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PubMed2006

The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R-positive CLL cells.

The cytokine B lymphocyte stimulator (BLyS) mediates its effect through cell-surface receptors BAFF-R, TACI, and BCMA. BLyS receptors are expressed only on B cells and not present in other normal cells including normal T lymphocytes. Chronic lymphocytic leukemia (CLL) is a B-cell disease and CLL lymphocytes express BLyS receptors. Gelonin, a type 1 ribosome-inactivating toxin, lacks cell membrane binding domain and hence is nontoxic to intact cells. We generated a construct of recombinant gelonin (rGel) fused to BLyS to specifically target quiescent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19(+) B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize into these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC(50) of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-mediated decrease in protein synthesis was associated with a decline in short-lived proteins such as MCL-1 and XIAP, the 2 survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hallmark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients.

Antigens, CD19↗

PubMed2002

Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog.

We have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) that induces apoptosis in a number of malignant cell types. We now describe our studies examining the effects of CD437 and a nonretinoidal analog (MM002) on the in vitro proliferation of the ALL-REH cell line, the in vitro and in vivo growth of a novel Epstein-Barr virus-negative (EBV(-)) B-cell chronic lymphocytic leukemia (B-CLL) cell line (WSU-CLL), and primary cultures of human B-CLL and acute lymphoblastic leukemia (ALL) cells. CD437 and MM002 induce apoptosis in both cell lines, as indicated by the activation of caspase-2 and caspase-3, cleavage of poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase, increase in annexin V binding, and subsequent nuclear fragmentation. CD437-mediated apoptosis was not associated with the modulation of Bcl-2, Bax, or Mcl-1 levels, but was associated with the cleavage of the antiapoptotic protein Bcl-X(L) to a proapoptotic 18-kD form. This cleavage of Bcl-X(L) was dependent on caspase-3 activation since Bcl-X(L) cleavage and apoptosis were inhibited by the caspase-3 inhibitor Z-DVED-fmk. CD437 markedly inhibited the growth of WSU-CLL cells in severe combined immunodeficiency (SCID) mice. Tumor growth inhibition, growth delay, and log cell kill were 85.7%, 21 days, and 2.1, respectively, in the treated mice. Moreover, 1 of the 5 treated mice was tumor-free longer than 150 days and thus was considered cured. Exposure of primary cultures of both B-CLL and ALL cells obtained from patients to CD437 and MM002 resulted in their apoptosis. These results suggest that CD437 and MM002 analogs may have a potential role in the treatment of B-CLL and ALL.

Acetylation↗

PubMed1994

Genetic predisposition of autoimmune disease and B-cell chronic lymphocytic leukemia (B-CLL).

Autoimmune disease is a polygenic disease in which various genetic factors play crucial roles. The familial clustering and the association of HLA haplotypes have been well-recognized. There is a close association between chronic lymphocytic leukemia (CLL) and autoimmune disease. Like autoimmune diseases, CLL is the type of leukemia most often occurring among close relatives. The patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. As the majority of CLL is of CD5+ B-cell type, and as CD5+ B cells are suggested to be involved in autoimmunity, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells may be involved in both B-CLL and autoimmune disease. I discuss here the possibility that different, but related, MHC haplotypes would predispose either to autoimmune disease or to B-CLL, based on our findings obtained from MHC (H-2)-congenic New Zealand mouse strains.

Animals↗

PubMedDate not supplied

Chromosomal DNA and p53 stability, ubiquitin system and apoptosis in B-CLL lymphocytes.

