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Biomedical subjects

K R Rai

Publications and source records attributed to K R Rai.

At least 19 recordsLinked to original sources
PubMed2002

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.

Adolescent↗
PubMed2002

Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia.

Autoimmune hemolytic anemia (AIHA) is a well known complication of chronic lymphocytic leukemia (CLL). Steroids are the first line of treatment and there are limited effective treatment options for steroid refractory AIHA of CLL. Rituximab, an active agent against B cell malignancies, has also been noted to be active in certain autoimmune hematologic disorders. We used a combination of rituximab, cyclophosphamide and dexamethasone (RCD) in eight CLL patients with steroid refractory AIHA. Rituximab was given at a dose of 375 mg/m(2) i.v. on day 1 (D-1). Cyclophosphamide was given at a dose of 750 mg/m(2) on D-2. Twelve mg of dexamethasone was given i.v. on D-1, D-2 and orally from D-3 to D-7. Cycles were repeated every 4 weeks till the best response. Response in AIHA was evaluated by frequent blood counts and Coombs test. All eight patients achieved a remission of their AIHA. Median pretreatment hemoglobin was 8.3 g/dl and post-treatment hemoglobin was 14.3 g/dl. Five patients converted to Coombs negative after RCD. Median duration of response was 13 months (7-23+). Retreatment with RCD was also effective in achieving a response on relapse of AIHA. Our results indicate that a rituximab-based combination regimen (RCD) is highly effective in treating steroid refractory AIHA of CLL.

Aged↗
PubMed2001

Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

Administration, Oral↗
PubMed2001

Chronic lymphocytic leukemia: case-based session.

Drs. Hartmut Döhner, Michael J. Keating, Kanti R. Rai and Emili Montserrat form the panel to review chronic lymphocytic leukemia (CLL) while focusing on the clinical features of a particular patient. The pace of progress in CLL has accelerated in the past decade. The pathophysiological nature of this disease, as had been known in the past, was based largely on the intuitive and empiric notions of two leaders in hematology, William Dameshek and David Galton. Now the works of a new generation of leaders are providing us with the scientific explanations of why CLL is a heterogeneous disease, perhaps consisting of at least two separate entities. In one form of CLL, the leukemic lymphocytes have a surface immunoglobulin (Ig) variable region gene that has undergone somatic mutations, with tell-tale markers suggesting that these cells had previously traversed the germinal centers. Such patients have a distinctly superior prognosis than their counterparts whose leukemic lymphocytes IgV genes have no mutations (these are indeed immunologically naive cells), who have a worse prognosis. The introduction of fluorescence in situ hybridization (FISH) technique has provided us with new insights into the diverse chromosomal abnormalities that can occur in CLL, and which have significant impact on the clinical behavior and prognosis of patients with this disease. Major advances in therapeutics of CLL also have occurred during the past decade. Two monoclonal antibodies, Campath-1H (anti-CD52) and rituximab (anti-CD20), and one nucleoside analogue, fludarabine, have emerged as three agents of most promise in the front-line treatment of this disease. Studies currently in progress reflect our attempts to find the most effective manner of combining these agents to improve the overall survival statistics for CLL patients. As in many other hematological malignancies, high dose chemotherapy followed by autologous or HLA-compatible allogeneic stem cells rescue strategies are under study as a salvage treatment for a relatively younger age group of CLL patients with poor prognosis characteristics.

Cytogenetic Analysis↗
PubMed2000

Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.

