Chlorambucil synergizes with purine analogs in inducing in vitro cytotoxicity in B-cell chronic lymphocytic leukemia

Combinations of different drug concentrations of CLB + FAMP and CLB + 2-CDA were synergistic in, respectively, 42.9% and 34.8%. At leukemic cell survival < or = 50%, 16.4% and 23.4% of all combinations were synergistic in the 2-CDA and FAMP groups, respectively. A significantly higher mean value of antagonistic interactions was observed in the 2-CDA group (p = 0.037).     

Myelomonocytic antigens in B-cell chronic lymphocytic leukemia

The clinical significance of myelomonocytic (MyMo) antigens in B-cell chronic lymphocytic leukemia (B-CLL) is unclear. We have analyzed the expression of MyMo antigens (CD13, CD14 (LeuM3, My4, Mo2), CD15, CD11b, CD11c, CD33 and CD68) on B-lymphocytes (CD19+) in 105 B-CLL patients and in 35 controls. A double direct staining technique and flow cytometric analysis was performed. The expression of MyMo antigens on the control group did not exceed 4% B-lymphocytes. A MyMo antigen was considered as positive when present in > or = 10% of B-lymphocytes. Among the B-CLL patients, 28 (26.7%) were positive for CD11c, 21 (20.0%) for CD11b, nine (8.6%) for CD15, five (4.8%) for CD13, two (1.9%) for Mo2, and one (1.0%) for My4. No patient was positive for LeuM3, CD33 or CD68. CD11c was more frequently expressed in patients with a short lymphocyte doubling time (< 12 months) (P = 0.05) and CD11b in the group with a higher number of lymphoid areas involved (P = 0.02). No correlation was found between lymphoid morphology and MyMo antigen expression. Fourteen of the 80 patients at risk subsequently progressed to a more advanced stage. Multivariate analysis identified hemoglobin (P = 0.004) and CD11b positivity (P = 0.009) as independent variables for disease progression. Fifteen patients died during evolution. Seven out of the 21 CD11b positive patients and eight of the 84 CD11b negative patients died (LR: P = 0.02, BG: P = 0.05). In the multivariate analysis, only CD11b positivity (> or = 10%) added prognostic value to clinical stages.     

Acquired CD40-ligand deficiency in chronic lymphocytic leukemia

Patients with B-cell chronic lymphocytic leukemia (CLL) acquire an immunodeficiency with many characteristics similar to those of persons with inherited defects in the gene encoding the CD40-ligand (CD154). We found that the blood and splenic CD4+ T cells of patients with CLL failed to express surface CD154 after CD3 ligation. However, using an enzyme-linked immunosorbent assay (ELISA)-based quantitative competitive polymerase chain reaction (PCR), we noted that CD3 ligation could induce such T cells to express CD154 messenger RNA at levels similar to that of CD3-activated T cells from normal donors. Moreover, addition of increasing numbers of CLL B cells to activated normal donor T cells rapidly resulted in progressively greater down-modulation of CD154. Such down-modulation of CD154 could be blocked by addition of CD40 monoclonal antibody to cultures in vitro. We propose that leukemia cell-mediated down-modulation of CD154 on activated T cells accounts for some of the acquired immune defects of patients with CLL.     

Intussuception as a complication of chronic lymphocytic leukemia

The case of a 58-year-old man with chronic lymphocytic leukemia (B-cell type) who later developed an intussuception of the small intestine due to a tumor is described. The histopathological findings of the removed tumor were compatible with those of diffuse small lymphocytic lymphoma (B-cell type). The residual tumor became smaller with CHOP therapy. It is considered that CLL cell infiltration into the small intestine resulted in intussuception. Since many tumors and lymphomas can form polypoid lesions causing an intussuception. This is a possible complication of CLL and it could occur even when the WBC count is well controlled.     

The cellular biology of B-cell chronic lymphocytic leukemia

In conclusion, B-CLL cells through their immunophenotype have the functional potential required to interact with cells in what has been called the immunological synapse, i.e. the cognate interactions between T-cells, antigen-presenting cells and B-cells during immunopoiesis. The data reviewed herein provides substantial evidence to suggest that B-CLL cells in fact can interact, not only with T-cells but also with endothelial cells and stromal cells in the bone marrow. These interactions, in particular signaling through CD40, contribute to extended survival and proliferation of B-CLL cells and, thereby, the risk of complete malignant transformation of the clone. Therefore, this review would suggest that the answers to how B-CLL is initiated may be found in molecules responsible for the normal regulation of immunopoiesis. Transformation to malignancy, by contrast, is likely to be caused by loss of control over the G1 restriction in the cell cycle in B-CLL cells.     

Sudden death in a patient with chronic lymphocytic leukemia

The authors describe a 51-year-old man with chronic lymphocytic leukemia who presented with respiratory distress and then died suddenly while in hospital. Autopsy revealed pulmonary leukostasis and a large intracardiac mass containing mostly mature lymphocytes and fibrin. Although leukostasis and lymphocyte thrombi have been described (albeit rarely) in chronic lymphocytic leukemia, an intracardiac "clot" has not. It seems plausible that this intracardiac mass caused the patient's death.     