The ubiquitin system regulates diverse biological processes such as DNA replication and repair, biogenesis of ribosome, peroxisome and nucleosome, cell cycle, stress response and signal transduction pathways. Thus, the reported role of the ubiquitin system in apoptotic death control as well the alteration of its control in carcinogenesis should come as no surprise. Indeed, we and other groups have reported that the ubiquitin system is involved in apoptotic cell death of normal human lymphocytes and that this control is altered in B lymphocytes derived from chronic lymphocytic leukemia patients (B-CLL), rendering these malignant cells hypersensitive to specific inhibition of protein degradation/processing through proteasomal function. This approach recently allowed us to demonstrate that the stability of the tumor suppressor and pro-apoptotic protein p53 is differentially regulated in B-CLL versus normal lymphocytes and that this difference might at least partly explain the impaired response of B-CLL lymphocytes to apoptotic death activation. These results strongly suggest an imbalance in p53 regulation in B-CLL cells that leads to a variable response to DNA damage and constitutively expressed chromosomal instability. The question we and others would like to address is whether this alteration, or more likely a subset of alterations of the ubiquitin-proteasome pathway, is specific to B-CLL malignancy or if it is a hallmark of cancer cells in general. In either case, a better understanding of the ubiquitin-dependent control of apoptosis should pave the way towards a methodological approach for in vitro development of discriminating treatments which may be of potential usefulness in clinical trials of B-CLL.

Apoptosis↗

PubMed1995

Immunophenotypic and DNA genotypic analysis of T-cell and NK-cell subpopulations in patients with B-cell chronic lymphocytic leukaemia (B-CLL).

Absolute numbers and distributions of peripheral blood T-cells and NK cells were immunophenotypically determined in 21 patients with B-CLL and compared with those obtained from a series of 13 elderly normal controls with an age range of 60-87 years. For absolute CD3+, CD4+ and CD8+ T-cell, and CD16+ NK subpopulation numbers, there were no consistent differences between the normal and B-CLL groups although some individual patient variation was seen. Immunophenotypic analyses did however reveal that CD3+ T-cells in almost half (10/21) of the B-CLL patients were Ia+ (defined as > 20% positive cells), compared to 0/13 of the elderly control group (p < 0.001), and that the proportions of CD4+ and CD8+ cells expressing membrane CD45RO were significantly increased compared to the control group. Subdivision of the B-CLL cases into those with low (< 20%) and high (> 20%) proportions of CD3+ T-cells co-expressing Ia further showed that CD45RO expression by CD4+ fractions was particularly prominent in the Ia+ subgroup, and that the relative increase of CD4+CD45RO+ cells was primarily a consequence of decreased absolute numbers of CD4+CD45RA+ lymphocytes. This study also examined extracted DNA from enriched CD3+ T-cell fractions (obtained by immunomagnetic bead selection in 9 of the B-CLL cases) by PCR analysis with two primers for the T-cell gamma gene locus. With the V gamma C (consensus) primer, 8/9 cases were polyclonal and the remaining case was oligoclonal. For comparison, 7/9 CD3+ fractions were oligoclonal with the V gamma 9 primer with the other two cases being polyclonal. No monoclonal CD3+ components were found. It is suggested that the observed increased Ia expression by CD3+ cells and the predominance of CD4+ cells expressing membrane CD45RO in patients with B-CLL may be of potential relevance to understanding the pathogenesis and patterns of disease progression.

Aged↗

PubMed2001

Treatment-induced expression of anti-apoptotic proteins in WSU-CLL, a human chronic lymphocytic leukemia cell line.

Bryostatin 1 (bryo 1) has been shown to potentiate the anti-tumor activity of 2-chloro-2-deoxyadenosine (2-CdA) in chronic lymphocytic leukemia (CLL) and in the WSU-CLL cell line. However, like resistant CLL, WSU-CLL cells lose their sensitivity to bryo 1/2-CdA treatment. We report that 2-CdA-induced IAP expression may be a possible mechanism whereby resistance to apoptosis is acquired in these cells. In WSU-CLL cells, three members of the Inhibitors of Apoptosis (IAP) family were identified. Bryo 1 treatment of WSU-CLL cells leads to initiation of the apoptotic cascade and induced a marginal increase in XIAP protein expression. In contrast, 2-CdA treatment, alone or in combination with bryo 1, induced a substantial increase in survivin and XIAP proteins and phosphorylation of BAD. Bryo 1 alone induced caspase-7 and -9 dependent [poly ADP-ribose] polymerase (PARP) cleavage, while sequential treatment with bryo 1 (72 h) followed by 2-CdA (24 h) induced caspase-3,-7, and -9 dependent PARP cleavage and increased apoptosis. Although exposure to bryo 1 initiated apoptotic events, apoptosis was first enhanced by 2-CdA, and then reversed in a time-dependent manner by 2-CdA-induced expression of survival proteins. Taken together, resistance to bryo 1/2-CdA treatment may be the result of 2-CdA-induced IAP inhibition of the intrinsic apoptotic pathway caspases.

