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NEOPLASIA
From Abteilung Innere Medizin III, University of Ulm,
Germany; Zentrale Einheit Biostatistik and Abteilung Organisation
komplexer Genome, Deutsches Krebsforschungszentrum, Heidelberg,
Germany.
In chronic lymphocytic leukemia (CLL), biologic risk factors such
as immunoglobulin variable heavy chain gene
(VH) mutation status, CD38 expression level,
and genomic aberrations have recently been identified, but the relative
prognostic impact of the individual parameters is unknown. In the
current study, we analyzed VH mutation status
by polymerase chain reaction and sequencing (n = 300), genomic
aberrations by fluorescence in situ hybridization (+3q, 6q Chronic lymphocytic leukemia (CLL) is characterized
by a highly variable clinical course. Some patients die within a few
months of diagnosis, whereas others survive prolonged periods without requiring therapy.1,2 To estimate prognosis in CLL, 2 major staging systems, mainly based on tumor load, are
used.3,4 These systems define distinct prognostic
subgroups, but their ability to predict the outcome of individual
patients at the time of diagnosis, in particular in early-stage
disease, is limited. Therefore, other factors related to the biology of
CLL, such as genetic markers, are currently evaluated for their
prognostic impact.
Clonal genomic aberrations can be identified in approximately 80% of
CLL patients by fluorescence in situ hybridization
(FISH)5; 17p deletion (17p Another genetic marker, related to the stage of B-cell differentiation,
is provided by the recombination of variable (V), diversity (D), and
joining (J) immunoglobulin gene segments and the process of somatic
hypermutation, which physiologically occurs in the germinal center (for
review, see 10). Although the CLL B cells were originally
considered to correspond to antigen-inexperienced pregerminal center
lymphocytes, recent data indicated that in approximately half of all
cases, somatically mutated variable region heavy chain genes
(VH) are present.11,12
In pivotal studies correlating the VH mutation
status with survival probability, Hamblin et al13 and Damle
et al14 have shown that the presence of unmutated
VH predicted for an inferior clinical course in
CLL. In one of these studies, a high CD38 expression level was found to
correlate with the presence of unmutated VH genes and an unfavorable clinical outcome,14 but the
relation of CD38 expression to VH mutation
status and survival is the subject of controversial
discussion.15-18 The objective of this study was to
evaluate the relation among genomic aberrations,
VH mutation status, and CD38 expression and the
relative prognostic impact of these factors in a large series of CLL patients.
Patients
Interphase cytogenetic analysis
Identification and sequencing of clonal VDJ rearrangements Genomic DNA was isolated from cryopreserved cells with the Trizol reagent (Gibco BRL, Eggenstein, Germany). In 273 of 300 patients, VDJ analysis was carried out from the same sample as the FISH analysis, and in the remaining 27 patients follow-up samples were used. Amplification of the VDJ rearrangements was performed by polymerase chain reaction (PCR) using (5'-VH) framework region (FR)I or leader region and (3'-JH) FRIV family-specific consensus oligonucleotide primers.12,19 To reduce the number of PCR reactions, the 5'-VH primers were labeled with fluorescent dyes for subsequent genescan analysis. In 2 multiplex PCR set-ups, the unlabeled (3'-JH) primer mix was combined with labeled mixtures of either VH1/7, 3, and 4 or VH2, 5, and 6 (5'-VH) family-specific primers. To detect which VH gene family was involved in the clonal VDJ re-arrangement, the 5'-VH primer leading to the amplification of the PCR product was identified by genescan analyses on a genetic analyzer model 377 (Applied Biosystems, Weiterstadt, Germany). PCR was performed in a final volume of 50µL with 10 pmol of each primer, 100 µmol of each deoxyribonucleoside triphosphate (dNTP), and 1.25 U HotStarTaq polymerase (Qiagen, Hilden, Germany) with reaction buffer. Amplification consisted of an initial denaturation step of 15 minutes at 95°C followed by 35 cycles of 94°C for 30 seconds, 65°C for 45 seconds, and 72°C for 1.5 minutes, with a final extension step of 10 minutes. Because of the PCR primer location in the FRI, this region was only partially evaluable with this set-up, and VH sequencing was successfully repeated in 217 of the 300 patients to allow analysis of the entire FRI with the corresponding leader