|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
NEOPLASIA
From the Departments of Hematopathology, Leukemia, and
Biostatistics; The University of Texas M. D. Anderson Cancer
Center, Houston, TX.
CD38 is a transmembrane glycoprotein expressed on the surface
of leukemic cells in a significant percentage of patients with B-cell
chronic lymphocytic leukemia (B-CLL). A recent study suggested that
CD38 expression has prognostic value in CLL. Peripheral blood samples
from 218 patients with B-CLL were analyzed by flow cytometry for CD38
expression on CD5/19+ leukemic cells. Various patient
characteristics were studied including age, sex, Rai and Binet stages,
splenomegaly, hepatomegaly, hemoglobin (Hgb) level, CD38 (also referred to as T10 antigen) was
initially characterized in 1980 as a T-cell differentiation
antigen.1 In the following years, several studies showed
that CD38 expression is not limited to T cells but is widely expressed
on different hematopoietic and nonhematopoietic
tissues.2-5 The strength of expression of CD38 on
hematopoietic cells varies, depending on their stage of maturation and
activation. It is expressed on CD34+ progenitor cells,
unstimulated pregerminal center B cells, germinal center B cells,
activated mature lymphocytes, plasma cells, and myeloid
precursors.6-7 The function of CD38 in B cells is not clearly defined, and its expression level varies with the stage of
maturation, the type of activation, and the milieu in which activation
takes place.8-14 CD38 expression on different types of leukemic cells and its value as a prognostic indicator has been
the subject of intense investigation.15-19
Although CLL is the most common leukemia in western countries, it is
still a poorly understood disease. CLL is responsible for more than
5000 deaths yearly in the United States.20 Some patients
with CLL die within 2 years of diagnosis, yet others have a normal
lifespan. Several staging systems have been developed to guide the
management of these patients, but the decision to treat or not to treat
patients, particularly in earlier stages of the disease, is still
difficult to make. The expression of CD5, CD19, and CD23 and the
absence of FMC7 and CD22 surface markers are routinely used as
diagnostic criteria in patients with B-CLL.21,22 However,
these markers do not help in determining the aggressiveness of the
disease or in predicting the outcome. Fais et al23 were the first to reported that the presence or absence of immunoglobulin gene mutation could classify patients with B-CLL into 2 groups. Hamblin
et al24 and Damle et al18 independently
confirmed this observation and demonstrated that patients without the
immunoglobulin gene mutation had more aggressive disease with shorter
survival times, whereas patients with the immunoglobulin gene mutation had less aggressive disease and prolonged survival times. Damle et
al18 studied CD38 expression in 37 samples from patients with B-CLL and reported that cells from patients with unmutated immunoglobulin genes were positive for CD38 expression (30% or more of
cells), and this was associated with aggressive disease. In contrast,
cells from patients with mutated immunoglobulin genes had low CD38
expression and indolent disease with significantly longer survival times.
In this study, we measured the levels of CD38 expression in 218 patients with B-CLL and correlated these values with various clinical
characteristics. Univariate and multivariate statistical analyses
showed that CD38 expression in B-CLL cells can identify a subgroup of
patients with significantly more aggressive disease.
Patient population
Quantification of Measurement of CD38 expression by flow cytometry Cryopreserved peripheral blood samples were obtained at the time of presentation and diagnosis and were used for flow cytometry analysis. Samples were prepared using a 3-color staining method. Isotype-matched negative control antibodies were used to separate positive from negative cells. Directly labeled monoclonal antibodies (mAbs) against the lymphoid antigens CD5-phycoerythrin (PE), CD19-PerCP (peridinin chlorophyll protein), and CD38-allophycocyanin (APC; Becton Dickinson Immunocytochemistry Systems, San Jose, CA) were used. Immunophenotyping expression was measured by FACScalibur (Becton Dickinson). B-CLL cells (CD5/19+) were gated. The degree of CD38 expression in this gated population was expressed as percentage positivity. Samples from 10 patients were analyzed when fresh and after freezing to test what effect freezing had on the surface expression of CD38. Spearman correlation showed complete correlation between the 2 measurements (P < .0001) and no significant difference between them. Mean and variance were 21.7 and 642.8 for the fresh samples and 21.5 and 642.88 for the frozen samples, confirming the reliability of the assay and that freezing had no effect on CD38 expression.Statistical analyses The univariate Cox proportional hazard model was used to evaluate the possible associations between overall survival and each risk factor singly. Variables identified as statistically significant (P < .05) in univariate analyses were subsequently included in the stepwise multivariate Cox proportional hazards model. Survival time was measured from the test date to either the last follow-up date (censored) or to the time of death by any cause. Variables examined were age, sex, Rai and Binet stages, splenomegaly, hepatomegaly, hemoglobin (Hgb) level, -2 microglobulin (2M) level
in the serum, white blood cell (WBC) count, platelet count, lymphocyte
count in the peripheral blood, lymphocyte percentage in the bone
marrow, cellularity of the bone marrow, number of nodal sites involved with disease, history of therapy, and survival time. All data were
collected from reviewing the patient's record and were entered into
the leukemia database. The Kaplan-Meier method was used to construct
survival curves, and results were compared using the log-rank test.