2-Chloroadenosine↗

PubMed2000

Bryostatin 1-induced modulation of nucleoside transporters and 2-chlorodeoxyadenosine influx in WSU-CLL cells.

WSU-CLL cells, a fludarabine resistant B-cell chronic lymphocytic leukemia cell line, has been shown to exhibit enhanced sensitivity to 2-chlorodeoxyadenosine (2-CdA) following 48-72 h exposure to bryostatin 1. For 2-CdA to manifest its chemotherapeutic activity, it must first enter the cell through one of several specific nucleoside transporter systems. We present data to show that bryostatin 1-induced enhanced influx of 2-CdA is in part the result of bryostatin 1-induced modulation of nucleoside transporters in WSU-CLL cells. The bi-directional equilibrative NBMPR sensitive transporters in WSU-CLL cells were significantly down-regulated 90 min post-exposure to 1-200 nM bryostatin 1. This down-regulation was evident up to 144 h. In contrast, WSU-CLL cells exhibited a transient increase in Na+-dependent concentrative 2-CdA influx from 48 to 96 h after bryostatin 1 exposure which was evident for a longer duration than that accounted for by the increase in deocycytidine kinase activity. These data may, in part, explain the enhanced efficacy of 2-CdA seen in WSU-CLL cells following 48-72 h exposure to bryostatin 1. It may raise questions as to the importance of the bi-directional transporters in determining the resistance or sensitivity of CLL cells to 2-CdA or other nucleoside analogues.

Aged↗

PubMed2004

Potential therapeutic applications of oblimersen in CLL.

Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited single-agent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.

Animals↗

PubMed2005

Significance of VH genes mutation status for prognosis of CLL patients.

AIM: The aim of this study was to evaluate significance of VH mutation status for prognosis of B-cell chronic lymphocytic leukemia (B-CLL) patients in comparison with other prognostic markers. MATERIALS AND METHODS: The VH mutation status was evaluated in 43 B-CLL patients by RT-PCR amplification and nucleotide sequencing, and CD38 expression - by two-color FACS analysis. The prognostic influence of VH mutation rate and CD38 expression level was tested by different statistical methods. RESULTS: The increasing number of advanced cases over the follow-up period, shorter median time from diagnosis to start of second line therapy, worse response to fludarabine treatment, poor survival for early stages B-CLL were found in unmutated versus mutated CLL patients. The significance of CD38 expression for CLL prognosis was revealed as predictor for response for fludarabine treatment and time of progression in advanced stages. The correlation between CD38 expression and VH mutation status was not found. CONCLUSION: Simultaneous determination of VH mutation status and CD38 expression may be helpful for prediction of CLL prognosis.

ADP-ribosyl Cyclase 1↗

PubMed1989

Differences in blood T and NK cell populations between chronic lymphocytic leukemia of B cell type (B-CLL) and monoclonal B-lymphocytosis of undetermined significance (B-MLUS).

