-2,83-87 which blocks will aid in the identification of specific patient risk groups
programedcell death (apoptosis) in B lymphocyte^.^^-^'
and the ongoing comparison of different therapeutic a p
McDonnell and Korsemeyer" found that transgenic mice
proaches. Early restaging with sensitive
techniques like Gabearing a bel-2Ig minigene that structurally mimics the
67 citrate scans may also identify patients with suboptimal
(t[ 14; 18][q32;q21])chromosomal translocation developed
responses to induction therapy at timepoints when addifollicularhyperplasia.Inalargepercentageofthese
tional therapeutic alternatives may be most effective.
transgenic animals, the follicular hyperplasia evolved into
immunoblastic lymphoma and inhalfof
these immuACKNOWLEDGMENT
noblastic lymphomas, c-myealleleswererearranged."
I thank Donna Favreau for manuscript preparation.
These data prompt speculation that in certain aggressive
NHLs, tumor progression may be related to the aberrant
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2) and cell growth(mye)."Becausebel-2
protein levels
Chiarieri D, Silver RT, Pasmantier MW Advances in chemotherwere also
elevated
in
aggressive
lymphomas without
apy for largecell lymphoma. Semin Hematol24:8, 1987
(t[ 14; 18][q32;q21]), mechanisms other than chromosomal
2. Skarin AT, Canellos GP, Rosenthal DS, Case DC Jr, Maclntyre JM, Pinkus CS, Moloney WC, Frei E: Improved prognosis of
translocation may also result in pathogenetically relevant
diffuse histiocytic and undifferentiated lymphoma by use of hi&
bel-2 overe~pression.~~
In a recent series
of 371 patients with
dose methotrexate alternating with standard agents
(M-BACOD).J
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1994 83: 1165-1173
Prognostic factors in aggressive non-Hodgkin's lymphoma: who has
"high- risk" disease?
MA Shipp
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