Spearman and Kruskal-Wallis tests were used for comparing correlations
and for performing nonparametric hypothesis tests between more than
2 subgroups.
Patient characteristics Patient characteristics are summarized in Table 1. Overall, our patient population was representative for this disease. The male to female ratio was 1.6:1, and the median age was 62 years. Seventy-four percent of patients had Rai stages 0 to II disease, and 66% were untreated. CD38 expression varied in patients with CLL (Figures 1, 2). Forty-four percent of the patients had CD38 expression in 20% or more of the cells, and 56% of the patients had CD38 expression in less than 20% of the cells. Sixteen percent of the patients had CD38 expression in more than 80% of the leukemic cells. Only 7 (3%) patients had CD38 expression in 20% to 30% of the cells. Using 20% as a cut-off point in our analysis was arbitrary, and most of the analysis was repeated using CD38 as a continuous variable. Of the 218 patients we studied, 142 (65%) were previously untreated. Our institution is a referral center, and it is possible that a significant number of our patients who had undergone previous therapy were heavily treated and by various therapies.
Comparison of CD38+ and
CD38 2M (P = .00001).
CD38 expression is associated with poor outcome As shown in Figure 3A, patients whose samples were positive for CD38 had significantly shorter survival times (median, 30 months) than patients whose samples were negative for CD38 (P = .00005). Of the 122 patients who did not express CD38, only 17 (14%) died whereas 38 (40%) of the CD38+ patients died. This remained true when comparisons were made for previously untreated patients with CLL (Figure 3B). Furthermore, CD38 positivity identified a subgroup of CLL patients with aggressive disease staged by Rai as indolent and intermediate (Rai stage 0-II) (Figure 4A). CD38 expression also distinguished a subgroup of patients with less aggressive disease whose Rai stage indicated aggressive disease (Rai III-IV) (Figure 4B). We also analyzed patients after separating them into 3 groups according to the National Cancer Institute-modified staging system for Rai classification. CD38+ patients in the Rai intermediate stage (Rai I-II) had poor outcome (P = .04). However, CD38+ patients in the low-risk group (Rai 0) had outcome not significantly different from those negative for CD38 (P = .16). Similarly, CD38 expression distinguished a group of patients with favorable prognoses among those with high (greater than 2.5 mg/L)2M levels, which are considered indicative
of unfavorable prognosis (Figure 4C). Analysis of the role of CD38 in
predicting overall survival in various subgroups was also performed
using the Cox proportional hazard model and CD38 as a continuous
variable rather than using the 20% cut-off. This analysis also showed
similar results in all subgroups.
To investigate the effects of therapy on CD38 expression, we used the Kruskal-Wallis test and compared CD38 expression between previously untreated patients and those previously treated. We found significantly higher levels of CD38 expression in previously treated patients (P = .0001). This raises the possibility that patients with high CD38 levels more frequently require therapy or that patients acquire CD38 expression after therapy. To investigate, we correlated CD38 expression with the length of time between appearance of disease and the time of testing. We found no correlation between CD38 expression and length of time from onset of disease and testing. This suggests that CD38 expression is more likely to be a feature of the disease at the time of presentation, and patients with CD38 expression are more likely to need therapy. Furthermore, history of therapy was associated with shorter survival in patients with low CD38 expression (P < .001) and in patients with high CD38 expression (P < 0.001). Statistical analyses for CD38 expression We used the univariate Cox proportional hazard model to assess associations between survival time and various risk factors in this group of patients with CLL (Table 3). As expected, Rai and Binet stages, age,2M, hemoglobin, WBC count,
peripheral blood lymphocytosis, history of therapy, splenomegaly,
number of sites with lymph node involvement, and CD38 positivity were all significant factors in determining overall survival. Hepatomegaly, bone marrow cellularity, and percentage of lymphocytic infiltration were factors not significantly associated with survival time. When some
prognostic factors, including Rai staging, hemoglobin, 2M, and CD38
were considered in a multivariate analysis that included 150 patients
with all variables (Table 4), only
hemoglobin and CD38 emerged as significant prognostic factors
associated with overall survival time. In this group of patients, the
prognostic value of CD38 masked that of 2M.
