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PubMed1999

Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group.

BACKGROUND: The randomized trials that evaluate the timing and intensity of initial chemotherapy for chronic lymphocytic leukemia (CLL) have, in general, been too small to provide separately reliable results. We compared the effects on survival of the following: a) immediate versus deferred chemotherapy for early-stage CLL and b) combination chemotherapy (e.g., cyclophosphamide and vincristine plus prednisone/prednisolone [COP] or COP plus doxorubicin [CHOP]) versus single-agent chlorambucil as first-line treatment for more advanced disease. METHODS: All relevant randomized trials, whether published or not, were sought for a collaborative meta-analysis involving centralized review of the data for each patient. RESULTS: There were 2048 patients with early disease in six trials of immediate versus deferred chemotherapy (chlorambucil or chlorambucil plus prednisone/prednisolone). The 10-year survival was slightly worse (but not statistically significantly so) with immediate chemotherapy (44% versus 47% survival; difference = -3%; 95% confidence interval [CI] = -10% to 4%). There were another 2022 patients in 10 trials of combination chemotherapy versus chlorambucil, with or without prednisone/prednisolone. The 5-year survival was 48 % in both cases (difference = 0%; 95% CI = -6% to 5%). A subgroup of six of these 10 trials involved an anthracycline-containing regimen but again overall survival appeared no better than with chlorambucil (anthracycline-based regimen: 325 deaths among 627 patients; chlorambucil: 306 deaths among 636 patients; death rate ratio = 1.07; 95% CI = 0.91-1.25; not statistically significant). CONCLUSIONS: In terms of survival, these trials support a conservative treatment strategy for CLL, i.e., no chemotherapy for most patients with early-stage disease, and single-agent chlorambucil as the first line of treatment for most patients with advanced disease, with no evidence of benefit from early inclusion of an anthracycline. This strategy will, however, need to be reconsidered as mature results become available from trials of other agents.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2026

To Treat or Not to Treat: Navigating Early-Stage CLL in the Era of Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.

Humans↗

PubMed1978

Lymphocyte subpopulations in chronic lymphocytic leukemia (CLL). Relation to the activity of the disease.

The blood lymphocytosis in CLL is caused mainly by a rise of immunoglobulin (Ig)-bearing leukemic lymphocytes. Most cells carry Fc-receptors, while the percentage with receptors for human complement is very low with the present technique. The leukemic lymphocytes carry only one of the light chain types, which suggests a monoclonal origin. CLL patients with lymphocytes expressing kappa light chains may have a more benign disease than lambda-CLL. T-lymphocyte levels are high during the early course of the disease but decrease with its progression and are low in patients with "active" disease.

Adult↗

PubMed1989

CD1 expression on B-CLL lymphocytes.

In a previous report we showed that D47 CD1a monoclonal antibody positively labelled B-CLL cells of some patients. Six cases were selected to further characterize CD1 antigenic expression at the leukaemic cell surface using flow cytometry with a battery of six CD1a, two CD1b and two CD1c monoclonal antibodies. CLL cells were positively labelled with CD1a antibodies except OKT6 and NA1/34; in all cases they were CD1b negative and CD1c positive. These results suggested that CD1a, c epitopes can be detected on leukaemic B cells in addition to other T cell differentiation antigens. In view of recently published data demonstrating the presence of CD1c molecule in normal B cell subsets, our results further question the relationship of B-CLL with a restricted subpopulation of B cells.

Antibodies, Monoclonal↗

PubMed1992

Immunophenotypic subclassification of chronic lymphocytic leukaemia (CLL).

To determine the significance of the immunophenotypic heterogeneity of B-cell chronic lymphocytic leukaemia (CLL), surface immunoglobulins (SIgs), mouse rosette assays (MR), and a panel of monoclonal antibodies for B cells, T cells and myeloid cells were performed on peripheral blood samples from 61 newly diagnosed cases. Four groups were observed: group I (SIg+, MR+, CD19/20+, CD5+, T antigen (Ag)-; 27 cases); group II (SIg+, MR+, CD19/20+, CD5+, T Ag+; 17 cases); group III (SIg+, MR+ CD19/20+, CD5-, T AG-; 12 cases); and group IV (SIg-, MR+, CD19/20+, Cd5+, T Ag-; 5 cases). Groups were compared according to French-American-British Cooperative Group subtypes, clinical and laboratory features, Rai staging, and survival. Typical CLL morphology (greater than 90% small lymphocytes) was present in 20/20 (100%) of group I cases and 23/27 (85%) group II, III and IV cases (P = 0.09). Expression of a myeloid antigen was seen in 5/27 group I cases (18%) and 1/16 group II cases (6%), but was not predictive of survival (P = 0.36). The CD5- group III had a lower haemoglobin level (P less than 0.0001), higher Rai stage (P less than 0.002), and poorer survival at 5 years (P less than 0.02) than the other groups. We conclude that at least four distinct immunophenotypic subgroups of B-cell CLL can be determined. Expression of myeloid or T-cell antigens does not appear to predict for patient survival; however, lack of CD5 antigen may be associated with more advanced stage of disease and poor patient survival.

