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Biomedical subjects

L A Kunkel

Publications and source records attributed to L A Kunkel.

14 recordsLinked to original sources
PubMed2001

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.

Adult↗
PubMed1998

Autologous transplantation of mobilized peripheral blood CD34+ cells selected by immunomagnetic procedures in patients with multiple myeloma.

In the use of autologous PBPC transplantation in patients with multiple myeloma, contamination of PBPC with myeloma cells is commonly observed. Enrichment for CD34+ cells has been employed as a method of reducing this contamination. In this study the reduction of myeloma cells in PBPC was accomplished by the positive selection of CD34+ cells using immunomagnetic bead separation (Isolex 300 system). PBPC were mobilized from 18 patients using cyclophosphamide (4.5 g/m2) and G-CSF (10 microg/kg/day). A median of two leukaphereses and one selection was performed per patient. The median number of mononuclear cells processed was 3.50 x 10(10) with a recovery of 1.11 x 10(8) cells after selection. The median recovery of CD34+ cells was 48% (range 17-78) and purity was 90% (29-99). The median log depletion of CD19+ cells was 3.0. IgH rearrangement, assessed by PCR, was undetectable in 13 of 24 evaluable CD34+ enriched products. Patients received 200 mg/m2 of melphalan followed by the infusion of a median of 2.91 x 10(6)/kg CD34+ cells (1.00-16.30). The median time to absolute neutrophil count >0.5 x 10(9)/l was 11 days, and sustained platelet recovery of >20 x 10(9)/l was 14 days. We conclude that immunomagnetic-based enrichment of CD34+ cells results in a marked reduction in myeloma cells without affecting engraftment kinetics.

Adult↗
PubMed1998

CD34+ cell engraftment, ex vivo expansion, and malignant cell depletion following immunomagnetic selection.

This review describes the published preclinical and clinical data on the use of a manual or semiautomated immunomagnetic selection device, termed the Isolex system. Preclinical evaluation of hematopoietic progenitor cells (CD34+ cells) selected from bone marrow, peripheral blood leukapheresis products, and umbilical cord blood is reviewed with respect to differentiation (CFU-GM, BFU-E, and CFU-GEMM formation) and proliferation. The purities and yields of CD34+ cell products from clinical trials performed since 1994 are presented along with data on malignant cell depletion. On average, the Isolex system resulted in a final product median purity of 67% and a final product median yield of 64%. Positive selection of CD34+ cells with this device decreased residual tumor cell levels by 2-3 logs in autologous transplant products and reduced T cell levels by 3-4 logs in allogeneic grafts. To evaluate the clinical effect of these immunomagnetically selected cells, data on the rate of engraftment were reviewed. Autologous CD34+ cell transplantation resulted in recovery time from neutropenia (ANC > 500/microliter) of 9-14 days and recovery time from thrombocytopenia (platelet count > 20,000/microliter) of 10-20 days. These data showed that the Isolex system can positively select progenitor cells to reconstitute the hematopoietic system following myeloablative therapy.

Antigens, CD34↗
PubMed1997

Composition of peripheral blood progenitor cell components collected from healthy donors.

BACKGROUND: Peripheral blood progenitor cell (PBPC) components are being collected from healthy donors for allogeneic transplantation, but the quantity, quality, composition, and variability of PBPCs collected from healthy people given granulocyte-colony-stimulating factor (G-CSF) have not been evaluated. STUDY DESIGN AND METHODS: PBPC components were collected from 150 healthy people who were given G-CSF (5, 7.5, or 10 microg/kg/day) for 5 days. The components were evaluated for white cell (WBC), mononuclear cell, CD34+ cell, neutrophil, platelet, and red cell (RBC) composition. RESULTS: The quantities collected were: WBCs, 35.0 +/- 16.4 x 10(9) (range, 11.9-163.3 x 10(9)); mononuclear cells, 33.3 +/- 14.4 x 10(9) (range, 11.9-139.6 x 10(9)); CD34+ cells, 412 +/- 287 x 10(6) (range, 70-1658 x 10(6)); neutrophils, 1.71 +/- 3.59 x 10(9) (range, 0-27.6 x 10(9)); RBCs, 7.2 +/- 4.0 mL (range, 0-22.1 mL); and platelets, 480 +/- 110 x 10(9) (range, 250-920 x 10(9)). PBPC components collected from people given G-CSF at 7.5 or 10 microg per kg per day contained significantly more CD34+ cells (respectively, 428 +/- 300 x 10(6); range, 70-1658 x 10(6) and 452 +/- 294 x 10(6); range, 78-1380 x 10(6)) than those from people given G-CSF at 5 microg per kg per day (276 +/- 186 x 10(6); range, 91-767 x 10(6)) (p = 0.007 and p = 0.002). When 10 microg per kg per day of G-CSF was given, 50 percent of the components contained enough CD34+ cells for transplantation to a 75-kg recipient (375 x 10(6) CD34+ cells), but 10.6 percent of the components contained less than 150 x 10(6) CD34+ cells and thus would provide a transplantable dose only for a 30-kg patient. CONCLUSION: One PBPC component collected from a healthy donor given 7.5 or 10 microg per kg per day of G-CSF should contain 70 to 1660 x 10(6) CD34+ cells, with 0 to 22 mL of RBCs. Because of the great variability in the number of CD34+ cells collected, the quantity of CD34+ cells in each component should be measured after each procedure to ensure that sufficient quantities of cells are present for a successful transplant.

