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K R Rai

Publications and source records attributed to K R Rai.

At least 37 records · Page 2Linked to original sources
PubMed1996

The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukemia cells treated with 2-chlorodeoxyadenosine.

The treatment of chronic lymphocytic leukemia includes the use of alkylating agents, steroids, and more recently nucleoside analogues. While prior studies have described potential mechanisms of 2-chlorodeoxyadenosine cytotoxicity including the accumulation of DNA strand breaks and induction of apoptosis or programmed cell death, the expression of p53 and its downstream target WAF1/CIP1 have not been examined. In this report we describe the induction of p53 and WAF1/CIP1 in the apoptotic chronic lymphocytic leukemia cells after exposure to 2-chlorodeoxyadenosine.

Antineoplastic Agents↗
PubMed1995

Recombinant alpha-2b-interferon in therapy of previously untreated hairy cell leukemia: long-term follow-up results of study by Cancer and Leukemia Group B.

In 1985, Cancer and Leukemia Group B initiated a multi-institutional study to define the role of interferon alpha in therapy of previously untreated active hairy cell leukemia (HCL). This is a long-term follow-up report of the study. Fifty-five evaluable patients were treated with recombinant interferon-2b 2 million units/m2 subcutaneously three times a week for 1 year. Treatment was well tolerated; toxicity mainly consisted of flu-like syndrome and pancytopenia, both of a transient nature. Seventy-three percent of patients had objective beneficial responses with 8.3 months median time to achieve at least a partial response (PR). After 1 year of therapy, the patients have been observed for a median of 5 years. There was a continual trend towards relapse throughout this period but 28% have remained in remission beyond 6 years. Forty-six patients (83%) are alive at 6 years. Among the 40 patients who achieved at least a PR, there were 28 with splenomegaly at the beginning of study: the spleen size was reduced in all with interferon alpha therapy and none required splenectomy. This study confirms the results of other investigators, and demonstrates that recombinant alpha interferon-2b is an effective agent for treatment of hairy cell leukemia.

Adult↗
PubMed1994

Comparison of pentostatin and alpha interferon in splenectomized patients with active hairy cell leukemia: an intergroup study. Cancer and Leukemia Group B and South-West Oncology Group.

In 90 splenectomized patients with active HCL, this multi-institutional intergroup study showed that as compared to alpha interferon (aIF), pentostatin resulted in a higher incidence of response, but the difference was not statistically significantly. Pentostatin-induced remissions occurred significantly faster and such responses lasted significantly longer when compared with aIF induced remissions. there were no unusual toxicities observed in this study. This study confirms previous observations that both these agents have important place in therapy of hairy cell leukemia.

Combined Modality Therapy↗
PubMed1994

Impaired interferon alpha response in hairy cell leukemia is corrected by therapy with 2-chloro-2'-deoxyadenosine: implications for susceptibility to opportunistic infections.

Patients with hairy cell leukemia (HCL) are susceptible to opportunistic intracellular infections, suggesting defects in cellular immunity. Prior studies have indicated an association between failure of IFN-alpha generation by peripheral blood mononuclear cells (MNC) and susceptibility to such infections. We here present results on IFN-alpha generation in HCL patients pre- and post-therapy. Prior to treatment with 2-chloro-2'-deoxyadenosine (CdA), MNC from 24 HCL patients with active disease produced little or not IFN-alpha (geometric mean < 40 IU/ml) compared with controls (n = 140, geometric mean 1730 IU/ml, p < 0.0005). After treatment with CdA, IFN-alpha generation was studied in 16 patients, with a geometric mean value of 650 IU/ml (p < 0.0005 compared with pre-CdA levels). The severe depression of IFN-alpha generation improved progressively following CdA therapy-induced clinical remission. We propose that deficiency of IFN-alpha production may play a role in the susceptibility to intracellular infections of patients with active HCL.

Adult↗
PubMed1993

Progress in chronic lymphocytic leukaemia: a historical perspective.