Twenty years of research on B-cell chronic lymphocytic leukemia

The typical MRI features of the most common pancreatic diseases, such as pancreatitis and adenocarcinoma of the pancreas, have been established. However, even in these common pancreatic disorders, MRI correlation with the underlying pathology is limited for clinical reasons. We emphasize MR-pathological correlation of inflammatory and neoplastic pancreatic changes, including pancreatitis, adenocarcinoma, acinar cell carcinoma, rare cystic and solid pancreatic neoplasms, and islet cell tumors. By highlighting the correlation of key pathological features with MR findings, a better understanding of the MR appearance of pancreatic pathology can be provided. In addition, MRI may prove a powerful tool in detection and characterization of pancreatic tumors.     

Total hip arthroplasty in patients who have chronic lymphocytic leukemia

Twenty patients who had chronic lymphocytic leukemia underwent 25 elective primary total hip arthroplasties at the Mayo Clinic. No patient had a postoperative prosthetic infection. No patient had an intraoperative or postoperative hemorrhagic complication. One patient had a revision for aseptic loosening. After an average follow-up period of 4.6 years, there were 84% good and excellent results. It is concluded that patients who have early-stage chronic lymphocytic leukemia may not be at increased risk for major perioperative or postoperative complications in total hip arthroplasty. The surgeon must remain vigilant for postoperative complications, but satisfactory clinical results can be obtained in this patient population.     

Chemotherapy-induced myocardial necrosis in a patient with chronic lymphocytic leukemia

Cardiac toxicity following the administration of chemotherapeutic agents is well documented. Vinca alkaloids, as well as high-dose cyclophosphamide, have been associated with myocardial ischemia. The present report describes a case of acute myocardial infarction occurring in a patient with no antecedent cardiac history who received both vincristine and conventional chemotherapeutic doses of cyclophosphamide for the treatment of chronic lymphocytic leukemia. Physicians should possess a heightened awareness of this potentially serious complication.     

Lymphopenic effect of carbamazepine in a patient with chronic lymphocytic leukemia

OBJECTIVE: To report a dramatic and reproducible suppressive effect of carbamazepine on circulating lymphocytes in an elderly woman with chronic lymphocytic leukemia. CASE SUMMARY: An elderly woman taking phenytoin for a stroke-associated seizure disorder had lymphocyte count of 28,800 x 10(6) cells/L. Speculating an unusual lymphadenopathic effect of the phenytoin therapy, carbamazepine therapy was substituted. After 15 weeks of carbamazepine treatment, the lymphocyte count declined to 3200 x 10(6) cells/L. Because of severe diarrhea, carbamazepine therapy was stopped and phenytoin therapy was reinstituted. At the end of 4 months of phenytoin treatment, the lymphocyte count had increased to 23,200 x 10(6) cells/L. Phenytoin therapy was discontinued and carbamazepine therapy was begun. The lymphocyte count decreased to 10,700 x 10(6) cells/L. Severe diarrhea recurred and phenytoin treatment was reinstituted. Over 12 days the lymphocyte count increased to 28,900 x 10(6) cells/L. Phenytoin therapy was stopped and valproic acid therapy was started. The lymphocyte count continued to increase during valproic acid therapy, reaching a peak of 114,300 x 10(6) cells/L. DISCUSSION: In this patient with chronic lymphocytic leukemia, carbamazepine therapy had a significant and reproducible lymphopenic effect that was readily reversible upon discontinuation of the drug. Unfortunately, this effect was associated with severe diarrhea, preventing further attempts at exploiting this potentially beneficial action. CONCLUSIONS: Carbamazepine had a reproducible suppressive effect on lymphocyte counts in an elderly patient with chronic lymphocytic leukemia. This unique observation raises the possibility that carbamazepine therapy may have a useful effect in patients with chronic lymphocytic leukemia.     

Advances in the treatment of chronic lymphocytic leukemia (CLL)

CLL is a chronic lymphoproliferative disorder which is characterized by the proliferation of a CD5 positive B cell clone. At diagnosis most patients are in early stage of the disease (stage A). It is well established that an early treatment in stage A is not associated with a survival advantage. Therefore, the disease should be treated only when signs of progression are present. The standard initial therapy is chlorambucil +/- prednisone. By this treatment remissions (mostly partial remissions) are achieved in about half of the patients. Fludarabine, a purine analogue, is more effective than chlorambucil as initial treatment (75% remissions, 27% complete remissions, 33 months progression free survival). However, the overall survival is not prolonged when compared to chlorambucil treatment. Fludarabine has a high efficacy in patients with recurrent disease, in particular in those who are resistant to alkylating agents. The allogeneic and autologous stem cell transplantation is an experimental treatment which may be indicated in younger patients who show a response to conventional treatment. With both procedures hematological remissions are frequently achieved and in some of the patients long lasting molecular remissions were obtained. Currently, it is unknown whether patients can be cured by stem cell transplantation and longer follow-up will be necessary to clarify this question. Monoclonal B-cell antibodies are effective in vivo and partial remissions can be obtained in chemotherapy refractory patients. Antibodies have a high efficacy in clearing lymphoma cells from peripheral blood and bone marrow but are less effective on the organomegaly.     