Analyses of sequential samples Sequential blood samples from 7 patients obtained at different time points during the course of the disease (from 4 to 56 months) were analyzed (Table 5). CD38 expression did not significantly change in 6 of the 7 patients. However, in one patient the percentage of CD38+ cells changed from 9% to 89% in a 36-month period, during which the patient received no treatment. This increase in CD38 expression was associated with significant worsening in the patient's clinical condition, manifested as liver and spleen enlargement with a decrease in platelet count and an increase in WBC count. Change in disease staging was also manifested as Rai 0 to 2 and Binet A to B.
In this study, we found that patients with B-CLL could be divided
into 2 prognostically different groups CD38 is a 45 000-d transmembrane type II glycoprotein with a short amino-terminal cytoplasmic tail, a single membrane-spanning region, and a long extracellular carboxy-terminal domain.14 It has ecto-enzymatic activity that serves in the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphate ribose, or cADP, an important regulator of intracellular Ca++ release.9,25 CD38 has no lineage restriction and mediates variable functions.13 In T cells it functions as an adherence molecule to the CD31 ligand expressed on vascular endothelium, and its ligation mediates the production of qualitatively different cytokines compared with ligation of the CD3 complex.26,27 In myeloid cells, CD38 is expressed on immature precursors and can be up-regulated using all-trans retinoic acid. Its presence has been associated with better prognosis in acute myeloid leukemia (AML), with the exception of AML-M3.19 CD38 has been reported to play a complex role in lymphocyte proliferation.13 Ligation of CD38 using an agonistic monoclonal antibody produced diverse responses manifested as growth or apoptosis.28 CD38 ligation on mature B cells protected against apoptosis and up-regulated the expression of the Bcl-2 proto-oncogene.10,29 In contrast, ligation of the CD38 molecule suppressed the growth of immature B cells in the bone marrow micro-environment.11 Clinically and morphologically, it is known that B-CLL is a heterogeneous group of diseases under the same name. These diseases have different progression patterns and require variable therapeutic modalities. Zupo et al30 reported that patients with B-CLL could be divided into groups based on their lymphocyte CD38 expression. Recent studies divided patients with B-CLL into 2 prognostic groups based on their IgH gene mutation status, one with mutation and good outcome and the other without mutation but with poor outcome.18,23,24 Damle et al18 found that patients with B-CLL with high CD38 expression did not have IgH mutations and that this correlated with poor prognosis, whereas patients with low CD38 expression had IgH mutations that correlated with good prognosis. Based on this observation, they proposed that the B-CLL subset with high CD38 expression arises from pregerminal center B cells (naive) and that the subset with low CD38 expression arises from postgerminal center (memory) cells. In contrast to immunoglobulin gene mutations, which are not reversible,
CD38 expression could be up-regulated or down-regulated based on the
stage of maturation or the antigenic stimulation. Although CD38
expression was constant (negative or positive) over a variable period
of time in 6 of 7 patients examined, it increased significantly in 1 patient (9% to 89%). This increase in CD38 expression was associated
with marked worsening of the patient's clinical parameters. This was
an unexpected finding and contradicted the concept that CD38 expression
reflects the origin of B cells from pregerminal or postgerminal
centers. Although we cannot rule out the possibility of an evolving new
clone of pregerminal center origin, the fact that the patient was
untreated suggests an evolution of the same disease. Omede et
al15 also reported that patients with multiple myeloma in
relapse showed an increase in CD38 expression levels. This observation
and ours CD38 expression stands as an excellent prognostic indicator because it
is readily available from a peripheral blood sample and is easily
measured; this adds a new dimension to the care available to patients
with CLL. In addition, it adds information to other prognostic factors
such as Rai and Binet stages or
Submitted May 12, 2000; accepted March 1, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Maher Albitar, Dept of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Box 72, 1515 Holcombe Blvd, Houston, TX 77030-4095; e-mail: malbitar{at}mdacc.tmc.edu.
1.
Reinherz EL, Kung PC, Goldstein G, et al.
Discrete stages of intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T lineage.