A historical review of gains in the body of knowledge on chronic lymphocytic leukaemia (CLL) reveals a continuous, steady process from the beginning of the century with the pioneering work of scholars to the present era of molecular biology. Several notable hallmarks of this progress have been recognized: (1) the early period of broad, loose grouping of all chronic lymphoproliferative disorders; (2) recognition of CLL as a discrete entity with clinical and cytological identification of different forms of lymphoid neoplasm; (3) development of clinical staging systems and prognostic factors; and (4) use of immunological techniques in the study of CLL. Studies currently in progress using molecular genetic techniques hold promise for future advances in unravelling the biology of leukaemic transformation of lymphocytes in CLL.

Germany↗
PubMed1990

Chronic lymphocytic leukemia: new insights into biology and therapy.

PURPOSE: To review the recent advances in the biologic and clinical research of chronic lymphocytic leukemia. DATA IDENTIFICATION: English-language literature search using MEDLINE (1980 to 1990) and CANCERLIT (1980 to 1990), review of meeting abstracts and reports, and an extensive manual search of bibliographies of identified articles. STUDY SELECTION: Approximately 800 articles, abstracts, and book chapters were selected for analysis. DATA EXTRACTION: The literature was reviewed and 227 articles were selected as representative of the important advances in chronic lymphocytic leukemia. RESULTS OF DATA SYNTHESIS: Chronic lymphocytic leukemia is a disease of lymphocytes that appear to be mature but are biologically immature. These B lymphocytes arise from a subset of CD5-B cells that appear to have a role in autoimmunity. The pathogenesis of chronic lymphocytic leukemia is likely a multistep process, initially involving a polyclonal expansion of CD5-B cells followed by transformation of a single cell. Chromosome studies indicate that trisomy 12 is the most common abnormality, followed by 14q+, 13q, and 11q. These abnormalities portend a poor prognosis. Recent progress in the treatment of chronic lymphocytic leukemia involves three new drugs: fludarabine, pentostatin, and 2-chlorodeoxyadenosine. Recent preliminary results of allogeneic bone marrow transplantation present insights into the potential curability of chronic lymphocytic leukemia. Therapy with intravenous immunoglobulin can prevent or delay moderate bacterial infections in persons with chronic lymphocytic leukemia. CONCLUSION: Major advances in the biologic research of chronic lymphocytic leukemia have resulted in new understanding of this complex disease. New therapies, such as those with intravenous immunoglobulin and fludarabine, may lead to improved outcome.

Agammaglobulinemia↗
PubMed1990

Distinct characteristics of lymphokine-activated killer (LAK) cells derived from patients with B-cell chronic lymphocytic leukemia (B-CLL). A factor in B-CLL serum promotes natural killer cell-like LAK cell growth.

We show that lymphokine-activated killer (LAK) cell precursors derived from patients with B-cell chronic lymphocytic leukemia (B-CLL) and cultured in the presence of recombinant interleukin-2 and normal human serum (NHS), develop into primarily NK cell-like (CD 57+) LAK cells, whereas identically prepared LAK cell precursors from normal subjects develop into mainly T cell-like (CD 3+, CD 8+) LAK cells. B-CLL LAK cells exhibited greater proliferative capacity than did normal LAK cells. When normal LAK cells were grown in B-CLL serum instead of NHS, their proliferation increased; NK cell levels also increased to those found in B-CLL LAK cells, suggesting that B-CLL serum contains a factor that promotes NK cell-like growth, LAK cells derived from normal or B-CLL patients demonstrated similar lytic activity toward K562 and Raji cells. Growth in B-CLL serum did not reduce their lytic potential. Thus, the altered phenotype and growth exhibited by B-CLL LAK cells and normal LAK cells grown in B-CLL serum does not lead to abnormalities in their cytolytic functions. We propose instead that the predominance of NK-like cells in B-CLL LAK cell populations and the presence of an NK cell-like growth factor in B-CLL serum reflect abnormalities related to NK cell-mediated B-cell regulation; ie, either inhibition of normal B-cell growth and/or growth stimulation of the leukemic clone in B-CLL.