T and NK cell blood subpopulations were determined in 33 patients with B-CLL and in 14 patients with B-MLUS by two-color immunofluorescence. CLL patients had significantly higher total numbers of Leu-7+ and CD8+ cells and lower numbers of CD16+/Leu-7- cells as well as a higher Leu-7/CD16 ratio and a lower CD4/CD8 ratio than MLUS patients and control donors. Moreover, MLUS patients exhibited a significantly lower Leu-7/CD16 ratio as well as a higher frequency of CD16+/Leu-7- cells than healthy donors. These results suggest that B-CLL patients have higher numbers of circulating immature NK cells compared to B-MLUS, while B-MLUS patients have a larger proportion of NK cells with a high lytic capability as compared to both CLL and normal controls. The imbalance between CD4+ and CD8+ cells was prominent in CLL with a low CD4/CD8 ratio, but within the upper normal range in MLUS. Differences in immunoregulatory cell subpopulations between B-CLL and B-MLUS might therefore contribute to the different clinical behavior of these two disorders.

Adult↗

PubMedDate not supplied

Cholesterol modulation of membrane fluidity and ecto-nucleotide triphosphatase activity in human normal and CLL lymphocytes.

Lymphocytes isolated from the peripheral blood of patients with chronic lymphocytic leukemia (CLL) and from healthy donors were studied for membrane fluidity and lipid phase separation. The degree of fluidity of the surface membrane lipids was estimated by fluorescence polarization analysis using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH) embedded in the lipid core of the surface membrane of intact cells. CLL lymphocytes showed a more fluid lipid bilayer in their plasma membrane than normal lymphocytes. Treatment of both groups of lymphocytes with cholesteryl hemisuccinate (CHS) complexed with PVP and BSA resulted in rigidification of cell membranes. A lipid thermotropic transition temperatures was observed at 23.6 + 1.1 degree in normal lymphocytes and 16.3 + 1.0 degree in CLL lymphocytes, which rose to 32.3 + 1.3 degree in normal and was abolished in CLL lymphocytes after treatment with CHS. "Compound lipid fluidizer" reduced the thermotropic transition temperature to 17.5 + 1.0 degree and 15.1 + 0.9 degree in normal and CLL lymphocytes, respectively. A statistically significant increase (p less than 0.01) in the specific activity of the ecto-ATPase was observed in CLL lymphocytes as compared to normal cells. A dramatic increase of the ecto-ATPase activity was also observed when normal lymphocytes were treated with 0.05-0.5 mM CHS. The biological significance of these results is discussed in terms of modifications in the lipid-protein interactions in lymphocyte plasma membrane induced by CHS and the implications in the proliferation of leukemic cells.

Adenosine Triphosphatases↗

PubMed1988

The UK Medical Research Council CLL trials 1 and 2.

The Medical Research Council (MRC) Working Party on Leukaemia in Adults has conducted two randomised trials in CLL since 1978. CLL 1 ran from 1978 to 1984 and recruited 660 eligible patients. The number of males was twice the number of females and the distribution of cases by stage was different in the sexes: 58% of females were stage A, 25% stage B and 17% stage C; in males the proportions for stages A, B and C were 40%, 30% and 30% respectively. The most important prognostic factor was stage (A, B, C), followed by age, sex and response to treatment, which were confirmed as independent variables by stratified log-rank and Cox multivariate analyses. Causes unrelated to CLL accounted for 28% of all deaths and were more common in older patients and in stage A disease. No significant difference was observed between the CLL 1 treatment schedules: chlorambucil, penta Cop and splenic irradiation (SI), although a somewhat better survival was seen for patients treated by SI. (When CLL deaths only were considered SI appeared superior to chlorambucil (p less than 0.05]. CLL 2 started in 1984 and is still accruing patients; 556 had been entered by July 1988. This trial compares early versus delayed therapy for stage A, chlorambucil with and without prednisolone for stages B and C in patients with a small or nonpalpable spleen, and SI vs chlorambucil with or without prednisolone for stages B and C in patients with a larger spleen (greater than or equal to 5 cm).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1981

Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation.