Proc Natl Acad Sci U S A
1980;77:1588-1592 2. Deaglio S, Dianzani U, Horenstein AL, et al. Human CD38 ligand: a 120-kDa protein predominantly expressed on endothelial cells. J Immunol. 1996;156:727-734[Abstract]. 3. Mizuguchi M, Otsuka N, Sato M, et al. Neuronal localization of CD38 antigen in human brain. Brain Res. 1995;697:235-240[CrossRef][Medline] [Order article via Infotrieve]. 4. Kramer G, Steiner G, Edinnger D, et al. High expression of a CD38-like molecule in normal prostatic epithelium and its differential loss in benign and malignant disease. J Urol. 1995;154:1636-1641[CrossRef][Medline] [Order article via Infotrieve].
5.
Kato I, Takasawa S, Akabane A, et al.
Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic beta cells: enhanced insulin secretion in CD38-expressing transgenic mice.
J Biol Chem.
1995;270:30045-30050 6. Malavasi J, Funaro A, Roggero S, et al. Human CD38: a glycoprotein in search of a function. Immunol Today. 1994;15:95-97[CrossRef][Medline] [Order article via Infotrieve]. 7. Oertel J, Oertel B, Schleicher J, et al. Immunophenotyping of blasts in human bone marrow. Ann Hematol. 1996;72:125-129[CrossRef][Medline] [Order article via Infotrieve]. 8. Funaro A, Spagnoli GC, Ausiello CM, et al. Involvement of the multilineage CD38 molecule in a unique pathway of cell activation and proliferation. J Immunol. 1990;145:2390-2396[Abstract].
9.
Howard S, Grimaldi JC, Bazan JF, et al.
Formation and hydolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38.
Science.
1993;262:1056-1059 10. Zupo S, Rugari E, Dono M, Tamborelli G, Malavasi F, Ferrarini M. CD38 signaling by agonistic monoclonal antibody prevents apoptosis of human germinal center B cells. Eur J Immunol. 1994;24:1218-1222[Medline] [Order article via Infotrieve].
11.
Kumagai M, Coustan-Smith E, Murry DJ, et al.
Ligation of CD38 suppresses human B lymphopoiesis.
J Exp Med.
1995;181:1101-1110 12. Funaro A, Horenstein AL, Malavasi F. Human CD38: a versatile leukocyte marker with emerging clinical prospective. Fundam Clin Immunol. 1995;3:101-113. 13. Lund FE, Yu N, Kim K-M, et al. Signaling through CD38 augments B cell antigen receptor (BCR) responses and is dependent on BCR expression. J Immunol. 1996;157:1455-1467[Abstract]. 14. Mehta K, Shahid U, Malavasi F. Human CD38, a cell surface protein with multiple functions. FASEB J. 1996;10:1408-1417[Abstract].
15.
Omede P, Boccadoro M, Gallone G, et al.
Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival.
Blood.
1990;76:1375-1379 16. Koehler M, Behm F, Hancock M, Pui CH. Expression of activation antigens CD38 and CD71 is not clinically important in childhood acute lymphoblastic leukemia. Leukemia. 1993;7:41-45[Medline] [Order article via Infotrieve].
17.
Mehta K, McQueen T, Mansouri T, et al.
Involvement of retinoic acid receptor-
18.
Damle RN, Wasil T, Fais F, et al.
Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
Blood.
1999;94:1840-1847 19. Keyhani A, Huh YO, Jendiroba D. Increased CD38 expression is associated with favorable prognosis in adult acute leukemia. Leuk Res. 1999;24:153-159. 20. Ries L, Miller B, Hankey B, et al. SEER cancer statistics review, 1972-1991: tables and graphs. Bethesda, MD: National Cancer Institute; 1994. NIH Publication 94-2789. 21. Matutes E, Owusu-Ankomah K, Morilla R, et al. The immunological profile of B cell disorder and proposal of a scoring system for the diagnosis of CLL. Leukemia. 1994;8:1640-1645[Medline] [Order article via Infotrieve]. 22. Cheson BD, Bennet JM, Grever M, et al. National Cancer Institute-sponsored working group for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;12:4990-4997. 23. Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998;102:1515-1525[Medline] [Order article via Infotrieve].
24.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK.
Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia.
Blood.
1999;94:1848-1854 25. Summerhill RJ, Jackson DG, Galione A. Human lymphocyte antigen CD38 catalyzes the production of cyclic ADP-ribose. FEBS Lett. 1993;335:231-233[CrossRef][Medline] [Order article via Infotrieve].