region I primers as described,12 except for the VH4 family for which the primer 5'-ATGAAACACCTGTGGTTCTT-3' was used.PCR products were spin column-purified (Qiagen) and directly sequenced using dye terminator chemistry (Big Dye Kit; Applied Biosystems) with the appropriate nonlabeled 5'-VH and 3'-JH PCR primers on a genetic analyzer model 377 (Applied Biosystems). If more than one product was detected for one VH family the PCR products were cloned and subsequently sequenced. All cases were verified by sequence analysis of at least one independent PCR product. The VDJ nucleotide sequences were aligned to current databases (EMBL/GenBank, V-base directory).20 Homology to the nearest germline gene was calculated in relation to the entire VH (n = 217) or to the length of the sequenced fragment available (n = 83) in patients who did not amplify with leader region primers or in whom no DNA was available. CDRIII was defined as the nucleotide sequence between the codon 94, the last codon of FRIII, and codon 102, the first codon of FRIV. CD38 expression CD38 expression was analyzed from cryopreserved cells in 157 cases by triple-color fluorescence-activated cell sorting (FACS) analysis. Mononuclear cells had been isolated before freezing by Ficoll-Hypaque density gradient centrifugation. In analogy with Damle et al,14 the cells were stained with anti-CD5, anti-CD19, and anti-CD38 using the following antibody conjugates: anti-CD5-FITC (clone L17F12), anti-CD19-PerCPCy5.5 (clone SJ25C1), and anti-CD38-PE (clone HB-7), (all from Becton Dickinson, Heidelberg, Germany). Isotype-matched negative controls were used in all assays to determine positive from negative cells. In accordance with previous studies,15 -18 the percentage of CD38+ cells was measured in the CD19+/CD5+ fraction. Flow cytometric analyses were performed on a Becton Dickinson FACScan flow cytometer. In 143 cases samples from the same time point as the cytogenetic analysis were studied. To investigate whether CD38 expression remains stable during the course of the disease, samples obtained at several different time points were studied in 12 patients; 2 time points in 6, and 3 time points in another 6 patients.Statistical analysis The primary end point was survival from the time of diagnosis. Survival time distributions were plotted using Kaplan-Meier estimates. Median duration of follow-up was calculated according to the method of Korn.21 Testing and estimation of possible cutoff values for the VH gene homology and CD38 expression was done by maximally selected log-rank statistics,22 and 95% CIs of the cut-off values were computed using 1000 bootstrap samples. The proportional hazards regression model of Cox was used to identify differences in survival time distribution from prognostic factors.23 As possible prognostic factors age, sex, stage according to Binet and Rai, hemoglobin (Hb) levels, white blood cell count (WBC), platelet count, serum lactate dehydrogenase (LDH) and alkaline phosphatase (AP) levels, presence or absence of splenomegaly and lymphadenopathy, extent of peripheral lymphadenopathy, greatest lymph-node diameter measured, presence or absence of genomic aberrations (17p ,11q,+12q,13q,6q), CD38 expression 7% or more
versus less than 7%, and VH homology 97% or
more versus less than 97% were included in the regression model.
Regression analysis was repeated with the same parameters, and the
classical VH homology cut-off at 98% (ie,
separation of 2 groups with VH homology 98% or
greater versus less than 98%). To correct for overestimation of the
relative risk estimate, shrinkage of the parameter estimates was
applied.24 Missing data were estimated using a
multiple-imputation technique with 10 random draws. A limited
backward-selection procedure was used to exclude redundant or
unnecessary variables.25
Groupwise comparisons of distributions of clinical, laboratory, and genetic data were performed with the Kruskal-Wallis test (quantitative) and the Fisher exact test (categorical variables). All tests were 2-sided. An effect was considered statistically significant at P = .05. To provide quantitative information on the relevance of statistically significant results, 95% CIs for hazard ratios were computed. Pairwise correlations were estimated using Pearson product-moment correlation coefficient. Statistical analyses were performed with the StatXact (Cytel Software, Cambridge, MA), S-Plus (Insightful, Seattle, WA), and Design software packages25 and with GraphPad Prism version 3.00 (GraphPad Software, San Diego, CA).
