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Biomedical subjects

Kanti R Rai

Publications and source records attributed to Kanti R Rai.

At least 19 recordsLinked to original sources
PubMed2006

Novel therapeutic strategies with alemtuzumab for chronic lymphocytic leukemia.

In the last 10 years purine analogs have become the chemotherapy of choice for the first-line treatment of chronic lymphocytic leukemia, principally because of their superior efficacy compared with alkylating agents. However, many patients experience a relapse after an initial response or become refractory to these agents. The introduction of immunotherapeutic agents has provided renewed hope for fludarabine-refractory patients. Several clinical trials have shown the efficacy of alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia, including those with poor prognostic factors. Current studies indicate that treatment with alemtuzumab can achieve remissions with undetectable residual disease, as assessed by highly sensitive methods such as quantitative polymerase chain reaction or 4-color flow cytometry. These results suggest new applications for alemtuzumab such as combination treatment with chemotherapeutics or immunotherapeutics, maintenance therapy, and in vivo bone marrow purging prior to transplantation. A number of clinical trials are under way assessing the role of alemtuzumab in these settings.

Alemtuzumab↗
PubMed2006

Chronic lymphocytic leukemia: current and emerging treatment approaches.

In the last decade, advances in the treatment of patients with chronic lymphocytic leukemia (CLL) have improved responses and survival outcomes dramatically. Chlorambucil had been the cornerstone of treatment for decades. Now, treatment approaches typically include a purine nucleoside analog, such as fludarabine, in combination with immunotherapy, most commonly rituximab but also alemtuzumab. Several clinical trials of patients with untreated CLL have reported overall response rates as high as 95% with chemoimmunotherapy. Combinations include fludarabine, cyclophosphamide, and rituximab (FCR); pentostatin, cyclophosphamide, and rituximab; fludarabine and rituximab; and fludarabine and alemtuzumab. FCR has demonstrated complete response rates of 70% as frontline therapy. In addition, molecular prognostic indicators, such as IgVH mutational status, ZAP-70 expression, and chromosomal mutations (trisomy 12; 17p, and 11q deletions) are proving useful in identifying patients with poor-risk disease. Furthermore, advanced technologies such as polymerase chain reaction and flow cytometry can be used to detect minimal residual disease with increasing sensitivity. Elimination of minimal residual disease has been linked to improved survival and become an important clinical goal. While overall response rates with current chemotherapy treatments are superior to those seen with single agents (eg, chlorambucil), many CLL patients still fall short of achieving a complete response. Novel agents with unique, nonoverlapping mechanisms of action (eg, oblimersen sodium, lenalidomide, HuMax-CD20, GX15-070), and other treatments are under investigation in an attempt to further improve outcomes.

Alemtuzumab↗
PubMed2005

Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia.

PURPOSE: To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. RESULTS: Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included > or = 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), > or = 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and > or = 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. CONCLUSION: Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Adult↗
PubMed2005

Malignant pleural effusions in lymphoproliferative disorders.

In order to determine variables that correlate with malignant pleural effusion and mortality in patients with lymphoproliferative disorders and pleural effusion, a retrospective study was performed. Clinical data of hospitalized patients with a lymphoid malignancy and pleural effusion who underwent thoracentesis from January 1993 to December 2002 were collected. A logistic regression analysis was carried out to determine prognostic variables that predict malignant pleural effusion and hospital mortality. There were 86 patients who were admitted on 91 occasions. The median age was 70 years (range 4 - 92) and the male:female ratio was 44:42. Sixty-four patients (74%) had advanced disease, 43 (50%) had received prior chemotherapy and 9 (10%) were in remission. Of 91 cases of pleural effusions, 44 (48%) were bilateral, 80 (88%) were exudates and 48 (53%) were due to malignant involvement of pleura. In multivariate analysis, symptomatic pleural effusion (odds ratio 10.3, 95% confidence interval 1.7 - 98.3), pleural fluid mesothelial cell count < 5% (odds ratio 8.0, 95% confidence interval 1.4 - 58.2), pleural fluid:serum lactate dehydrogenase (LDH) > or =1 (odds ratio 6.4, 95% confidence interval 1.2 - 45.6) and pleural fluid lymphocyte percentage > or =50 (odds ratio 6.4, 95% confidence interval 1.2 - 50) were significantly correlated with malignant effusion. A secondary cancer (odds ratio 11.9, 95% confidence interval 2.3 - 88.8), pleural fluid:serum LDH > or =1 (odds ratio 10.9, 95% confidence interval 2.6 - 64.9), and pneumonia (odds ratio 6.4, 95% confidence interval 1.7 - 28.6) were significantly correlated with hospital mortality. In conclusion, malignant pleural effusion is the common etiology of pleural effusion in patients with lymphoid malignancy. Many clinical and cytochemical markers have discriminatory values in identifying malignant effusion. A high pleural fluid to serum LDH level correlates with malignant pleural involvement and hospital mortality.