26.
Deaglio S, Morra M, Mallone R, et al.
Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, and Ig superfamily member.
J Immunol.
1998;160:395-402 27. Ausiello CM, Urbani F, LaSala A, et al. CD38 ligation induces discrete cytokine mRNA expression in human cultured lymphocytes. Eur J Immunol. 1995;25:1477-1480[Medline] [Order article via Infotrieve]. 28. Funaro A, Morra M, Calosso L, et al. Role of the human CD38 molecule in B cell activation and proliferation. Tissue Antigens. 1997;49:7-12[Medline] [Order article via Infotrieve]. 29. Santos-Argumedo L, Teixira C, Preece G, et al. A B-lymphocyte surface molecule mediating activation and protection from apoptosis via calcium channels. J Immunol. 1993;151:3119-3130[Abstract].
30.
Zupo S, Isnardi L, Megna M, et al.
CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies to apoptosis.
Blood.
1996;88:1365-1374
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  R. Chen, W. G. Wierda, S. Chubb, R. E. Hawtin, J. A. Fox, M. J. Keating, V. Gandhi, and W. Plunkett Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia Blood, May 7, 2009; 113(19): 4637 - 4645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hewamana, T. T. Lin, C. Rowntree, K. Karunanithi, G. Pratt, R. Hills, C. Fegan, P. Brennan, and C. Pepper Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia J. Clin. Oncol., February 10, 2009; 27(5): 763 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. BOELENS, S. LUST, B. VANHOECKE, and F. OFFNER Chronic Lymphocytic Leukaemia Anticancer Res, February 1, 2009; 29(2): 605 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Sargent, D. Jones, L. V. Abruzzo, H. Yao, J. Bonderover, M. Cisneros, W. G. Wierda, M. J. Keating, and R. Luthra Customized Oligonucleotide Array-Based Comparative Genomic Hybridization as a Clinical Assay for Genomic Profiling of Chronic Lymphocytic Leukemia J. Mol. Diagn., January 1, 2009; 11(1): 25 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pepper, T. T. Lin, G. Pratt, S. Hewamana, P. Brennan, L. Hiller, R. Hills, R. Ward, J. Starczynski, B. Austen, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers Blood, November 1, 2008; 112(9): 3807 - 3817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Kujawski, P. Ouillette, H. Erba, C. Saddler, A. Jakubowiak, M. Kaminski, K. Shedden, and S. N. Malek Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia Blood, September 1, 2008; 112(5): 1993 - 2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Z. Rassenti, S. Jain, M. J. Keating, W. G. Wierda, M. R. Grever, J. C. Byrd, N. E. Kay, J. R. Brown, J. G. Gribben, D. S. Neuberg, et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia Blood, September 1, 2008; 112(5): 1923 - 1930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Malavasi, S. Deaglio, A. Funaro, E. Ferrero, A. L. Horenstein, E. Ortolan, T. Vaisitti, and S. Aydin Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology Physiol Rev, July 1, 2008; 88(3): 841 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Li, S. Ding, J. Pan, M. A. Shakhmatov, E. Kashentseva, J. Wu, Y. Li, S.-j. Soong, N. Chiorazzi, and R. S. Davis FCRL2 expression predicts IGHV mutation status and clinical progression in chronic lymphocytic leukemia Blood, July 1, 2008; 112(1): 179 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hallek, B. D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, H. Dohner, P. Hillmen, M. J. Keating, E. Montserrat, K. R. Rai, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines Blood, June 15, 2008; 111(12): 5446 - 5456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. M. Patten, A. G. S. Buggins, J. Richards, A. Wotherspoon, J. Salisbury, G. J. Mufti, T. J. Hamblin, and S. Devereux CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment Blood, May 15, 2008; 111(10): 5173 - 5181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hewamana, S. Alghazal, T. T. Lin, M. Clement, C. Jenkins, M. L. Guzman, C. T. Jordan, S. Neelakantan, P. A. Crooks, A. K. Burnett, et al. The NF-{kappa}B subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target Blood, May 1, 2008; 111(9): 4681 - 4689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Cutrona, M. Colombo, S. Matis, M. Fabbi, M. Spriano, V. Callea, E. Vigna, M. Gentile, S. Zupo, N. Chiorazzi, et al. Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells Haematologica, March 1, 2008; 93(3): 413 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Roos, A. Krober, P. Grabowski, D. Kienle, A. Buhler, H. Dohner, R. Rosenquist, and S. Stilgenbauer Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia Blood, February 15, 2008; 111(4): 2246 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Gattei, P. Bulian, M. I. Del Principe, A. Zucchetto, L. Maurillo, F. Buccisano, R. Bomben, M. Dal-Bo, F. Luciano, F. M. Rossi, et al. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia Blood, January 15, 2008; 111(2): 865 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Willimott, M. Baou, S. Huf, S. Deaglio, and S. D. Wagner Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4 Haematologica, October 1, 2007; 92(10): 1359 - 1366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sabattini, R. Orduz, C. Campidelli, P. L. Zinzani, V. Callea, S. Zupo, G. Cutrona, F. Morabito, M. Ferrarini, and S. Pileri B cell chronic lymphocytic leukaemia/small lymphocytic lymphoma: role of ZAP70 determination on bone marrow biopsy specimens J. Clin. Pathol., June 1, 2007; 60(6): 627 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Josefsson, C. H. Geisler, H. Leffers, J. H. Petersen, M. K. Andersen, J. Jurlander, and A. M. Buhl CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia Blood, June 1, 2007; 109(11): 4973 - 4979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O'Brien, J. O. Moore, T. E. Boyd, L. M. Larratt, A. Skotnicki, B. Koziner, A. A. Chanan-Khan, J. F. Seymour, R. G. Bociek, S. Pavletic, et al. Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia J. Clin. Oncol., March 20, 2007; 25(9): 1114 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tinhofer, G. Rubenzer, C. Holler, E. Hofstaetter, M. Stoecher, A. Egle, M. Steurer, and R. Greil Expression levels of CD38 in T cells predict course of disease in male patients with B-chronic lymphocytic leukemia Blood, November 1, 2006; 108(9): 2950 - 2956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. H. Frey, H. Nuckel, L. Sellmann, D. Siemer, R. Kuppers, J. Durig, U. Duhrsen, and W. Siffert The GNAS1 T393C Polymorphism Is Associated with Disease Progression and Survival in Chronic Lymphocytic Leukemia. Clin. Cancer Res., October 1, 2006; 12(19): 5686 - 5692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deaglio, T. Vaisitti, S. Aydin, E. Ferrero, and F. Malavasi In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia Blood, August 15, 2006; 108(4): 1135 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Koller, B. N. Bekele, X. Zhou, C. Park, Z. Estrov, S. O'Brien, M. Keating, I. Jilani, F. J. Giles, H. M. Kantarjian, et al. Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia Blood, August 1, 2006; 108(3): 1001 - 1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. E. Lund, H. Muller-Steffner, H. Romero-Ramirez, M. E. Moreno-Garcia, S. Partida-Sanchez, M. Makris, N. J. Oppenheimer, L. Santos-Argumedo, and F. Schuber CD38 induces apoptosis of a murine pro-B leukemic cell line by a tyrosine kinase-dependent but ADP-ribosyl cyclase- and NAD glycohydrolase-independent mechanism Int. Immunol., July 1, 2006; 18(7): 1029 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Hus, M. Podhorecka, A. Bojarska-Junak, J. Rolinski, M. Schmitt, M. Sieklucka, E. Wasik-Szczepanek, and A. Dmoszynska The clinical significance of ZAP-70 and CD38 expression in B-cell chronic lymphocytic leukaemia Ann. Onc., April 1, 2006; 17(4): 683 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Binet, F. Caligaris-Cappio, D. Catovsky, B. Cheson, T. Davis, G. Dighiero, H. Dohner, M. Hallek, P. Hillmen, M. Keating, et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia Blood, February 1, 2006; 107(3): 859 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marasca, R. Maffei, M. Morselli, P. Zucchini, I. Castelli, S. Martinelli, M. Fontana, S. Ravanetti, M. Curotti, G. Leonardi, et al. Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia J. Mol. Diagn., November 1, 2005; 7(5): 566 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ruiz-Ballesteros, M. Mollejo, A. Rodriguez, F. I. Camacho, P. Algara, N. Martinez, M. Pollan, A. Sanchez-Aguilera, J. Menarguez, E. Campo, et al. Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis Blood, September 1, 2005; 106(5): 1831 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deaglio, T. Vaisitti, L. Bergui, L. Bonello, A. L. Horenstein, L. Tamagnone, L. Boumsell, and F. Malavasi CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival Blood, April 15, 2005; 105(8): 3042 - 3050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Chiorazzi, K. R. Rai, and M. Ferrarini Chronic Lymphocytic Leukemia N. Engl. J. Med., February 24, 2005; 352(8): 804 - 815. [Full Text] [PDF]