VH mutation status In all cases clonal VDJ rearrangements were amplifiable using the 5'-VH FRI PCR primers, whereas VDJ amplification with corresponding 5'-VH family specific leader region I primers was successful in 217 patients. Further analysis was therefore based on the sequence of the entire VH, obtained with leader region I primers in 217 patients, and on the sequence of VH lacking part of the FRI, obtained with the 5'-VH FRI primers in the remaining 83 patients. According to the following criteria, the VDJ rearrangements were considered to be nonfunctional: rearrangement of a pseudogene, stop codon, or frameshift in the CDRIII, incomplete rearrangement. Applying these criteria, 265 patients had functional VDJ rearrangement.Considering the classical VH homology
cutoff value of 98%, 132 (44%) patients had mutated and 168 (56%)
patients had unmutated VH genes. The germline
homology rate ranged from 84% to 100% (median, 98.97%; interquartile
range, 94.58% to 100%). To study the prognostic influence of
different VH mutation rates, maximally selected
log-rank tests were performed. According to the corrected P
(Pcor) of the maximally selected log-rank statistics, the
estimated VH homology rate allowing the best
separation of 2 subgroups with different survival probabilities
was not 98% but was 97% (95% CI, 96%-98%; Pcor <.001) (Figure
1A). One hundred eighty-eight (63%)
patients had a VH homology of 97% or greater,
and 112 (37%) patients had a VH homology less
than 97%. Median overall survival (OS) time of the subgroup with
VH homology less than 97% could not be
estimated. The last observed death was after 152 months of follow-up
time with a corresponding estimated survival probability of 56%.
Estimated median survival time of the group with
VH homology 97% or greater was 79 months
(Figure 2A). When only patients diagnosed
at Binet stage A were considered (n = 189), 91 (48%) had a
VH homology less than 97% and 98 (52%) had a
VH homology of 97% or greater. Estimated median
OS of the group with VH homology of 97% or
greater in the Binet A patients was 79 months. The last death in the
group with VH homology less than 97% was
observed after 152 months of follow-up time, with a corresponding
estimated survival probability of 53% (Figure 2B). The same analyses
were performed for the classical VH homology
cutoff value of 98%. Estimated median OS of the groups with
VH homology of 98% or greater was 79 months for
all patients and for Binet A patients, whereas the median OS was 152 months for the groups with VH homology less than
98% for all patients and for Binet A patients (Figure 2C-D).
CD38 expression CD38 expression level of the tumor cell population was evaluated in 157 patients. The proportion of CLL cells expressing CD38 above the isotype control level ranged from 0.24% to 98.99%, with a median of 9.99% (interquartile range, 1.99%-57.4%). Examples of representative scatterplots are shown in Figure 3A-C.Survival probabilities of patients expressing CD38 in more (56 patients, 36%) or less (101 patients, 64%) than 30% of tumor cells
was not significantly different (estimated median OS, 79 vs 113 months;
P = .13, log-rank test; Figure
4A). Maximally selected log-rank
statistics were performed to evaluate a possible cut-off value for CD38
expression with respect to changes in the survival time distribution.
Estimated CD38 expression level yielding the best separation of 2 subgroups with different survival probabilities was 7% (95% CI,
20%-71%; Pcor = .02; Figure 1B). Estimated
median OS of cases with a CD38 expression less than 7% (75 patients, 48%) was 114 months versus 79 months in the group expressing CD38 in
7% or more (82 patients, 52%) of tumor cells (Figure 4B).
Table 1 and Figure
5A,B summarize the relation and
distribution of CD38 expression and the VH
mutation status. A high CD38 expression correlated with unmutated
VH, but in at least 34% of patients, depending
on the VH homology and CD38 expression cut-off value chosen, CD38 expression failed to predict the
VH mutation status.