T-cell function directly influences several B-cell functions. The effect of T-cell subgroups on B-cell function (DNA synthesis) was evaluated for controls and patients with B-cell type of CLL. Control and CLL intact T cells, T cells with receptors for IgG (T gamma), and T cells without Fc receptors at isolation (T non-gamma) were admixed with control B cells. Two predominant differences between control and CLL T cells were observed. First, CLL T gamma cells were excessively effective at suppressing B-cell DNA synthesis, and secondly, control T non-gamma cells were more efficient than CLL T non-gamma at promoting control B-cell DNA synthesis. While it is unclear whether the qualitative and quantitative T-cell abnormalities are part of the CLL disease process, it is possible that excessive T gamma cell numbers and function may reflect an appropriate immune response to a malignant B-cell clone.

B-Lymphocytes↗

PubMed1980

Individual cell-by-cell quantitation of lymphocyte surface membrane Ig in normal and CLL lymphocyte and during ontogeny of mouse B lymphocytes by immunoperoxidase assay.

A new quantitative immunoperoxidase method is presented for determining absolute amounts of peroxidase and, consequently, surface antigen densities of individual cells in B lymphocytes from normal individuals, from subjects with CLL and prolymphocytic leukemia, and during ontogeny of B lympocytes in the mouse. The following results were observed: (1) The density of B antigenic sites were lower on CLL than on normal B lymphocytes. (2) The B antigens density of leukemic lymphocytes varied less from cell to cell, forming a homogeneous peak on histograms. (3) In a very rare case of CLL, the antigen density was measured at the time of initial diagnosis (22,500 sites or 647 U) and during the development of a blastic crisis (135,000 sites or 2576 U). The cell by cell distribution changed from a homogeneous peak with a low number of antigenic sites per cell to a heterogeneous peak with a high number of antigenic sites per cell. (4) In prolymphocytic leukemia, the density of B antigenic sites was greater than on normal B lymphocytes and much more heterogeneous than on CLL lymphocytes. (5) During ontogeny of B lymphocytes in the mouse, maturation is associated with the appearance of a population of cells of intermediate to high Smig density. The finding of a decrease in, and altered distribution of, surface markers in CLL is compared with these ontologic findings in the mouse, and the concept that a monoclonal B lymphocyte in CLL may be arrested at a particular stage in its differentiation is discussed.

Animals↗

PubMed1994

Leukemic cells from progressive B-CLL respond strongly to growth stimulation in vitro.

Isolated leukemic B cells from patients with B-chronic lymphocytic leukemia (B-CLL) were tested for proliferative response in vitro to Staphylococcus Aureus strain Cowan 1 (SAC), IL-2, and low molecular weight (MW) BCGF. Patients were classified according to clinical stage and progressiveness. Ten of eighteen cell populations from patients with progressive B-CLL responded in vitro with a stimulation index (SI) > 20. Only 1/16 non-progressive patients had a proliferative but low response. Normal unfractionated tonsillar B cells responded to SAC and BCGF, whereas normal high buoyant density B cells were unresponsive. After 3 days of stimulation, responding B-CLL cells had multiplied and the B cells expressed CD5, CD19, and weakly CD21. No cells in the responding cultures exhibited CD3 or the EBV nuclear antigen EBNA-1. Cell maturation, measured as IgM secretion, was found in some, but not in all responding B-CLL cultures. Thus, B-CLL cells from patients with progressive disease have the capacity to respond to signaling through surface Ig receptors and to certain T-cell factors which was not the case for B-CLL cells from non-progressive patients. The pattern of in vitro response may be related to disease progression, reflecting a dependency of normal immunoregulatory mechanisms and/or a dysregulation of the growth control in the leukemic cells.

Aged↗

PubMed1994

Chlorambucil induced apoptosis in chronic lymphocytic leukemia (CLL) and its relationship to clinical efficacy.