Adult↗

PubMed1995

Theophylline, a new inducer of apoptosis in B-CLL: role of cyclic nucleotides.

We report a case of indolent B-chronic lymphocytic leukaemia (B-CLL) in a stage A patient, treated for 10 years only by theophylline for bronchial asthma. As suggested by the spontaneous apoptosis in the patient's blood (10%), theophylline at 50 micrograms/ml increased spontaneous apoptosis after 72 h in culture by a mean percentage of 90% (range 79-98%) in six B-CLL cases studied in vitro. This effect was partially reversed with Rp-cAMP, a cAMP antagonist, which implies a potent role for this second messenger. We describe a new property of theophylline, which might be an alternative treatment in B-CLL.

Aged↗

PubMed1991

Urinary excretion of CD23 antigen in normal individuals and patients with chronic lymphocytic leukaemia (CLL)

A soluble form of CD23 (sCD23) was found in the urine from 12 normal individuals but was not present in 20 normal sera, suggesting that sCD23 produced by cells in tissues is eliminated in the urine. The sCD23 from urine differed in physicochemical properties from the sCD23 found in supernates from B-lymphoblastoid cell lines (B-LCL) and in the sera of patients with B type chronic lymphocytic leukaemia (B-CLL). On SDS-PAGE analysis under reducing conditions urinary sCD23 showed two bands corresponding to molecular weights of 45-60 kD and 28-35 kD indicating that sCD23 may be excreted in combination with another molecule. When subjected to gel filtration in its native state, sCD23 from urine showed a major peak at approximately 150 kD and a minor peak (probably a breakdown product) at 21 kD. Urinary sCD23 was more strongly held by DEAE-cellulose and required 0.5 M buffer pH 8.0 for elution, suggesting that it is more anionic than sCD23 from culture supernates. Five MoAbs recognizing different epitopes on sCD23 from B-LCL supernates were tested on urinary sCD23. Four of the MoAbs were reactive but one (EBVCS-1) was not. Urinary sCD23 did not bind to IgE. The level of sCD23 found in normal urine (approximately 0.02-0.05 micrograms/ml) was exceeded in 17 of 24 cases of B-CLL. In one case with a high cell count and a serum concentration of 10 micrograms/ml, the urine contained 80 micrograms/ml sCD23. In another case a high serum sCD23 was not matched by a high urinary level. In this case the gel filtration pattern was closer to that found with urine sCD23 rather than the B-LCL pattern found with sera of other B-CLL patients.

Antibodies, Monoclonal↗

PubMed2005

Successful treatment of a patient with chronic lymphocytic leukaemia (CLL) presenting with bony metastases with aggressive antibody and chemotherapy.

Osteolytic lesions are rare in chronic lymphocytic leukaemia (CLL) and thought to result from Richter's transformation or metastatic disease from nonlymphoid malignancies. We report a patient who presented with a large femoral metastatic lesion and hypercalcaemia caused by CLL itself. Complete remission of CLL with resolution of the osteolytic lesion was achieved with rituximab and cyclophosphamide, adriamycin, oncovin and prednisolone [CHOP (R-CHOP)] combination chemotherapy.

Aged, 80 and over↗

PubMed1994

Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study.

Proliferation centres, also known as pseudofollicles, are present in approximately 90% of lymphocytic lymphomas (B-CLL). They consist of loosely arranged larger cells that often contain prominent nucleoli. In contrast to true B-cell follicles, which may be found entrapped within the small lymphocytic infiltrate in sections of B-CLL, proliferation centres are said not to contain follicular dendritic cells, although their presence has been occasionally recorded. We have carried out an immunohistochemical study of proliferation centres from 30 lymph node specimens of known cases of B-CLL, classified according to the Kiel classification, in six of which fresh frozen in addition to paraffin embedded tissue was available. We have compared proliferation centres with the surrounding small lymphocytic infiltrate and reactive B-cell follicles with respect to the presence of follicular dendritic cells and their associated network of IgM and complement, the cell proliferation fraction, the concentration of T-cells and the expression of bcl-2 protein. Most proliferation centres contained a delicate follicular dendritic cell network which was associated with IgM and complement, and showed a higher proliferation fraction than the surrounding small lymphocytic infiltrate. The proliferation centres contained more T-cells than the surrounding infiltrate and showed decreased expression of bcl-2 protein. Entrapped reactive B-cell follicles contained a much denser network of follicular dendritic cells, associated with much stronger expression of IgM and complement, and exhibited a very high proliferation fraction; they contained many T-cells and expressed very little bcl-2 protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗

PubMed1978

Chronic lymphocytic leukemia showing pituitary tumor with massive leukemic cell infiltration, and special reference to clinicopathological findings of CLL.