CD38 expression level was analyzed in follow-up samples of 12 patients over a median time interval of 29 months (range, 8 to 60 months) to investigate whether the CD38 expression level remains constant over time. All but one patient received chemotherapy, consisting of alkylating agents or purine analogs, or both, within this period. The median change in the proportion of CD38-expressing cells was 8% (range, 0%-51%). Among the 12 patients, 3 exhibited initial CD38 expression levels less than 7% and 7% or more in follow-up samples. Four patients exhibited CD38 expression levels less than 30% or 30% or more at different time points. Of these, CD38 expression changed from less than 30% to 30% or more in 2 patients and from 30% or more to less than 30% in another 2 patients. Thus, at least 3 of 12 patients, depending on the cutoff chosen, would have been classified in different prognostic subgroups at different time points according to the CD38 expression level. Relation of VH mutation status and genomic aberrations By interphase cytogenetics, 246 (82%) of 300 patients exhibited genomic aberrations. Table 2 lists these aberrations in order of decreasing frequency and shows the comparison of specific genomic aberrations according to the VH mutation status. The overall incidence of genomic abnormalities in the VH mutated and unmutated subgroups was similar, as was the incidence of trisomy 12q (Table 2). Prognostically favorable aberrations, such as 13q deletion or 13q deletion as a single aberration, were significantly more frequent in the VH mutated group. High-risk genomic aberrations such as 17p deletion and 11q deletion were detected almost exclusively in VH unmutated patients. However, only approximately one third of the VH unmutated patients did show high-risk genomic aberrations (11q or 17p deletion) (Table 2).
VH mutation status, genomic aberrations, clinical data, and survival Based on a VH homology cutoff value of 97%, the proportional-hazards regression model identified 5 significant prognostic factors: VH homology of 97% or greater (P < .001), 17p deletion (P < .001), age (P < .001), WBC (P < .001), and LDH (P < .001). The 11q deletion was identified as an additional independent factor in multivariate analysis when a VH homology of 98% was used as cutoff value. Hazard ratios, together with their 95% confidence limits, are shown in Table 3. Disease stage was not selected as a significant independent factor when VH mutation status and genomic aberrations were included in the multivariate analysis. However, the relevance of stage according to Binet as a prognostic factor was evident if tested alone (P < .001).
Table 4 shows the clinical and laboratory
data for the patients in the subgroups 17p deletion,
VH homology 97% or greater, and
VH homology less than 97% at the time of
enrollment. Distribution of age and sex was comparable in the 3 subgroups. Patients with 17p deletion and VH
homology of 97% or greater had more advanced disease, whereas patients
with VH homology less than 97% had the highest
proportion at Binet stage A. The subgroups with 17p deletion and
VH homology of 97% or greater were more likely
to have extensive splenomegaly and lymphadenopathy. Moreover, fever,
night sweats, or weight loss (B symptoms) were more frequent in the
groups with 17p deletion or VH homology of 97%
or greater. These subgroups also had lower Hb levels, lower platelet
counts, higher WBC, and higher LDH and AP levels. As indicated by the
treatment-free intervals, patients with 17p deletion,
VH homology 97% or greater and less than
97% showed significant differences in their rates of disease progression (median treatment-free intervals, 3.5 vs 33 vs 105 months).
Based on the results of the regression model, 4 genetic subgroups were
defined in which each patient was allocated to one category only:
patients with a 17p deletion regardless of their VH mutation status, patients with an 11q
deletion and no 17p deletion regardless of their
VH mutation status, patients with unmutated VH but not a 17p or 11q deletion, and patients
with mutated VH but not a 17p or 11q deletion.
As illustrated in Figure 6, the estimated
median survival times for these categories were 30 months for 17p
deletion, 70 months for 11q deletion, and 89 months for unmutated
VH (homology cut-off at 97% or 98%), whereas
in the group with mutated VH, the last observed
death was at 152 months, corresponding to an estimated survival
probability of 58% at less than 97% and of 54% at less than 98%
homology cut-off, respectively. The impact of the genetic risk
categories held also true when only patients diagnosed at Binet stage A
were evaluated (Figure 6).
