close

Вход

Забыли?

вход по аккаунту

?

01.smj.0000085747.15986.b6

код для вставкиСкачать
Original Article
Absolute CD4 and CD8 Counts and CD4-toCD8 Ratios in Eight Patients with Indolent
B-cell Chronic Lymphocytic Leukemia
Jefferson D. Upshaw, Jr.,
MD,
and Thomas R. Callihan,
Background: There are some patients with B-cell chronic lymphocytic leukemia who exhibit an extraordinary natural resistance to
this malignancy, which lasts for many years. In this study, we report
the T-cell subset values and ratios in eight such patients.
Methods: Impath (New York, NY) evaluated immunophenotyping
by performing flow cytometry. Absolute CD4 and CD8 counts and
CD4:CD8 ratios were performed at Memphis Pathology Laboratory,
Memphis, Tennessee.
Results: CD4 and CD8 counts and CD4:CD8 ratios were normal in
all eight patients, in contrast to the suppressor cell proliferation and
low helper-suppressor ratios that have been previously reported in
other patients with B-cell chronic lymphocytic leukemia.
Conclusion: These results require further study to determine their
significance. Implications for further study are discussed.
Key Words: B-cell chronic lymphocytic leukemia, CD4:CD8 ratios, natural resistance
O
ne of us (JDU) has been observing eight patients with
B-cell chronic lymphocytic leukemia (B-CLL) who have
exhibited a symbiotic relationship with this malignancy for 6
to 25 years (median, 14 years) with little or no treatment. We
believe that there is more than just good fortune involved, and
that these patients have a remarkable natural resistance to this
disease. Natural resistance to B-CLL has been observed in the
past, the best examples being in reports of spontaneous complete remissions, which some authors have estimated to occur
in approximately 1% of patients with B-CLL.1 The purpose
of this article is to report the absolute CD4 and CD8 counts
and CD4:CD8 ratios found in these eight patients, and to
From the Memphis Cancer Center and the Pathology Group of the Midsouth,
Memphis, TN.
No financial support, no proprietary interest, no experimental results.
Reprint requests to Jefferson D. Upshaw, Jr., MD, 1068 Cresthaven Road,
Suite 500, Memphis, TN 38119.
Accepted May 30, 2003.
Copyright © 2004 by The Southern Medical Association
0038-4348/04/9703-0236
236
MD
compare these results with those previously reported in other
patients with ordinary B-CLL. T-cell subset values have not
been reported previously in this type of B-CLL patient.
Patients and Methods
Methods
All initial diagnoses were made on the basis of examination of Wright-stained peripheral blood smears and bone
marrow aspirates and hematoxylin and eosin-stained sections
of bone marrow biopsy specimens. In all patients, the diagnosis of B-CLL was confirmed by immunophenotyping by
flow cytometry of peripheral blood in 1999 or 2000 (performed by Impath, New York, NY). Absolute CD4 and CD8
counts and CD4:CD8 ratios were performed at Memphis Pathology Laboratory, Memphis, Tennessee, in 1999 or 2000.
Patient Characteristics
The age of patients at the time of diagnosis was 49 to 75
years (median, 56 years). As shown in Table 1, six patients
(patients 2, 3, 4, 5, 7, and 8) had Rai Stage 0 B-CLL2 at the
time of initial diagnosis. Patient 5 progressed to Rai Stage I
(cervical and axillary adenopathy) 10 years after initial diagnosis. The other five patients remained Rai Stage 0 throughout the entire period of observation (6 –25 years; median, 16
years). Two patients (patients 1 and 6) had palpable bilateral
inguinal adenopathy and splenomegaly by computerized axial
tomography (not palpable) at the time of initial diagnosis and
Key Points
• Some patients with B-cell chronic lymphocytic leukemia exhibit a remarkable natural resistance to this
malignancy, which lasts for many years.
• CD4 and CD8 counts and CD4:CD8 ratios in eight
such patients are normal, unlike the finding of lowered CD4:CD8 ratios in B-cell chronic lymphocytic
leukemia patients studied in the past.