An autopsy case of a 33 years old doctor with chronic lymphocytic leukemia (CLL) was reported. Two remissions were noted with chemotherapy and irradiation. The special characteristic of this case was the tumor formation in the sellar fossa similating a pituitary tumor which was considered as a type of meningeal leukemia, showing visual disturbance. Leukemic cell infiltration was hardly observed in any other organs. From the analysis of five cases of CLL, the author proposes that CLL may be classified into two types: the one is the severe type showing a short clinical course and the other is a mild one, showing a long clinical course. Details such as histopathological findings, cause of death and clinical findings were discussed.

Adult↗

PubMed2006

An unusual case of systemic mastocytosis associated with chronic lymphocytic leukaemia (SM-CLL).

AIMS: Whereas focal accumulations of reactive lymphocytes around mast cell (MC) infiltrates are often seen in indolent systemic mastocytosis (ISM) involving the bone marrow, an association of systemic mastocytosis (SM) with malignant lymphoma/lymphatic leukaemia is very rare. This report contributes to the differential diagnosis of ISM by demonstrating that such lymphocytic aggregates may be neoplastic. METHODS: Biopsy specimens (bone marrow and gastrointestinal mucosa) of a 69 year old woman with mild blood lymphocytosis and a history of urticaria pigmentosa-like skin lesions that had disappeared a few years earlier, were investigated immunohistochemically using antibodies against CD3, CD5, CD20, CD23, CD25, CD34, CD117, chymase, and tryptase. Rearrangements of the IgH and TCRy genes were studied by seminested PCR. Mutation analysis of c-kit was performed by melting point analysis of nested PCR using amplified DNA from pooled microdissected single cells (MC and B cells) of both sites. RESULTS: The histomorphological features of the bone marrow corresponded to that of ISM with multifocal accumulations of MC surrounded by clusters of lymphocytes of mature appearance. However, these lymphocytes revealed an aberrant immunophenotype with coexpression of CD5, CD20, and CD23, thus enabling the final diagnosis of SM with an associated clonal haematological non-MC lineage disease, in particular SM with associated B cell chronic lymphocytic leukaemia (SM-CLL). Monoclonality for both ISM and B-CLL could be confirmed by demonstrating the typical activating c-kit point mutation D816V in bone marrow MC, and a monoclonal IgH rearrangement in bone marrow B cells. CONCLUSIONS: Usually, focal accumulations of lymphocytes around MC infiltrates in the bone marrow of patients with SM are reactive in nature (lymphocytosis). However, a low grade malignant lymphoma should also be included in the differential diagnosis. We describe here the first case, to our knowledge, with synchronous diagnosis of SM and associated B-CLL. This diagnosis could only be established by application of appropriate immunohistochemical and molecular techniques, as the bone marrow histology on first investigation resembled that of typical ISM.

Aged↗

PubMed2006

Retrospective analysis of CD38 expression in 102 patients with B-CLL with a maximum follow-up of 18 years: incidence and prognostic significance.

BACKGROUND: The aim of this study was to evaluate the incidence of CD38 expression in all CLL patients of our institution and to determine its prognostic significance in correlation with other parameters of the disease. PATIENTS AND METHODS: We analyzed the CD38 expression in 102 B-CLL patients referred to our department over a period of 12 months. RESULTS: The follow-up period ranged from 0 to 18 years. 30 patients (29%) were CD38-positive (CD38+) and 72 patients (71%) were CD38-negative (CD38-) with a median age of 65 and 64 years, respectively. Of the Binet A patients (77), 25% showed an expression of CD38; in Binet B/C patients (25), 67% expressed CD38. Median survival of the CD38- group was 77.5 months and of the CD38+ group 56.3 months. CD38 expression was associated with shorter lymphocyte doubling time (p < 0.0001), a more advanced stage of the disease, and a shorter therapy- and progression-free time (p < 0.0017/p < 0.0012), which was also true in the Binet A subgroup. In 2 cases, we detected a shift from the CD38- to the CD38+ phenotype. CONCLUSION: We found a low incidence of CD38+ CLL patients, and CD38 expression predicted significantly a more advanced stage of the disease, shorter lymphocyte doubling time and shorter therapy- and progression-free time.