VH mutation status, CD38 expression, genomic aberrations, and clinical data were analyzed in a series of 300 CLL patients. In this study we confirm that CLL patients with unmutated VH have significantly shorter survival times than patients with mutated VH.13,14 Interestingly, in our series the estimated VH homology rate yielding the best separation of 2 subgroups with different survival probabilities was not the classical cut-off value of 98% but was 97% VH homology to the nearest germline gene. This finding is still compatible with published data because the 95% CI of the analysis ranged from 96% to 98% homology. We cannot rule out that this effect is attributable to methodological aspects because in patients in whom there was no amplification with leader region primers (n = 83), the amplification was performed with FRI primers, and, therefore, the first part of the FRI was not amenable for sequence homology evaluation. However, in a separate analysis of the 217 patients amplifiable with leader region I 5'-VH primers, a cut-off value of 97% VH homology was obtained by maximally selected log-rank statistics (data not shown). On the other hand, one should note that the classical 98% homology cut-off definition for mutated VH was based on germline polymorphism considerations and was not derived from the analysis of survival probability in CLL patients according to VH mutation status. The biologic significance of this finding is not clear and will be further studied. The proportion of CLL cells expressing CD38, a parameter proposed to serve as a surrogate marker for VH mutation status,14 was investigated in our series in 157 CLL patients. High CD38 expression levels correlated with unmutated VH genes and low CD38 expression levels with mutated VH genes, but, as described by others, in approximately one third of patients the CD38 expression level did not predict the VH mutation status.15-17 In agreement with Thunberg et al,16 there was no significant difference in the estimated median survival times when using the 30% cut-off value for CD38 positivity. However, by maximally selected log-rank statistics the best separation of 2 prognostic subgroups was achieved for a cut-off value of 7% CD38 positivity. Of note is the wide 95% CI of the analysis, ranging from 20% to 71%. As in the current study, a lower CD38 cut-off value, namely 20%, was also used recently by Ibrahim et al,18 to demonstrate an inferior outcome of CD38+ CLL patients. In their series the prognostic impact of CD38 expression was significant in multivariate analysis (P = .0258), but 17p deletion, 11q deletion, and VH mutation status, which are the strongest adverse prognostic factors in our study, were not included as parameters in their model. As shown by Ibrahim et al,18 who found a significant CD38 expression change in 1 of 6 patients, at least 25% of patients in our study would have been classified in different CD38 expression subgroups at different time points. Chemotherapy was initiated in 11 of the 12 patients showing variability in CD38 expression. Although at the 7% cut-off 3 patients and at the 30% cut-off 2 patients exhibited increasing CD38 expression, in 2 patients CD38 expression decreased from greater than 30% to less than 30%. The variation observed among different studies on the CD38 expression in CLL might have been caused by methodological aspects. Therefore, an interlaboratory survey, coordinated by N. Chiorazzi (North Shore-Long Island Research Institute, NY), is being performed to evaluate this issue. Apart from the VH mutation status, another genetic parameter of prognostic significance in CLL is provided by genomic aberrations.5 In a previous study applying chromosome banding, a higher rate of trisomy 12 was observed in the VH unmutated CLL subgroup.13 In this study the lower incidence of trisomy 12 coincided with a lower overall ability to detect genomic aberrations in the VH mutated compared with the unmutated subgroup, a fact likely reflecting the different in vitro proliferative potential.13 In the current study interphase FISH, a more sensitive technique not dependent on in vitro proliferation, was used. The overall incidence of genomic aberrations and the incidence of trisomy 12 were similar in the VH mutation subgroups. In contrast, high-risk genomic aberrations such as 17p deletion and 11q deletion occurred significantly more frequently in the unmutated VH subgroup, whereas favorable prognostic markers such as 13q deletion and 13q deletion as a single aberration were overrepresented in the mutated VH subgroup. The unbalanced distribution of genomic aberrations might point toward a distinct biologic background of the CLL subgroups defined by VH mutation status and may in part explain their different clinical behaviors. To evaluate