• Further study is necessary to determine the significance of these findings.
© 2004 Southern Medical Association
Original Article
Table 1. Patient characteristics and results
Absolute
lymphocyte count
(per mm3)
Patient
Duration of
B-CLLa (yr)
1
25
2
25
3
21
4
16
5
10
6
10
7
8
8
6
Highest
(yr)
Lowest
(yr)
42,000
(1976)
21,000
(1981)
9,600
(1980)
53,000
(2001)
40,000
(2000)
51,000
(1991)
8,000
(2000)
3,300
(1999)
3,000
(1999)
9,360
(1986)
10,000
(1992)
12,000
(2001)
8,000
(1994)
47,000
(2000)
2,000
(2000)
5,500
(1995)
a
B-CLL, B-cell chronic lymphocytic leukemiq.
b
See text.
Absolute
CD8 count
(per mm3)
CD4:CD8
ratio
402
135
2.98
None
0
924
243
3.8
None
0
523
201
2.8
None
0
1,699
890
1.9
Leukeranb
03I
1,824
905
2.02
Leukeranb
IIb
697
417
1.78
Leukeranb
0
481
51
9.43
None
0
1,216
343
3.6
Leukeranb
Rai Stage
II
b
were assigned Rai Stage II. The inguinal adenopathy did not
progress and their spleens never became palpable during 25
years (patient 1) and 10 years (patient 6) of observation.
As shown in Table 1, four patients (patients 1, 2, 3, and
7) received no treatment throughout the entire period of observation (8 –25 years). Patient 5 received chlorambucil (Leukeran, GlaxoSmithKline, Research Triangle Park, NC) 2 mg
po three times daily for 8 weeks in year 9 after initial diagnosis. Patient 8 received chlorambucil (same dose) for 1
month in year 4 of observation, and again for 5 weeks in year
6 of observation. Patient 4 received chlorambucil (same dose)
for 5 weeks in year 16 after initial diagnosis. Patient 6 received chlorambucil (same dose) for 4 weeks at the time of
his initial diagnosis. Subsequently, he has received chlorambucil (same dose) for 3 to 5 weeks on six occasions (total of
7 months of therapy with chlorambucil in 10 years). These
patients were seen for clinical evaluation, physical examination, and complete blood count every 2 to 4 months from the
time of initial diagnosis. None of them had symptoms related
to their B-CLL during the entire period of observation.
Absolute
CD4 count
(per mm3)
Treatment
count trended upward slowly and progressively, and they
received short courses of therapy with chlorambucil (see Patients and Methods section for details). Overall, these patients, who have had B-CLL for a combined total of 121
years, have received treatment with chlorambucil, 2 mg tid,
for a combined total of 11 months. As shown in Table 1,
absolute CD4 counts (normal, 400 –2,120/mm3) ranged between 402 and 1,824/mm3 (median, 796/mm3). Absolute CD8
counts (normal, 120 –1,320/mm3) ranged between 51 and 905/
mm3 (median, 293/mm3). CD4:CD8 ratios (normal, 1.5–3.7)
ranged between 1.78 and 9.43 (median, 2.79).
Discussion
The highest and lowest absolute lymphocyte counts, the
year in which these occurred, and any therapy given are shown
in Table 1. In four patients (patients 1, 2, 3, and 7), the
absolute lymphocyte count became lower spontaneously during the period of observation (no treatment). In four cases
(patients 4, 5, 6, and 8), the average absolute lymphocyte
In patients with B-CLL reported previously, changes occur in T-lymphocyte subsets that adversely affect the normal
immune process. Most studies report a disproportionate proliferation of the suppressor cell (CD8) population that leads to
a lowering of the helper-suppressor ratio (CD4:CD8 ratio).