Antigens, CD34↗
PubMed1996

An association between renal cell carcinoma and lymphoid malignancies. A case series of eight patients.

BACKGROUND: Second primary malignancies have been described in patients with both solid tumors and hematologic malignancies. However, an association between renal cell carcinoma and lymphoid malignancies has rarely been described. Eight patients with both disorders are described and possible explanations for the association are reviewed. METHODS: A retrospective review of records from patients with renal cell carcinoma, lymphoma, leukemia, or myeloma discharged from the University of California at Los Angeles between July 1, 1993 and June 30, 1995 was performed. Renal cell carcinoma was diagnosed in 186 patients, whereas 405 had a lymphoid malignancy. Eight patients with both disorders were identified. RESULTS: In four of the eight patients, the renal cell carcinoma was diagnosed prior to their hematologic malignancy, whereas in the remaining four patients, the lymphoid malignancy was diagnosed first. Renal cell carcinoma is observed in the general population in 12.5 persons per 100,000 and hematologic malignancies in 31.8 per 100,000. The number of cases of lymphoid malignancies expected in the 186 renal cell carcinoma patients is lower than the 4 cases actually observed (P < 0.01). Likewise, the number of renal tumors expected in the 405 patients with hematologic malignancies is fewer than the 4 cases observed (P < 0.01). CONCLUSIONS: The incidence of renal cell carcinoma and lymphoid malignancy occurring in the same patient is higher than that expected in the general population. This association cannot be explained by treatment-related development of a second malignancy. A common genetic mutation or an immunomodulatory role of the first malignancy predisposing to the second are possibilities but further investigation is warranted.

Aged↗
PubMed1996

Production of anti-erythrocyte antibodies by leukemic and nonleukemic B cells in chronic lymphocytic leukemia patients.

We have assessed the specificity of antibodies from the leukemic B cells of five patients with both chronic lymphocytic leukemia and autoimmune hemolytic anemia (CLL-AHA). Leukemic cells from one patient displayed surface immunoglobulin with heavy and light chain isotypes identical to that of the patient's anti-red blood cell (RBC) antibodies, and the leukemic cells secreted antibodies in vitro with anti-RBC activity. However, in the remaining patients, the leukemic cells displayed surface immunoglobulin with light chain isotypes different from that of the patient's anti-RBC antibodies and secreted antibodies in vitro with no detectable anti-RBC activity. Thus, there are two distinct classes of CLL-AHA patients, differentiated by the presence or absence of an anti-RBC antibody-producing leukemic B cell clone. The apparent heterogeneity in the source of pathogenic anti-RBC antibodies may impact the treatment response of the two classes of CLL-AHA patients.

Aged↗
PubMed1994

Autoimmune anemia, neutropenia, Eaton-Lambert syndrome, and cerebellar degeneration in a patient with lymphoid hyperplasia.

We report a case of Coombs-positive anemia, neutropenia, Eaton-Lambert syndrome, and cerebellar degeneration with anti-Purkinje cell antibodies. No definitive cause has been established despite an extensive search for a malignancy or a known autoimmune disease. The histology of spleen and lymph nodes showed marked polyclonal B and T cell hyperplasia, noncaseating granulomas, and increased eosinophils. The disease failed to improve after splenectomy and treatment with prednisone and cyclophosphamide; partial response was achieved with azathioprine plus prednisone.

Adult↗
PubMed1992

Acquired circulating anticoagulants.