the relative prognostic impact of VH mutation status, CD38 expression level, genomic aberrations, and clinical, as well as laboratory parameters, multivariate analysis was performed. VH homology of 97% or more (P < .001), 17p deletion (P < .001), age (P < .001), WBC (P < .001), and serum LDH (P < .001) were identified as significant prognostic factors at the 97% VH homology cut-off value. Deletion 11q entered the model as an additional independent prognostic factor on the use of the classical 98% VH homology cut-off. Clinical staging provided a significant separation of prognostic subgroups with respect to their survival time distributions but did not contribute additional information regarding survival probability in the knowledge of VH mutation status and genomic aberrations. This may be illustrated by Figure 2. Patients with VH mutated CLL were frequently diagnosed at Binet stage A (91 of 112 at the less than 97% and 106 of 132 at the less than 98% VH homology cutoffs) and showed a good outcome. However, among patients diagnosed at Binet stage A, unmutated VH status had the power to identify a large subgroup (98 of 189 at the 97% or greater and 83 of 189 at the 98% or greater VH homology cutoffs) with an inferior outcome. In this study 17p deletion, 11q deletion, and unmutated
VH status were the strongest adverse prognostic
factors, indicating that the clinical heterogeneity of
CLL1-4 might have a biologic basis. Genomic aberrations
and VH mutation status appeared to have a
complementary role in estimating prognosis. A risk model derived from
multivariate regression analysis allowed the definition of 4 subgroups
of CLL patients based on 17p deletion, 11q deletion, and
VH mutation status. The subgroups appear to be
characterized by markedly different survival probabilities and may
allow a prediction of the clinical course of CLL patients at an early
stage of disease. Therefore, the value of genetic risk parameters in
relation to other factors, such as Rai and Binet staging, lymphocyte
doubling time, bone marrow infiltration pattern,
We thank Annett Habermann, Katrin Scherer, and Andreas Bühler for excellent experimental assistance and Dr Lutz Edler for statistical advice. We thank Drs Freda Stevenson, David Oscier, Terry Hamblin, Nick Chiorazzi, and Guillaume Dighiero for open discussions during the project.
Submitted September 4, 2001; accepted March 12, 2002.
Supported by grants from Wilhelm Sander-Stiftung (2001.004.1), Deutsche Krebshilfe (10-1289-St I), University of Ulm (P.679), and BMBF (01KW9934, 01KW9938, and NGFN/KB-6).
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: Hartmut Döhner, Department of Internal Medicine III, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany; e-mail: hartmut.doehner{at}medizin.uni-ulm.de.
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S. Falt, M. Merup, G. Tobin, U. Thunberg, G. Gahrton, R. Rosenquist, and A. Wennborg Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia Blood, July 15, 2005; 106(2): 681 - 689. [Abstract] [Full Text] [PDF]
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P. Grabowski, M. Hultdin, K. Karlsson, G. Tobin, A. Aleskog, U. Thunberg, A. Laurell, C. Sundstrom, R. Rosenquist, and G. Roos Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status Blood, June 15, 2005; 105(12): 4807 - 4812. [Abstract] [Full Text] [PDF]
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D. L. Kienle, C. Korz, B. Hosch, A. Benner, D. Mertens, A. Habermann, A. Krober, U. Jager, P. Lichter, H. Dohner, et al. Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes J. Clin. Oncol., June 1, 2005; 23(16): 3780 - 3792. [Abstract] [Full Text] [PDF]
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C. Moreno, N. Villamor, D. Colomer, J. Esteve, R. Martino, J. Nomdedeu, F. Bosch, A. Lopez-Guillermo, E. Campo, J. Sierra, et al. Allogeneic Stem-Cell Transplantation May Overcome the Adverse Prognosis of Unmutated VH Gene in Patients With Chronic Lymphocytic Leukemia J. Clin. Oncol., May 20, 2005; 23(15): 3433 - 3438. [Abstract] [Full Text] [PDF]
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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]
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H. Nuckel, V. Rebmann, J. Durig, U. Duhrsen, and H. Grosse-Wilde HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia Blood, February 15, 2005; 105(4): 1694 - 1698. [Abstract] [Full Text] [PDF]
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G. Dighiero CLL Biology and Prognosis Hematology, January 1, 2005; 2005(1): 278 - 284. [Abstract] [Full Text] [PDF]
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D. W. Milligan, S. Fernandes, R. Dasgupta, F. E. Davies, E. Matutes, C. D. Fegan, C. McConkey, J. A. Child, D. Cunningham, G. J. Morgan, et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses Blood, January 1, 2005; 105(1): 397 - 404. [Abstract] [Full Text] [PDF]