Antigens, CD↗
PubMed1990

Characteristics of CD11c+CD5+ chronic B-cell leukemias and the identification of novel peripheral blood B-cell subsets with chronic lymphoid leukemia immunophenotypes.

Previous studies have indicated that chronic lymphocytic leukemias (CLL) are characterized by the coexpression of CD5 and B-cell antigens, while hairy cell leukemias (HCL) typically express CD11c+CD5- B-cell immunophenotypes. In this report we describe the features of B-cell leukemias with CD11c+CD5+ immunophenotypes and the identification of novel circulating B-cell subsets defined by the expression of CD20, CD5, and CD11c antigens. Morphologic evaluation of 14CD11c+CD5+ B-cell leukemias showed that they generally had larger cellular diameters (14 to 21 microns) and lower nuclear:cytoplasm ratios than typical small lymphocyte CLL. These cases did not exhibit the well-defined nucleoli characteristic of prolymphocytic leukemia (PLL). The presenting clinical features of CD11c+CD5+ B-cell leukemias were most consistent with CLL or PLL, and none of the evaluated cases had pancytopenia, splenomegaly, and cytoplasmic villi characteristic of HCL. Examination of normal peripheral blood (n = 6) by three-color flow cytometry identified four novel B-cell subsets with the following immunophenotypes (mean percent of total CD20+ B cells +/- SE): CD20+CD5+CD11c+ (8.0 +/- 1.6); CD20+CD5-CD11c+ (12.0 +/- 2.0); CD20+CD5+CD11c- (35.0 +/- 4.9); and CD20+CD5-CD11c- (44.0 +/- 5.0). Our findings suggest that CD11c+CD5+ B-cell leukemias with atypical morphologic features represent forms of CLL or PLL rather than HCL. In addition, we have identified novel subsets of circulating B cells defined by patterns of CD20, CD5, and CD11c expression that correspond to the immunophenotypes of chronic B-cell leukemias.

Adult↗
PubMed1990

Management of chronic lymphocytic leukemia.

Significant progress has been made in the past two decades in the understanding of immunobiology of CLL and the development of clinical staging systems and identification of other prognostic factors in CLL. A significant advance in the management of CLL has also been made. Now we know when to initiate therapy. We recommend that patients with stage 0 and patients with stages I and II associated with good prognostic features such as absence of disease-related symptoms, long lymphocyte doubling time, nondiffuse bone marrow infiltration, and low tumor load not be treated; they should be followed at 2- to 6-month intervals. We recommend initiation of therapy for patients with stages I and II, associated with poor prognostic features such as presence of disease-related symptoms, short lymphocyte doubling time, diffuse bone marrow infiltration, and high tumor load and for patients with stages III and IV. However, we still do not know what constitutes the optimal therapy for the disease. In one large randomized study, the response rate as well as survival superiority of CHOP (with low-dose Adriamycin) over COP in previously untreated patients with stage C disease was observed. In another large randomized study, only a response rate advantage of CHOP (with standard dose Adriamycin) over chlorambucil and prednisone (in previously untreated patients with stages B and C) was seen. No randomized studies have compared CHOP versus chlorambucil and prednisone in patients with stages III and IV or stage C. At present, our recommendation for the treatment of patients with advanced disease is chlorambucil and prednisone therapy. New drugs under clinical trials for CLL include (1) deoxycoformycin, (2) 2-chlorodeoxyadenosine, and (3) fludarabine monophosphate. Both deoxycoformycin and 2-chlorodeoxyadenosine have been shown to have some activity in previously treated CLL patients with advanced disease. The effectiveness of these agents, however, has not been tested yet in untreated patients with advanced disease. Fludarabine monophosphate, on the other hand, has been shown to be very effective in both previously treated and untreated patients with advanced disease. Allogeneic bone marrow transplantation recently has been found to be of benefit in some patients (37 to 46 years) in a preliminary study; this therapeutic procedure should be tested further in a larger population of younger patients (less than 50 years) with advanced CLL. New agents such as lymphokines (interferons and IL-2) and monoclonal antibodies have been investigated for their efficacy and found to be minimally effective in previously treated patients with advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1990

Prognostic factors and clinical staging in chronic lymphocytic leukemia.