Acquired inhibitors of blood coagulation, which are pathologic circulating substances that directly inhibit clotting factors or their reactions, most commonly occur in patients with hereditary bleeding disorders. This article contains a discussion of acquired circulating anticoagulants that arise de novo in patients with previously normal hemostatic mechanisms. Pathogenesis and management are also discussed. Treatment of these patients poses a challenge for the hematologist because, unlike hereditary hemophiliacs who have learned to adjust their lifestyle, the acquired hemophiliac is unprepared for hemorrhagic episodes.

Autoantibodies↗
PubMed1992

Disseminated intravascular coagulation syndromes.

Current concepts of the etiology, pathophysiology, diagnosis and management of fulminant as well as low-grade disseminated intravascular coagulation have been presented. Considerable attention has been devoted to interrelationship within the hemostasis system. Only by clearly understanding these pathophysiological interrelationships can the clinician and laboratory scientists appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with disseminated intravascular coagulation. Many therapeutic decisions to be made in these patients are controversial and will remain so until more series of patients are published about specific therapeutic modalities and survival patterns. Also, therapy must be highly individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamic and other clinical parameters. Many syndromes which are organ specific share common pathophysiology with disseminated intravascular coagulation but are typically identified as an independent disease entity, such as hemolytic uremic syndrome, adult shock lung syndrome, eclampsia, and many other isolated "organ-specific" disorders. Many of these similar disorders, some systemic and some organ specific or multi-organ specific are listed in Table 8.

Disseminated Intravascular Coagulation↗
PubMed1990

Transient stress lymphocytosis during crisis of sickle cell anemia and emergency trauma and medical conditions. An immunophenotyping study.

Transient absolute lymphocytosis of peripheral blood has been described in "stress"-related emergency trauma and medical conditions. There are no reports of this phenomenon in patients with sickle cell anemia with vaso-occlusive crisis. We studied initial and follow-up immunophenotypic characteristics of 10 adult patients with sickle cell anemia in crisis and 15 adult patients with emergency conditions who presented with absolute lymphocytosis. On admission, both groups demonstrated increases in the numbers of CD20+ B cells and T cells of the CD2, CD4, CD8, and CD56 (NKH-1) phenotypes compared with control values. Findings in both groups of patients mimicked the results of parenteral epinephrine administration: a pan-B and -T lymphocytosis with marked increase in CD56 (fourfold to fivefold) and CD8 cells (threefold to fourfold) as well as moderate increases in CD20 and CD4 cells (twofold), resulting in a decrease in the CD4/CD8 ratio compared with control values. In patients with sickle cell anemia, there was an expected increase in the CD56 and CD4 populations; however, CD8 cells only doubled at the time of crisis. Therefore, the CD4/CD8 ratio was normal compared with control values. CD20+ B cell numbers exceeded those seen in the patients with medical and trauma emergencies. Elevated corticosteroid levels have been measured after injury in previous studies. Parenterally administered cortisol produces a lymphocytopenia after 4 to 6 hours that selectively decreases T cells. At 10 to 38 hours after admission, there was a marked reduction in the number of T cells in both groups of "stressed" patients, probably reflecting at least partial effects of endogenous corticosteroids. In contrast to the patients with medical and trauma emergencies, the mean lymphocyte count in the patients with sickle cell anemia remained elevated in the "high normal" range and consisted of increased numbers of B cells and CD4 cells. This finding persisted in the patients with sickle cell anemia for up to 3 months after presentation. The lymphocyte responses in both groups probably reflect interactions between adrenergic and steroidal factors.

Acute Disease↗
PubMed1981

Metabolic inhibitors render "resistant" target cells sensitive to natural killer cell-mediated lysis.

L-929 cells were lysed by activated but not by endogenous natural killer (NK) cells, as reported previously. Nevertheless, L-929 cells bound to endogenous NK cells, as shown by target binding cell, cold target competition, and monolayer absorption assays. Treatment of L-929 cells with actinomycin-D or cycloheximide rendered them sensitive to lysis by endogenous NK cells and markedly increased their sensitivity to lysis by activated NK cells. Treatment with these drugs under the prescribed conditions did not affect the binding of L-929 cells to NK cells. Since others have shown that treatment with these drugs inhibits membrane repair processes and renders cells more sensitive to complement-mediated lysis, we hypothesize that membrane repair may be an important factor influencing a cell sensitivity to NK cells. This may be more important than NK-binding ability, since most cells can be lysed by (and therefore bind to) activated NK cells.

Animals↗