Chlorambucil induced apoptosis was measured in CLL cells treated with clinically achievable drug doses in vitro. While spontaneous apoptosis occurred in CLL cells incubated in vitro in the absence of drug, the level of apoptosis, as measured by the extent of DNA fragmentation, was greater in cells treated with chlorambucil. In addition, macrophages were shown to engulf drug treated CLL cells in vitro. To determine if chlorambucil can also induce apoptosis in vivo, CLL cells were isolated from patients before treatment and at intervals after clinical therapy with chlorambucil (0.9 mg/kg given over 3 days). Apoptosis was measured in these cells immediately after isolation and following incubation in vitro for 72 hr. No apoptotic changes were detected in cells immediately after isolation either before or after clinical treatment. In contrast, apoptosis was observed in cells that were incubated ex vivo for 72 hr, and the level of apoptosis was greater in cells that were isolated after chlorambucil treatment compared with cells obtained prior to therapy. The increased apoptosis observed in CLL cells ex vivo after therapy was related to the fall in the patient's lymphocyte count. In general, a large increase in apoptosis ex vivo after treatment was followed by a significant decrease in the patient's lymphocyte count. Thus, chlorambucil may produce its antitumor effect in CLL by inducing apoptosis-associated membrane changes that result in rapid clearance of the apoptotic cells by the immune system.

Apoptosis↗

PubMed1996

[Histo-morphometry of bone mass and cellularity using image analysis: characterization of infiltration patterns in CLL].

PURPOSE: The aim of this study was to investigate a possible influence of lymphocytic infiltration in Chronic Lymphocytic Leukemia (CLL) on bone mass, according to the infiltration patterns. MATERIAL AND METHODS: We have studied histological preparations from decalcified and paraffin included bone biopsies and used a histomorphometric study through a mixed (interactive-automatic) image analysis, in order to quantify bone trabecular (BT/TV) and cellular volume (CV). Preparations were visualized via a 2.5 objective; a video camera was adapted and connected to a computer with analogical-digital converter incorporated. After the image was captured, a binarization was made by trabecular and medullary spaces segmentation; automatically, we calculated trabecular area (TA) and cellular area (CA). Expressions indicated above were used to calculate BV/TV and CV, expressed in percentage: BV/TV (%) = [TA/(TA + CA)] x 100, and CV (%) = [CA/(TA + CA)] x 100. RESULTS: 92 normal biopsies and 79 CLL biopsies were studied (Nodular 12, Diffuse 22, Interstitial 23, Mixed 22). BT/TV in normal subjects age over 45, was 18.40%; it was lower in CLL subjects, 17.25%. CV was 33.62% in normal cases and significantly higher in CLL with 42.95%. According to the infiltration patterns, Nodular pattern showed similar value to normal biopsies, versus Diffuse pattern with BT/TV of 16.19% and CV of 51.49%. Significantly, a high CV value was accompanied of a low B/TV value, in normal and CLL subjects. CONCLUSIONS: We analyzed histomorphometrically trabecular volume as expression of bone mass in undecalcified biopsies. CLL infiltration tended to show a lower trabecular volume. Diffuse pattern presented the higher cellular infiltration and bone mass destruction.

Aged↗

PubMed1997

Is there a place for 2-CDA in the treatment of B-CLL?

There is no doubt about 2-CDA being a very potent lymphotoxic agent that displays high efficacy in the treatment of CLL. It interferes with the intranuclear machinery of DNA regulation, and causes death to proliferative active, as well as resting lymphocytes. Interruption of crucial pathways that are evident for cell survival translates into high clinical response rates in CLL. CR and PR rates comparable to those reported on fludarabine are achieved in relapsed or refractory CLL. Even though trials on previously untreated CLL are still ongoing, a consistent trend towards durable, high CR rates becomes apparent. The toxicity is comparable to that of fludarabine and consists of infections, as well as thrombocytopenia. Clinical as well as in vitro studies suggest a crossresistance between the two purine analogues, indicating that sequential treatment is not useful. Given these data, although preliminary in case of de novo CLL, 2-CDA has to be recognized as one of the most effective cytostatic drugs currently available for CLL treatment. Large prospective trials (in comparison with fludarabine) will assess the role of 2-CDA as standard treatment. Such trials should also have the aim to substantiate the potential of 2-CDA as induction treatment followed by high-dose consolidation.

Antineoplastic Agents↗