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G. Tobin, U. Thunberg, K. Karlsson, F. Murray, A. Laurell, K. Willander, G. Enblad, M. Merup, J. Vilpo, G. Juliusson, et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia Blood, November 1, 2004; 104(9): 2879 - 2885. [Abstract] [Full Text] [PDF]
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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]
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T. Hamblin CLL: to mend it or be rid of it Blood, October 15, 2004; 104(8): 2210 - 2210. [Full Text] [PDF]
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G. F. Widhopf II, L. Z. Rassenti, T. L. Toy, J. G. Gribben, W. G. Wierda, and T. J. Kipps Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins Blood, October 15, 2004; 104(8): 2499 - 2504. [Abstract] [Full Text] [PDF]
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M. Ritgen, S. Stilgenbauer, N. von Neuhoff, A. Humpe, M. Bruggemann, C. Pott, T. Raff, A. Krober, D. Bunjes, R. Schlenk, et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR Blood, October 15, 2004; 104(8): 2600 - 2602. [Abstract] [Full Text] [PDF]
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C. Haslinger, N. Schweifer, S. Stilgenbauer, H. Dohner, P. Lichter, N. Kraut, C. Stratowa, and R. Abseher Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status J. Clin. Oncol., October 1, 2004; 22(19): 3937 - 3949. [Abstract] [Full Text] [PDF]
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L. Z. Rassenti, L. Huynh, T. L. Toy, L. Chen, M. J. Keating, J. G. Gribben, D. S. Neuberg, I. W. Flinn, K. R. Rai, J. C. Byrd, et al. ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia N. Engl. J. Med., August 26, 2004; 351(9): 893 - 901. [Abstract] [Full Text] [PDF]
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H. Kohlhammer, C. Schwaenen, S. Wessendorf, K. Holzmann, H. A. Kestler, D. Kienle, T. F. E. Barth, P. Moller, G. Ott, J. Kalla, et al. Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions Blood, August 1, 2004; 104(3): 795 - 801. [Abstract] [Full Text] [PDF]
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L. J. Rush, A. Raval, P. Funchain, A. J. Johnson, L. Smith, D. M. Lucas, M. Bembea, T.-H. Liu, N. A. Heerema, L. Rassenti, et al. Epigenetic Profiling in Chronic Lymphocytic Leukemia Reveals Novel Methylation Targets Cancer Res., April 1, 2004; 64(7): 2424 - 2433. [Abstract] [Full Text] [PDF]
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P. Dreger, S. Stilgenbauer, A. Benner, M. Ritgen, A. Krober, M. Kneba, N. Schmitz, and H. Dohner The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status Blood, April 1, 2004; 103(7): 2850 - 2858. [Abstract] [Full Text] [PDF]
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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]
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J. C. Byrd, S. Stilgenbauer, and I. W. Flinn Chronic Lymphocytic Leukemia Hematology, January 1, 2004; 2004(1): 163 - 183. [Abstract] [Full Text] [PDF]
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Y. Vasconcelos, F. Davi, V. Levy, P. Oppezzo, C. Magnac, A. Michel, M. Yamamoto, O. Pritsch, H. Merle-Beral, K. Maloum, et al. Binet's Staging System and VH Genes Are Independent but Complementary Prognostic Indicators in Chronic Lymphocytic Leukemia J. Clin. Oncol., November 1, 2003; 21(21): 3928 - 3932. [Abstract] [Full Text] [PDF]
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Z. A. Davis, J. A. Orchard, M. M. Corcoran, and D. G. Oscier Divergence from the germ-line sequence in unmutated chronic lymphocytic leukemia is due to somatic mutation rather than polymorphisms Blood, October 15, 2003; 102(8): 3075 - 3075. [Full Text] [PDF]
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D. Kienle, A. Krober, T. Katzenberger, G. Ott, E. Leupolt, T. F. E. Barth, P. Moller, A. Benner, A. Habermann, H. K. Muller-Hermelink, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome Blood, October 15, 2003; 102(8): 3003 - 3009. [Abstract] [Full Text] [PDF]
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 O Moshynska, K Sankaran, and A Saxena Molecular detection of the G(-248)A BAX promoter nucleotide change in B cell chronic lymphocytic leukaemia Mol. Pathol., August 1, 2003; 56(4): 205 - 209. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
CLL cells (28.9% CD38+
cells).
2-microglobulin, thymidine kinase, and so on is being
evaluated in prospective multicenter trials of the German CLL Study
Group (GCLLSG). Based on these trials future treatment strategies using
biologic risk stratification at the time of diagnosis for individual
patients may be envisaged.