BACKGROUND: Fludarabine is an effective treatment for chronic lymphocytic leukemia that does not respond to initial treatment with chlorambucil. We compared the efficacy of fludarabine with that of chlorambucil in the primary treatment of chronic lymphocytic leukemia. METHODS: Between 1990 and 1994, we randomly assigned 509 previously untreated patients with chronic lymphocytic leukemia to one of the following treatments: fludarabine (25 mg per square meter of body-surface area, administered intravenously daily for 5 days every 28 days), chlorambucil (40 mg per square meter, given orally every 28 days), or fludarabine (20 mg per square meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square meter every 28 days). Patients with an additional response at each monthly evaluation continued to receive the assigned treatment for a maximum of 12 cycles. RESULTS: Assignment of patients to the fludarabine-plus-chlorambucil group was stopped when a planned interim analysis revealed excessive toxicity and a response rate that was not better than the rate with fludarabine alone. Among the other two groups, the response rate was significantly higher for fludarabine alone than for chlorambucil alone. Among 170 patients treated with fludarabine, 20 percent had a complete remission, and 43 percent had a partial remission. The corresponding values for 181 patients treated with chlorambucil were 4 percent and 33 percent (P< 0.001 for both comparisons). The median duration of remission and the median progression-free survival in the fludarabine group were 25 months and 20 months, respectively, whereas both values were 14 months in the chlorambucil group (P<0.001 for both comparisons). The median overall survival among patients treated with fludarabine was 66 months, which was not significantly different from the overall survival in the other two groups (56 months with chlorambucil and 55 months with combined treatment). Severe infections and neutropenia were more frequent with fludarabine than with chlorambucil (P=0.08), although, overall, toxic effects were tolerable with the two single-drug regimens. CONCLUSIONS: When used as the initial treatment for chronic lymphocytic leukemia, fludarabine yields higher response rates and a longer duration of remission and progression-free survival than chlorambucil.

Administration, Oral↗
PubMed1999

Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V(H) and V(L) gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38(+) B-CLL cells (>/=30%) than those with mutated V genes that had lower percentages of CD38(+) cells (<30%). Patients in both the unmutated and the >/=30% CD38(+) groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38(+) groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38(+) groups, males and females were virtually equally distributed, whereas in the unmutated and the >/=30% CD38(+) groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38(+) B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Antigens, CD↗
PubMed1999

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute myelogenous leukemia in 1st remission.

BACKGROUND: Despite considerable data, there is still controversy over which adults with acute myelogenous leukemia (AML) in 1st remission should receive high-dose therapy and a bone marrow transplant rather than conventional-dose chemotherapy. Analyses of data from randomized trials are complex, conclusions sometimes contradictory and results not sufficiently detailed to allow subject-level decisions. OBJECTIVE: To determine appropriate use of high-dose therapy and bone marrow transplants in persons with AML in 1st remission with specific features. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, WBC, cytogenetics and FAB-type were permuted to define 72 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a nine-point ordinal scale (1, most inappropriate, 9, most appropriate) considering 3 types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm developed. CONCLUSIONS: In people with an HLA-identical sibling, this type of transplant was rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. In people without an HLA-identical sibling, an alternative donor transplant was rated appropriate in those < 30 years with unfavorable cytogenetics, uncertain in those > 30 years and unfavorable cytogenetics and inappropriate in all other settings. Autotransplants were rated appropriate in people with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor, when available, was always preferred to an alternative donor transplant or autotransplant. In people without an HLA-identical sibling, an autotransplant was almost always favored over an alternative donor transplant with the magnitude of preference inversely correlated with transplant appropriateness.

Adult↗
PubMed1999

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in chronic myelogenous leukemia in chronic phase.

BACKGROUND: It is uncertain which people with chronic myelogenous leukemia (CML) in chronic phase should receive conventional treatment (interferon and/or chemotherapy) versus high-dose therapy and a bone marrow transplant. There are no randomized trials comparing these approaches and analyses of data from non-randomized studies are complex, contradictory without sufficient detail to allow subject-level treatment decisions. OBJECTIVE: Determine appropriateness of high-dose therapy and bone marrow transplants in persons with CML in chronic phase with specific features. Develop a treatment algorithm. PANELISTS: nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of chronic myelogenous leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, prognostic score, disease duration, and type of conventional therapy and response were permuted to define 90 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional therapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of similar settings and a treatment algorithm developed. CONCLUSIONS: In people with CML in chronic phase and an HLA-identical sibling donor and in those with an alternative donor (but no HLA-identical sibling), a transplant was rated appropriate in those with a < or = partial cytogenetic response to interferon and uncertain or inappropriate in all other settings. Autotransplants were rated uncertain or inappropriate in all settings. Most of the variance in appropriateness ratings between different clinical settings was accounted for by response to interferon: complete versus < or = partial response. An HLA-identical sibling donor, when available, was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling, an alternative donor was favored over an autotransplant at higher appropriateness indices and the converse at lower appropriateness indices.

Adolescent↗
PubMed1999

Future strategies toward the cure of indolent B-cell malignancies. New biologic therapies.