ADP-ribosyl Cyclase 1↗

PubMed1988

Patients with CLL and hypocomplementaemia have an impaired serum bactericidal activity against the Salmonella minnesota Re mutant.

The bactericidal effect of 25 serum samples from 23 patients with chronic lymphocytic leukaemia (CLL) against the Salmonella minnesota S form and Re mutant has been studied. No killing of the S form was observed in any of the sera tested, whereas a normal bactericidal effect was found against the Re mutant (group 1) in 17/25 sera of CLL patients. By contrast, in 8 serum samples from 6 CLL patients no killing or a markedly delayed killing of the Re strain was observed (group 2). Significant differences in the complement levels were found between the sera of group 1 and group 2. In group 1 mostly normal or elevated complement levels were observed, while in group 2 levels of C4 and C2 were found to be strongly decreased. A significant correlation was found between the bactericidal effect on the one hand and the C4 and C2 levels on the other.

Blood Bactericidal Activity↗

PubMed2005

Salvage therapy for CLL and the role of stem cell transplantation.

Chronic lymphocytic leukaemia (CLL) remains an incurable disease and, notwithstanding the excellent remission rates now achieved with purine analogs and monoclonal antibodies, the vast majority of patients with CLL are destined to relapse after primary treatment. The management of relapsed CLL patients is then dependent upon a number of factors, most importantly age, performance status, previous therapy administered, the response and duration of response to such therapy, and time from last therapy. Although prior therapy and response to such therapy are important factors in determining next therapy, it is often difficult to determine their importance from published studies. Furthermore, the goal of therapy, whether palliative or aggressive, must also be weighed into the decision when deciding on the next line of treatment. With many potential treatments available, the sequence of treatments and the timing of procedures such as stem cell transplantation remain controversial and are the focus of ongoing clinical trials.

Antibodies, Monoclonal↗

PubMed2002

Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).

This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.

Adult↗

PubMed2005

Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP.

Myeloid cell leukemia-1 (MCL-1) acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to triphosphate (8-Cl-adenosine triphosphate [ATP]), which preferentially incorporated into mRNA and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these actions, we hypothesized that 8-Cl-Ado would be ideal to target CLL lymphocytes. In the present study we demonstrate that leukemic lymphocytes incubated with 8-Cl-Ado display time- and dose-dependent increase in the accumulation of 8-Cl-ATP, with a parallel depletion of the endogenous ATP pool. Inhibition of global RNA synthesis resulted in a significant decline in the expression of transcripts with a short half-life such as MCL1. Consistent to this, protein expression of MCL-1 but not B-cell lymphoma-2 (BCL-2) was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3, and PARP (poly-adenosine diphosphate [ADP]-ribose polymerase), and increased DNA fragmentation. In conclusion, 8-Cl-Ado induces apoptosis in CLL lymphocytes by targeting cellular bioenergy as well as RNA transcription and translation of key survival genes such as MCL1.

Adenosine Triphosphate↗

PubMed2005

A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival.

B-cell chronic lymphocytic leukemia (B-CLL) is a clinically variable disease where mutations in DNA damage response genes ATM or TP53 affect the response to standard therapeutic agents. The in vitro cytotoxicity of a novel cyclin-dependent kinase inhibitor, CYC202, was evaluated in 26 B-CLLs, 11 with mutations in either the ATM or TP53 genes, and compared with that induced by ionizing radiation and fludarabine. CYC202 induced apoptosis within 24 hours of treatment in all 26 analyzed tumor samples independently of ATM and TP53 gene status, whereas 6 of 26 B-CLLs, mostly ATM mutant, showed marked in vitro resistance to fludarabine-induced apoptosis. Compared with B-CLLs, normal T and B lymphocytes treated with CYC202 displayed reduced and delayed apoptosis. Using global gene expression profiling, we found that CYC202 caused a significant down-regulation of genes involved in regulation of transcription, translation, survival, and DNA repair. Furthermore, induction of apoptosis by CYC202 was preceded by inhibition of RNA polymerase II phosphorylation, leading to down-regulation of several prosurvival proteins. We conclude that CYC202 is a potent inducer of apoptosis in B-CLL regardless of the functional status of the p53 pathway, and may be considered as a therapeutic agent to improve the outcome of resistant B-CLL tumors.

Aged↗

PubMed2005

More ZAP for chronic lymphocytic leukemia (CLL).

Antigen stimulation of the leukemic clone is increasingly implicated in the pathogenesis of CLL. Chen and colleagues provide evidence that expression of ZAP-70 in CLL B cells renders IgM signaling more effective and thereby could contribute to the more rapidly progressive clinical course of ZAP-70-positive CLL.

Animals↗