|
|
|
|
|
|
A. Rodriguez, N. Martinez, F. I. Camacho, E. Ruiz-Ballesteros, P. Algara, J.-F. Garcia, J. Menarguez, T. Alvaro, M. F. Fresno, F. Solano, et al. Variability in the Degree of Expression of Phosphorylated I{kappa}B{alpha} in Chronic Lymphocytic Leukemia Cases With Nodal Involvement Clin. Cancer Res., October 15, 2004; 10(20): 6796 - 6806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Shanafelt and T. G. Call Current Approach to Diagnosis and Management of Chronic Lymphocytic Leukemia Mayo Clin. Proc., March 1, 2004; 79(3): 388 - 398. [Abstract] [PDF]
|
|
|
|
|
|
T. D. Shanafelt, S. M. Geyer, and N. E. Kay Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL Blood, February 15, 2004; 103(4): 1202 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deaglio, A. Capobianco, L. Bergui, J. Durig, F. Morabito, U. Duhrsen, and F. Malavasi CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells Blood, September 15, 2003; 102(6): 2146 - 2155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Guarini, G. Gaidano, F. R. Mauro, D. Capello, F. Mancini, M. S. De Propris, M. Mancini, E. Orsini, M. Gentile, M. Breccia, et al. Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features Blood, August 1, 2003; 102(3): 1035 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wiestner, A. Rosenwald, T. S. Barry, G. Wright, R. E. Davis, S. E. Henrickson, H. Zhao, R. E. Ibbotson, J. A. Orchard, Z. Davis, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile Blood, June 15, 2003; 101(12): 4944 - 4951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. I. Camacho, P. Algara, A. Rodriguez, E. Ruiz-Ballesteros, M. Mollejo, N. Martinez, J. A. Martinez-Climent, M. Gonzalez, M. Mateo, A. Caleo, et al. Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations Blood, May 15, 2003; 101(10): 4042 - 4046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Crespo, F. Bosch, N. Villamor, B. Bellosillo, D. Colomer, M. Rozman, S. Marce, A. Lopez-Guillermo, E. Campo, and E. Montserrat ZAP-70 Expression as a Surrogate for Immunoglobulin-Variable-Region Mutations in Chronic Lymphocytic Leukemia N. Engl. J. Med., May 1, 2003; 348(18): 1764 - 1775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Durig, H. Nuckel, A. Huttmann, E. Kruse, T. Holter, K. Halfmeyer, A. Fuhrer, R. Rudolph, N. Kalhori, A. Nusch, et al. Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia Blood, April 1, 2003; 101(7): 2748 - 2755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ghia, G. Guida, S. Stella, D. Gottardi, M. Geuna, G. Strola, C. Scielzo, and F. Caligaris-Cappio The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression Blood, February 15, 2003; 101(4): 1262 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lanham, T. Hamblin, D. Oscier, R. Ibbotson, F. Stevenson, and G. Packham Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia Blood, February 1, 2003; 101(3): 1087 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Keating, N. Chiorazzi, B. Messmer, R. N. Damle, S. L. Allen, K. R. Rai, M. Ferrarini, and T. J. Kipps Biology and Treatment of Chronic Lymphocytic Leukemia Hematology, January 1, 2003; 2003(1): 153 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Byrd, B. L. Peterson, V. A. Morrison, K. Park, R. Jacobson, E. Hoke, J. W. Vardiman, K. Rai, C. A. Schiffer, and R. A. Larson Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) Blood, January 1, 2003; 101(1): 6 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D'Arena, G. Nunziata, G. Coppola, M. L. Vigliotti, A. Tartarone, N. Carpinelli, R. Matera, R. C. Bisogno, G. Pistolese, and N. Di Renzo CD38 expression does not change in B-cell chronic lymphocytic leukemia Blood, September 26, 2002; 100(8): 3052 - 3052. [Full Text] [PDF]
|
|
|
|
|
|
