Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 372-373
CORRESPONDENCE
Prognostic Significance of Quantitative Viral Markers
in Adult T-Cell Leukemia/Lymphoma
 |
LETTER |
To the Editor:
Adult T-cell leukemia/lymphoma (ATL) is a T-cell non-Hodgkin's
lymphoma frequently associated with a leukemic phase and is caused by
human T-cell lymphotropic virus type I (HTLV-I).1 Development of ATL is preceded by high HTLV-I antibody
titers2 and characterized by monoclonal integration of
proviral DNA in mononuclear cells in peripheral blood and/or lymph
nodes.3 ATL has a broad clinical spectrum with several
subtypes and corresponding differences in survival.4 The
acute and lymphoma subtype have a prognosis of less than 1 year, while
chronic and smoldering have longer survival and frequently precede the
more severe types. Because proviral DNA level (proviral load) and
antibody titers are important diagnostic markers, we evaluated their
utility as predictors of survival in ATL.
We analyzed 30 ATL patients (acute, lymphoma, chronic subtype) from the
Non-Hodgkin's Lymphoma Registry at the University of the West Indies
in Jamaica. All participants were enrolled in studies approved by
Protocol and Human Subjects' Review Committees at the National Cancer
Institute (Bethesda, MD) and the University of the West Indies
(Kingston, Jamaica).
Serum samples were screened by whole-virus enzyme-linked
immunoassay (EIA) (Dupont, Wilmington, DE) and confirmed by Western blot (Biotech, Rockville, MD). HTLV-I antibody titers were assayed by
the end-point dilution method using an EIA (Genetic Systems, Seattle,
WA, or Cambridge-Biotech, Rockville, MD) at fourfold dilutions.
Quantitative proviral DNA levels were detected by a real-time automated
polymerase chain reaction (PCR) method. Ten microliters of DNA was
amplified for 45 cycles with AmpliTaq Gold polymerase using an ABI
PRISM Sequence Detection System and TaqMan PCR Reagent [P/N
N808-0230] (PE Applied Biosystems, Foster City, CA) in a 96-well
format. The HTLV-I/II primers were from highly conserved sequences
(GenBank National Center for Biotechnology Information, Bethesda, MD)
from the tax gene [HTV-F5 (7358-7378) and HTV-R4
(7518-7499)]. Triplicate reactions were performed and unknown copy
numbers were automatically calculated by interpolation from a plasmid
control regression curve and reported as copy equivalents per
105 lymphocytes. The assay reliably detects at least 3 copies per 105 lymphocytes. Samples with undetectable virus
were scored as 1 copy per 105 lymphocytes for calculations.
Kaplan-Meier life-table methods were used to estimate survival and 95%
confidence intervals. The log-rank statistic was used to evaluate
differences between survival curves. A dichotomized variable above or
below the median value was used to compare survival by white blood cell
count, proviral DNA, and antibody titer levels at diagnosis.
Lymphocytosis was defined as lymphocyte count exceeding 4,000/µL.
Each numeric value was log10 transformed and ultimately reported as arithmetic values. Kruskal-Wallis test was used to compare
mean values between groups. Correlations were examined using
Spearman's rank order statistic. All P values were two-sided.
Median survival was significantly shorter for acute (101 days, 95%
confidence interval [CI] [54 to 124 days]) and lymphoma (83 days,
95% CI [63 to 314 days]) subtypes compared with the chronic subtype (P = .009) whose median survival could
not be determined because 3 of 6 patients were still alive. Significant adverse clinical prognostic factors at diagnosis included
hypercalcemia, hepatomegaly, splenomegaly, and B
symptoms. Other factors that were not significant included white blood
cell count and lymphocytosis. Proviral load and antibody titers
were also not significant. Differences in proviral load between
subtypes were significant (P = .01), with higher levels among
acute and chronic subtypes compared with lymphoma subtype (Table
1). Interestingly, acute ATL patients had a
higher white blood cell count compared with the chronic and lymphoma
subtypes. The elevated white blood count among acute ATL cases did not
correspond to the highest proviral load, although white blood cell
count was significantly correlated with proviral DNA level in all
patients (R = .47; P = .009). Chronic and acute ATL
patients had similar median absolute lymphocyte counts (9,679 and 8,742 cells/µL, respectively) and about 50% of both subtypes had
circulating abnormal lymphocytes. These data suggest that chronic ATL
patients may have more detectable virus per cell. Antibody titer levels
were similar between the subtypes (P = .23). However, a trend
toward better survival, 471 days (95% CI 102 to 935) versus 83 days
(95% CI 54 to 314), was observed for cases with titer levels above the
median (1:29,765) at diagnosis.
Viral markers were not significant predictors of survival among ATL
patients, although others have shown that the ability to detect
proviral DNA declines in complete remission after therapy.3 In this study, higher antibody titers at diagnosis appeared to be
associated with longer survival. Chronic ATL patients with high
antibody titer levels, reflective of a heightened immune response,
either require no immediate therapy or respond well to various
treatment approaches,5 despite highest proviral load. The
lymphoma subtype characterized by a low level of circulating malignant
cells had the lowest proviral load but poorest survival. This may
explain why these cases would fail to respond to anti-viral-containing regimens such as zidovudine and interferon-
6,7 and other immunotherapeutic approaches.5 To improve response rates
among ATL patients, targeted, tumor-specific therapy that also enhances immunity is needed.
Angela Manns
Viral Epidemiology
Branch
Division of Cancer Epidemiology and Genetics
National
Cancer Institute
Bethesda, MD
Wendell J. Miley
David Waters
SAIC, NCI-Frederick Cancer Research and Development
Center
Frederick, MD
Barrie Hanchard
Gilian Wharfe
Beverley Cranston
Elaine Williams
Departments of Hematology
and Pathology
University of the West Indies
Kingston,
Jamaica
William A. Blattner
Institute of Human
Virology
University of Maryland
Baltimore, MD
| |
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