Chromosome aberrations in atypical chronic lymphocytic leukemia: a cytogenetic and interphase cytogenetic study

To define better the chromosomal profile of atypical chronic lymphocytic leukemia (aCLL), cytogenetic and interphase cytogenetic studies were performed in 43 cases, using mitogen-stimulated cultures and DNA probes detecting the two most frequently occurring aberrations in CLL, ie +12 and 13q14 deletions. All cases showed monoclonal CD5/CD19-positive lymphocytosis, with more than 10% large lymphocytes and/or prolymphocytes in peripheral blood smears and reactivity with FMC7, or bright expression of surface immunoglobulins in a fraction of the cases. Karyotype aberrations were detected in 27 of 43 cases (62.8%). Recurrent chromosome changes were +12 (nine cases), 13q14 aberrations (five cases), 11q anomalies (three cases), 6q21-q23 abnormalities and 4q anomalies with different breakpoints (two cases each). Additional chromosome changes were seen in four cases with +12, in three cases with 13q14 anomalies, in two cases with 11q anomalies, in one case with 6q and 4q anomalies. Trisomy 12 was associated with 13q14 anomalies in three cases, one of which also had an 11q abnormality; other associations, found in one case each, were: 13q14 deletion with a 6q anomaly, 11q anomaly with 13q- and 7q-, a 6q anomaly with 7q- and +12. Interphase cytogenetics confirmed the results of chromosome banding analysis and showed that six patients with normal karyotype or no mitosis in fact had concomitant +12 and 13q14 deletion in four cases and isolated +12 or 13q14 deletion in one case each, with a resultant 76% overall incidence of cytogenetic abnormalities. The presence of +12, 13q14 deletions, 11q, and 6q21-q23 anomalies in 19 cases was associated with a 2-month median interval between diagnosis and start of treatment, as compared with a 24-month median interval in 14 cases with normal karyotype or non-recurrent chromosome changes (P = 0.003). We conclude that aCLL is characterized by a relatively high incidence of chromosome anomalies, with recurrent chromosome changes, involving chromosomes 12, 13q14, 6q21q23, 11q, and, possibly, 4q. The presence of complex karyotypes, with concomitant abnormalities of 13q, +12, 6q, 11q, suggests that the development of sequential chromosome changes, rather than any single specific anomaly, may underlie leukemogenesis in this cytologic subset of CLL, partially accounting for the relatively aggressive clinical course.     

Induction of apoptosis by 2-chlorodeoxyadenosine in B cell chronic lymphocytic leukemia

We investigated whether 2-chlorodexoyadenosine could induce apoptosis in B cell chronic lymphocytic leukemia (B-CLL) cells in vitro using clinically achievable drug doses, measuring apoptosis ratio by flow cytometry. B cells were isolated from previously untreated patients and apoptosis was measured in these cells immediately after isolation and following incubation in vitro, without and with 2-chlorodeoxyadenosine at different concentrations, for 24 and 48 h. Distribution of cellular DNA content and quantitative analysis of apoptosis were determined by standard propidium iodide staining and flow cytometry. Spontaneous apoptosis occurred in B-CLL cells incubated in vitro in the absence of drug, but the level of apoptosis was greater in cells treated with 2-chlorodeoxyadenosine after the second day of culture. The present in vitro study of B-CLL cells from previously untreated patients suggests this chemotherapeutic agent activates a program of cell death by apoptosis using a drug dose equivalent to the physiological concentration used in patients in vivo. These data reveal an interesting possibility in the 2-chlorodeoxyadenosine treatment of untreated patients by neoplastic B cell apoptosis induction.     

Simultaneous occurrence of B-cell chronic lymphocytic leukemia and chronic myeloid leukemia with further evolution to lymphoid blast crisis

The coexistence of chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (CLL) in the same patient is rare. A 71-year-old woman developed a B-lineage lymphoid blast crisis at 18 months after diagnosis of Ph-positive CML. At this time, a lymphoid cell population with morphologic and immunophenotypic features of CLL was demonstrated. The retrospective review of the tests performed at diagnosis and thereafter disclosed the presence of lymphoid nodules in the initial bone marrow biopsy in the absence of lymphocytosis. Subsequently, there was an appearance of moderate lymphocytosis in the following months. Therefore, diagnosis of CML and coexistent CLL was established. Although a transient remission of blast crisis was achieved, blast cells reappeared two months later and the patient died shortly afterwards. Molecular studies of the immunoglobulin heavy chain gene (IH) rearrangement pattern point to the origin of the diseases in two different cell clones. In addition, previously published cases of simultaneous CLL and CML are reviewed.