A. C. Rawstron, M. R. Yuille, J. Fuller, M. Cullen, B. Kennedy, S. J. Richards, A. S. Jack, E. Matutes, D. Catovsky, P. Hillmen, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion Blood, September 18, 2002; 100(7): 2289 - 2290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Oscier, A. C. Gardiner, S. J. Mould, S. Glide, Z. A. Davis, R. E. Ibbotson, M. M. Corcoran, R. M. Chapman, P. W. Thomas, J. A. Copplestone, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors Blood, July 30, 2002; 100(4): 1177 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ferrajoli, M. J. Keating, T. Manshouri, F. J. Giles, A. Dey, Z. Estrov, C. A. Koller, R. Kurzrock, D. A. Thomas, S. Faderl, et al. The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia Blood, July 30, 2002; 100(4): 1215 - 1219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Krober, T. Seiler, A. Benner, L. Bullinger, E. Bruckle, P. Lichter, H. Dohner, and S. Stilgenbauer VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia Blood, July 30, 2002; 100(4): 1410 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lin, P. D. Sherrington, M. Dennis, Z. Matrai, J. C. Cawley, and A. R. Pettitt Relationship between p53 dysfunction, CD38 expression, and IgVH mutation in chronic lymphocytic leukemia Blood, July 30, 2002; 100(4): 1404 - 1409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishibe, M. Albitar, I. B. Jilani, L. R. Goldin, G. E. Marti, and N. E. Caporaso CXCR4 expression is associated with survival in familial chronic lymphocytic leukemia, but CD38 expression is not Blood, July 18, 2002; 100(3): 1100 - 1101. [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Chang and R. P. Cleveland Conversion of CD38 and/or myeloid-associated marker expression status during the course of B-CLL: association with a change to an aggressive clinical course Blood, July 18, 2002; 100(3): 1106 - 1106. [Full Text] [PDF]
|
|
|
|
|
|
A. C. Rawstron, M. J. Green, A. Kuzmicki, B. Kennedy, J. A. L. Fenton, P. A. S. Evans, S. J. M. O'Connor, S. J. Richards, G. J. Morgan, A. S. Jack, et al. Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts Blood, June 28, 2002; 100(2): 635 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Damle, F. Ghiotto, A. Valetto, E. Albesiano, F. Fais, X.-J. Yan, C. P. Sison, S. L. Allen, J. Kolitz, P. Schulman, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes Blood, May 13, 2002; 99(11): 4087 - 4093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Till, K. Lin, M. Zuzel, and J. C. Cawley The chemokine receptor CCR7 and alpha 4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes Blood, April 15, 2002; 99(8): 2977 - 2984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Matutes New additions to antibody panels in the characterisation of chronic lymphoproliferative disorders J. Clin. Pathol., March 1, 2002; 55(3): 180 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Hamblin, J. A. Orchard, R. E. Ibbotson, Z. Davis, P. W. Thomas, F. K. Stevenson, and D. G. Oscier CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease Blood, February 1, 2002; 99(3): 1023 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Kay, T. J. Hamblin, D. F. Jelinek, G. W. Dewald, J. C. Byrd, S. Farag, M. Lucas, and T. Lin Chronic Lymphocytic Leukemia Hematology, January 1, 2002; 2002(1): 193 - 213. [Abstract] [Full Text]
|
|
|
|
|
|
K. R. Rai, H. Dohner, M. J. Keating, and E. Montserrat Chronic Lymphocytic Leukemia: Case-Based Session Hematology, January 1, 2001; 2001(1): 140 - 156. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
, and Ig
), cytogenetics, and molecular studies (immunoglobulin
heavy- and light-chain gene rearrangement and T-cell receptor
rearrangement). Patients were selected for the study based on the
availability of peripheral blood samples at the time of presentation,
and complete clinical data were recorded from time of diagnosis (time
of collecting samples) to the date of the study. Samples were collected
at the time of presentation, before therapy was initiated. Of the 218 patients, 142 patients were previously untreated and the rest were
previously treated at other institutions. All patients were selected
randomly, and patients were not selected based on their history of
therapy. All samples were collected under an approved protocol with
consent forms signed by the patients. Therapy was mainly based on fludarabine.
patient subgroups
those with worse prognoses had
high CD38 expression on malignant cells (20% or more), and those with
a good prognoses had low CD38 expression (less than 20%). Multivariate
analyses confirmed that CD38 expression is an important prognostic
factor. We also correlated this observation to most of the known
prognostic parameters for B-CLL to bolster our findings that CD38 is an
important prognostic factor. Whether CD38 expression reflects the
mutation status of the VgH gene will be further
evaluated. Regardless of this association (or lack of it), CD38
expression is a powerful prognostic tool that should be considered a
standard clinical test for all patients with B-CLL.
-mediated signaling pathway in induction of CD38 cell-surface antigen.
Blood.
1997;89:3607-3614