Although chronic lymphocytic leukemia (CLL) cells provide an excellent target for antibody therapy, to date this approach has met with limited success in patients with CLL. Promising data are emerging with a new generation of antibodies, such as Campath-1H, which may offer effective therapeutic options not only as single agents but also in combination with such drugs as fludarabine. Other new antibodies, including rituximab and several new radioimmunoconjugates, have provided impressive results in the indolent non-Hodgkin's lymphomas and warrant further investigation.

Antibodies, Neoplasm↗
PubMed1998

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission.

BACKGROUND: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.

Adolescent↗
PubMed1998

Old and new therapies in chronic lymphocytic leukemia: now is the time for a reassessment of therapeutic goals.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia for which therapeutic options remain unsatisfying as cure has remained elusive. Recent laboratory discoveries and promising results from completed phase III studies with fludarabine provide reason to reassess therapeutic goals in the treatment of patients with symptomatic CLL. Early enrollment of patients on protocols using combination therapies with fludarabine and new agents such as flavopiridol, IDEC-C2B8, Campath-1H, UCN-01, bryostatin, FR 901228, and melarsoprol will hopefully represent the next advance to improved overall survival and ultimately the cure of CLL.

Alkaloids↗
PubMed1998

Cladribine for the treatment of hairy cell leukemia and chronic lymphocytic leukemia.

Cladribine (Leustatin; Janssen-Cilag, Ortho Biotech Inc, Raritan, NJ) is a novel injectable nucleoside analogue with marked efficacy against hairy cell leukemia and considerable, although less dramatic, activity against chronic lymphocytic leukemia and non-Hodgkin's lymphoma. The effect is thought to be due to the drug's ability, after intracellular phosphorylation, to inhibit repair of single-strand DNA breaks in certain malignant lymphocyte and monocyte subtypes. We treated 49 patients with active hairy cell leukemia with continuous infusion of cladribine at a dose of 0.1 mg/kg/ d for 7 days. A single course of therapy gave a complete response rate of 76% and a partial response rate of 24%; the effect was durable for several years in most cases. We also treated 14 patients with chronic lymphocytic leukemia with cladribine and obtained an overall response rate of 43%; this required several courses of monthly treatment. These responses tended to be short-lived and did not substantially change life expectancy of chronic lymphocytic leukemia patients. In both diseases, myelosuppression and immunosuppression, sometimes resulting in neutropenic fever, were the only toxicities associated with cladribine.

Antineoplastic Agents↗
PubMed1997

Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up.

PURPOSE: To analyze initial and long-term outcomes after treatment of patients with active hairy-cell leukemia (HCL) with a single cycle of cladribine (2-CdA). PATIENTS AND METHODS: Forty-nine patients with active HCL were treated with 2-CdA by continuous intravenous infusion at 0.1 mg/kg/d for a total of 7 days at the Long Island Jewish Medical Center between September 1990 and August 1992. Here we report on all patients followed-up until April 1996. RESULTS: At 3 months after treatment, complete response (CR) occurred in 37 patients (76%) and partial response (PR) occurred in 12 patients (24%), for an overall response rate of 100% (95% confidence interval, 94% to 100%). At a median follow-up of 55 months, the relapse-free survival is 80% and overall survival is 95%. Ten patients (20%) have relapsed. Of the 26 patients in whom lymphocyte phenotyping was performed, four were found to have a CD25-negative phenotype. All four of these patients had PRs only and all relapsed. Eight patients have been re-treated with 2-CdA, and all achieved at least a partial remission; two of these have already relapsed with remission durations of less than 1 year. Five second malignancies have occurred in four patients. CONCLUSION: With a median follow-up of more than 4 years, 39 patients (80%) continue in remission. Only two deaths have occurred. A CD25-negative phenotype may predict for a poorer response to 2-CdA. Patients who relapse may be re-treated with 2-CdA, but subsequent remissions may be of shorter duration. There has not been a markedly increased incidence of second malignancies or late opportunistic infections.

Adult↗
PubMed1997

Chronic lymphocytic leukemia in the elderly population.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly with an incidence of about 20 to 30 per 100,000 population in the group aged 70 years or older. Chemotherapy with chlorambucil controls major clinical features of CLL but without prolongation of survival time. Addition of prednisone is necessary when autoimmune complications occur, but its usage in the elderly requires special caution. Fludarabine has better response rates than chlorambucil in treating CLL and has been proved to be an effective salvage therapy in patients previously treated with chlorambucil.

Aged↗