Adolescent↗
PubMed2005

In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells.

Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water (2H2O) daily for 84 days, and 2H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.

Aged↗
PubMed2005

Evolution of treatment strategies in chronic lymphocytic leukemia. Part 2 of a 3-Part series: Advances in the treatment of hematologic malignancies.

Over the past few decades, the management of chronic lymphocytic leukemia (CLL) has evolved considerably. This advancement is due in part to increasing awareness of prognostic factors and molecular heterogeneity of the disease which has helped to identify distinct risk groups of CLL. In addition, novel treatment regimens have demonstrated much higher complete and overall response rates than previously seen with conventional CLL therapy. Indeed, as complete response rates exceed 50%, curative therapy for CLL is within reach. Ongoing clinical research may define the optimal treatment strategies and improve outcomes for patients with CLL.

Biomedical Research↗
PubMed2004

ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.

BACKGROUND: The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV(H)) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV(H) but lack expression of ZAP-70. METHODS: We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV(H) gene. We then investigated the association between the results and the time from diagnosis to initial therapy. RESULTS: We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV(H) gene (71 percent), but in only 24 of the 143 patients with a mutated IgV(H) gene (17 percent, P<0.001). Among the patients with ZAP-70-positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV(H) gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV(H) gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70-negative CLL cells who had either mutated or unmutated IgV(H) genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV(H) gene and 7.1 years in those with an unmutated IgV(H) gene (P<0.001). CONCLUSIONS: Although the presence of an unmutated IgV(H) gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

B-Lymphocytes↗
PubMed2004

Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia.

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.

Amino Acid Sequence↗
PubMed2004

Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic lymphocytic leukemia patients contain recurrent mutations in the signal sequence of the type I TGF-beta receptor.

B cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in western societies, and is currently incurable. B cells of some B-CLL patients are resistant to the anti-proliferative effects of transforming growth factor-beta (TGF-beta). Herein, we identified two mutations within the putative signal sequence of TGF-beta type I receptor (TbetaR-I) gene of TGF-beta-resistant B-CLL patients (i.e., a Leu12Gln substitution together with an in-frame single Ala deletion). Although TbetaR-I mutants were expressed to the cell surface and interacted normally with TGF-beta-bound TbetaR-II, their expression significantly reduced gene transcription stimulated by TGF-beta, suggesting a causal relationship in the development of TGF-beta-resistant B-CLL. Screening of additional B-CLL patients solely for the presence of TbetaR-I signal sequence mutations showed that these mutations correlated with and predicted for B-CLL patient insensitivity to TGF-beta. Our results demonstrate that TGF-beta-resistant B-CLL is linked to signal sequence mutations within the TbetaR-I gene, and may eventually be employed as a prognostic indicator in B-CLL.

B-Lymphocytes↗
PubMed2004

Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare disease.

Bronchial-associated lymphoid tissue (BALT) lymphoma is a distinct subgroup of low-grade B-cell extranodal non-Hodgkin's lymphoma, classified as marginal-zone lymphoma. This study was performed in order to assess the natural history of this rare entity. We evaluated retrospectively the clinical data of 22 patients with biopsy-proven BALT lymphoma at two tertiary-care institutions from 1996 to 2002. Immunophenotyping was done to confirm the abnormal populations of B-lymphoid cells in all cases, and clonality was determined by flow cytometry or molecular studies. There were 11 men and 11 women in the sample, median age 61 years (range 21-80 years); nine were asymptomatic at diagnosis. All 13 symptomatic patients had non-specific pulmonary complaints. On computed tomographic examination of the chest, 11 patients had bilateral disease, 12 had lung nodules, and 10 had a mass or air-space consolidation. In all but one case the disease was localised to the lung at diagnosis and none had peripheral blood or bone marrow involvement. Out of 22 patients, 20 received treatment in various combinations, 12 had chemotherapy and/or rituximab, six had surgery, and two received radiation therapy as primary treatment. A complete response (CR) was achieved in nine patients and a partial response was obtained in 10 patients. Seven of 10 patients who had unilateral disease achieved a CR. The estimated progression-free survival was 53 months. All patients were alive during the median follow-up period of 36 months (range 12-76 months). It appears that BALT lymphoma tends to be localised to lung at the time of diagnosis, responds well to local or systemic therapy, and has a favourable prognosis.