Most cases of Rai Stage 0 B-CLL reported show these
changes, and the suppressor cell proliferation increases and
helper-suppressor ratios become even lower as the stage of
B-CLL advances. Reports indicate that the helper-suppressor
ratio in Rai Stage 0 is usually in the range of 1, whereas in
patients with Rai Stages III and IV the helper-suppressor ratio
is usually 0.5 or below. In some studies, helper cell (CD4)
counts have been reported to be lowered; in others, they were
normal or even elevated.3– 8 There are, in addition, reports of
a myriad of functional defects that appear in the T lympho-
Southern Medical Journal • Volume 97, Number 3, March 2004
237
Results
Upshaw and Callihan • CD4 and CD8 Counts and Ratios in Chronic Lymphocytic Leukemia
cytes, including a marked increase in suppressor activity.9 –15
The end result in Rai Stages III and IV is a numerically
distorted and functionally impotent T-lymphocyte system. At
the same time this virtual paralysis of T-lymphocyte capacity
is occurring, there is an unrestrained and rapid accumulation
of B-CLL cells, and resistance to infection is severely impaired, resulting in median survival time plummeting from
approximately 12 years in Rai Stage 0, to 1 to 2 years in Rai
Stages III and IV.
The normal CD4 and CD8 counts (except for Patient 7,
who actually had a low CD8 count) and normal CD4:CD8
ratios found in our eight patients are in sharp contrast to the
abnormal numbers and low helper-suppressor ratios that have
been reported in other patients with B-CLL in the past (see
above). We recently reported a patient who exhibited the
ultimate expression of natural resistance to B-CLL—a spontaneous remission. He had normal CD4 and CD8 counts and
a normal CD4:CD8 ratio in the peripheral blood. An important remission-associated event in this patient was T-lymphocyte hyperplasia in his bone marrow, measured after spontaneous remission had occurred.1 We are not contending that
the normal T-cell subset counts and ratios are the cause of
these patients’ natural resistance to B-CLL, but are identifying them as important resistance-related events in these eight
patients.
We acknowledge that a study including only eight patients asks more questions than it answers, and our intention
in submitting this report is to make these findings available to
others better positioned than we are for further study. These
patients were selected for study because they have exhibited
a potent natural resistance to B-CLL over many years. Four
of these patients (patients 1, 2, 3, and 7) are bona fide examples of spontaneous regression of cancer, which was eloquently defined and discussed at the Conference on Spontaneous Regression of Cancer in 1976. This conference was
held to “explore these experiments of nature with a new audacity in thinking, and to listen more attentively and closely
to see if there is more to hear than meets the ear in these
‘whispers of nature.’ ”16 It is in this spirit that this report is
submitted.
One avenue that we believe would be productive for
further investigation is whether or not CD4 and CD8 counts
and CD4:CD8 ratios would be valuable prognostic indicators
in patients with B-CLL, as proposed by Hermann et al4 in
1982. It would also be of great interest to know whether there
is any correlation between CD4 and CD8 counts and ratios,
and mutated versus unmutated immunoglobulin gene status
or CD38 status. It is possible that progressive lowering of the
CD4:CD8 ratio could serve as an early warning that the BCLL is beginning to get the upper hand in the individual
patient. Prospective study of a much larger group of patients
would be necessary to examine this possibility.
Most importantly, the findings in these select patients
raise the possibility that therapeutic measures designed to
238
nurture or enhance the normal T-lymphocyte system, such as
patient-specific vaccination,17 taken in early B-CLL (Rai
Stage 0, most Rai Stage I, and some Rai Stage II patients),
when tumor burden is low, could delay or even prevent accumulation of an excessive tumor burden and perhaps interrupt the downward spiral in T-lymphocyte competence that is
associated with severely shortened survival times in patients
with Rai Stages III and IV B-CLL. We believe this would be
an important avenue for further study. Finally, we believe that
whatever value this report may have will depend entirely on
the extent to which it stimulates others to take a new look at
some old friends.