There has been significant progress in the past 10 years in our ability to prospectively predict prognosis in CLL. The clinical staging systems have helped us identify three broad groups of patients with respect to their overall outlook for survival: low risk (stage 0), intermediate risk (stages I and II), and high risk (stages III and IV). It seems reasonable to distinguish those low- and intermediate-risk patients who are likely to have a benign or indolent clinical course if their blood lymphocyte doubling time is longer than 12 months and their bone marrow biopsy pattern of lymphocytic infiltration is nondiffuse. With these guidelines, it will be possible to initiate meaningful and reliable therapeutic trials in CLL in the immediate future.

Biomarkers, Tumor↗
PubMed1988

Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group.

The National Cancer Institute (NCI)-sponsored Chronic Lymphocytic Leukemia (CLL) Working Group was convened to develop a set of standardized eligibility, response, and toxicity criteria for clinical trials. We recognized the previous efforts in 1967 (published again in 1973 as the report of the Chronic Leukemia-Myeloma Task Force [1] and 1978 of Cancer and Leukemia Group B (CALGB) [2]). We have used these reports for guidance during the current effort. Several noteworthy developments in the past few years have made it necessary to modify the previous guidelines. First, the diagnostic criteria for CLL and its clinical staging have been developed and well defined. Second, although staging systems facilitated entry of comparable and relatively homogeneous groups of patients in clinical trials, the definitions of response (CR) and partial response (PR) were not uniformly adopted from the previous guidelines in the clinical trials (Tables IA, IB); therefore, comparisons of results obtained in different studies became difficult. Third, there has been an improvement in our understanding of the immunology and biology of CLL. Finally, we are witnessing the emergence of several chemotherapy agents that promise impressive activity in CLL (e.g., 2'-deoxycoformycin [3], fludarabine monophosphate [4, 5]), and thereby offer the potential for improving survival time in this disease. To best identify regimens worthy of continued pursuit in large comparative trials, standardized guidelines for evaluation are essential. A number of laboratory investigations are also presented for which scientific interest is high yet relevance remains to be determined; thus, they are presented as companion studies to the clinical trials. This mechanism allows for flexibility in the testing of these questions and for additional ideas in the future without requiring modification of an entire treatment protocol. The following guidelines were developed to be used as a form of standardization for clinical trials, incorporating current technologies, yet remaining relevant to the general hematology/oncology community. Based on the membership of the Working Group, it is expected that these guidelines will serve as the criteria for most clinical trials in the near future.

Antineoplastic Agents↗
PubMed1988

Analysis of treatment response in chronic lymphocytic leukemia: new approaches.

As therapeutic protocols to treat chronic lymphocytic leukemia evolve, new criteria will be required to define remission and identify early relapse. Two techniques that detect low numbers of residual monoclonal B-lymphocytes currently include immunoglobulin (Ig) gene rearrangement and clonal excess analysis. Ig-gene rearrangement studies are time consuming and expensive. Clonal excess analysis by FC may be insensitive because of minimal surface immunoglobulin (SIg) expression. Three antigens, CD5, CD11c and CD14 are expressed on B-lymphocytes of CLL. CD14 is also expressed on most normal B-lymphocytes. In contrast, CD5 and CD11c are expressed on few normal B-lymphocytes. Consequently CD5 and CD11c are useful markers for detecting residual CLL cells. Appropriate selection of the second B-cell marker such as SIg, CD19, CD20 or other, is critical. We evaluated this approach in persons with CLL receiving therapy. Preliminary results will be presented.

Biomarkers, Tumor↗