Adult↗
PubMed2004

The role of monoclonal antibodies in stem cell transplantation.

Monoclonal antibodies directed at the lymphoid antigens have become established treatments for hematological malignancies either alone or in combination with chemotherapy. However, their incorporation in the transplant setting remains investigational. This review focuses on the currently available data for in vitro and in vivo purging with these antibodies as well as their role in modulating graft-versus-host disease (GVHD).

Antibodies, Monoclonal↗
PubMed2004

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia.

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged V(H)DJ(H) and V(L)J(L) genes of 25 non-IgM-producing B-CLL cases, we found five IgG(+) cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb's reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG(+) B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both.

B-Lymphocytes↗
PubMed2003

Pulmonary complications in chronic lymphocytic leukemia.

BACKGROUND: Although pulmonary complications account for significant morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), to the authors' knowledge there are sparse data available in published literature. The authors evaluated pulmonary complications in patients with CLL and identified prognostic variables that predict hospital mortality in these patients. METHODS: Clinical data were analyzed retrospectively from patients with CLL who required hospitalization for a respiratory illness at a tertiary care institution from January 1993 to December 2001. A logistic regression analysis with a backward elimination procedure was carried out to determine prognostic variables that predict hospital mortality. RESULTS: There were 110 patients who were admitted on 142 occasions with a pulmonary complication. The median age was 75 years (range, 43-97 years), and the male:female ratio was 1.7:1.0. Among 142 admissions, 68% were high risk according to the Rai criteria, 68% of patients admitted had received prior therapy for CLL, and 35% had received treatment within 3 months of admission. The most common pulmonary complications were pneumonias (75%), malignant pleural effusion/and or lung infiltrate due to CLL (9%), pulmonary leukostasis (4%), Richter transformation or nonsmall cell lung carcinoma (3%), and upper airway obstruction (2%). Forty-four of 110 patients (40%) died. In multivariate analysis, admission absolute neutrophil counts </= 0.5 x 10(9)/L (odds ratio, 4.6; 95% confidence interval [95% CI], 1.3-16.6) and blood urea nitrogen (BUN) levels >/= 20 mg/dL (odds ratio, 3.0; 95% CI, 1.1-8.3) were correlated significantly with mortality. CONCLUSIONS: Pneumonia was the major pulmonary complication in hospitalized patients with CLL. Severe neutropenia and high BUN levels were correlated significantly with increased mortality.

Adult↗
PubMed2003

Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations.

Patients with B-cell chronic lymphocytic leukemia (B-CLL) segregate into subgroups with very different survival times. Because clinical observations suggest that leukemic cells accumulate at different rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replication. Our data indicate that the telomeres of B-CLL cells are shorter than telomeres of B cells from healthy subjects, indicating that the leukemic cells have a prolonged proliferative history. Leukemic cells of the immunoglobulin V gene mutation subgroups differ in telomere length and telomerase activity. B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. Differences in telomere length appear to largely reflect the proliferative histories of precursors of the leukemic cells, although differences in cell division, masked by the action of telomerase, cannot be excluded. These results may provide insight into the stages of maturation and the activation pathways of the cells that give rise to B-CLL. In addition, they reinforce the concept that B-CLL is not simply an accumulative disease of slowly dividing B lymphocytes but possibly one of B cells with extensive proliferative histories.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2003

Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone.

The degree of somatic mutation of immunoglobulin variable (Ig V) region genes is an important prognostic indicator of clinical course and outcome in B-cell chronic lymphocytic leukemia (B-CLL), although the reason for this association remains unclear. Furthermore, some B-CLL cells continue to acquire Ig V gene mutations after the transforming event. Because activation-induced cytidine deaminase (AID) is an essential component of the canonical somatic hypermutation process in healthy B cells, its expression in B-CLL is potentially relevant to the disease. We detected full-length AID transcripts and 3 splice variants by conventional reverse transcription polymerase chain reaction (RT-PCR) in approximately 40% of the cases examined. More sensitive real-time quantitative PCR detected AID transcripts in virtually all B-CLL samples tested, although the range of transcript levels was very large between different cases and varied within individual cases over time. Limiting dilution assays revealed that AID expression was restricted to a small fraction of the leukemic cells in the blood. However, this small fraction is not unique in its ability to express AID, because in vitro stimulation of B-CLL cells with appropriate stimuli significantly increased the fraction of AID-expressing cells. These data suggest that AID-mediated DNA alterations may occur in a variably sized, minor subset of B-CLL cells at any given time.

Alternative Splicing↗