Conclusion
Study of CD4 and CD8 counts and CD4:CD8 ratios in
eight patients who have exhibited a remarkable natural resistance to B-CLL are found to be normal. This is in sharp
contrast to the suppressor cell proliferation and the low CD4:
CD8 ratios previously reported by others in other patients
with B-CLL. Further study will be necessary to determine
whether CD4 and CD8 counts and ratios would be valuable
prognostic indicators in B-CLL. Further study will also be
necessary to determine whether therapeutic measures designed to nurture or enhance normal T-lymphocyte activity
taken in early B-CLL would be effective in preventing or
delaying progression to late stages.
References
1. Upshaw JD Jr, Callihan TR. Spontaneous remission of B-cell chronic
lymphocytic leukemia associated with T lymphocytic hyperplasia in
bone marrow. South Med J 2002;95:647– 649.
2. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic
lymphocytic leukemia. Blood 1975;46:219 –234.
3. Jandl JH. Chronic lymphocytic leukemia, in Blood: Textbook of Hematology. Boston, Little, Brown, 1996, ed 2, pp 991–1018.
4. Mittelman A, Denny T, Gebhard D, et al. Analysis of T-cell subsets in
B-cell chronic lymphocytic leukemia: A correlation with the stage of
disease. Am J Hematol 1984;16:67–73.
5. Herrmann F, Lochner A, Philippen H, et al. Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell
type. Clin Exp Immunol 1982;49:157–162.
6. Lauria F, Foa R, Mantovani V, et al. T-cell functional abnormality in
B-chronic lymphocytic leukaemia: Evidence of a defect of the T-helper
subset. Br J Haematol 1983;54:277–283.
7. Dianzani U, Omedè P, Marmont F, et al. Expansion of T cells expressing
low CD4 or CD8 levels in B-cell chronic lymphocytic leukemia: Correlation with disease status and neoplastic phenotype. Blood 1994;83:
2198 –2205.
8. Kay NE. Abnormal T-cell subpopulation function in CLL: Excessive
suppressor (T ␥) and deficient helper (T ␮) activity with respect to B-cell
proliferation. Blood 1981;57:418 – 420.
9. Utsinger PD. Impaired T-cell transformation in chronic lymphocytic
leukemia (CLL): Demonstration of a blastogenesis inhibitory factor.
Blood 1975;46:883– 890.
10. Kay NE, Perri RT. Evidence that large granular lymphocytes from BCLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis. Blood 1989;73:1016 –1019.
© 2004 Southern Medical Association
Original Article
11. Ayanlar-Batuman O, Ebert E, Hauptman SP. Defective interleukin-2
production and responsiveness by T cells in patients with chronic lymphocytic leukemia of B cell variety. Blood 1986;67:279 –284.
12. Kay NE, Kaplan ME. Defective expression of T cell antigens in chronic
lymphocytic leukaemia: Relationship to T cell dysfunction. Br J Haematol 1984;57:105–111.
13. Herrmann F, Sieber G, Chen Z, et al. Further evidence for T cell abnormalities in chronic lymphocytic leukaemia of the B cell type. Clin
Exp Immunol 1983;53:109 –114.
14. Chiorazzi N, Fu SM, Montazeri G, et al. T cell helper defect in patients
with chronic lymphocytic leukemia. J Immunol 1979;122:1087–1090.
15. Perri RT, Kay NE. Abnormal T cell function in early-stage chronic
lymphocytic leukemia (CLL) patients. Am J Hematol 1986;22:55– 61.
16. Lewison EF. Introductory remarks: Conference on spontaneous regression of cancer. Natl Cancer Inst Monogr 1976;44:1.
17. Bendandi M, Gocke CD, Kobrin CB, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte
colony-stimulating factor against lymphoma. Nat Med 1999;5:1171–
1177.
A bargain is something you have to find a use for once
you have bought it.
—Benjamin Franklin
Southern Medical Journal • Volume 97, Number 3, March 2004
239
Документ
Категория
Без категории
Просмотров
2
Размер файла
60 Кб
Теги
smj, 15986, 0000085747
1/--страниц
Пожаловаться на содержимое документа