Showing papers by "Richard E. Champlin published in 1998"
TL;DR: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.
Abstract: PURPOSEDiffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation.PATIENTS AND METHODSForty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants.RESULTSHyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplanta...
351 citations
TL;DR: Allogeneic PBPC transplantation is a feasible procedure for patients with poor-risk metastatic breast cancer and the regression of tumor associated with GVHD provides suggestive clinical evidence that graft-versus-tumor effects may occur against breast cancer.
Abstract: PURPOSETo evaluate the feasibility of allogeneic peripheral-blood progenitor-cell (PBPC) transplantation and to assess graft-versus-tumor effects in patients with metastatic breast cancer.PATIENTS AND METHODSTen patients with metastatic breast cancer that involved the liver or bone marrow were treated with high-dose chemotherapy and allogeneic PBPC transplantation. The median age was 42 years (range, 29 to 55). The median number of metastatic sites was three (range, one to five). The conditioning regimen was cyclophosphamide (6,000 mg/m2), carmustine (BCNU; 450 mg/m2), and thiotepa (720 mg/m2) (CBT regimen). Patients received graft-versus-host disease (GVHD) prophylaxis using cyclosporine- or tacrolimus-based regimens.RESULTSAll patients had engraftment and hematologic recovery. Three patients developed grade > or = 2 acute GVHD and four patients had chronic GVHD. After transplantation, one patient was in complete remission (CR), five achieved a partial remission (PR), and four had stable disease (SD). In...
263 citations
TL;DR: It is concluded that development of antiviral resistance in immunocompromised individuals should be considered when they have been treated with antivirals and have shed influenza virus for a prolonged period and isolates from five of six patients were resistant.
Abstract: The importance and significance of amantadine- or rimantadine-resistant influenza viruses in immunocompromised patients was studied in a population of adult bone marrow transplant (BMT) recipients and patients with leukemia prospectively cultured for respiratory viruses. Influenza A viruses were isolated from 29 patients with acute respiratory illness (14 BMT recipients and 15 patients with leukemia). Fifteen patients (52%) received amantadine (n = 4) or rimantadine (n = 11) therapy. All influenza isolates recovered from six patients shedding virus for > or = 3 days were screened for antiviral susceptibility; resistant isolates were further genetically characterized. Initial influenza isolates were susceptible to amantadine or rimantadine, but subsequent isolates from five of six patients were resistant. Influenza-associated mortality was similar among patients with and without documented antiviral resistance (2 of 5 vs. 5 of 24). We conclude that development of antiviral resistance in immunocompromised individuals should be considered when they have been treated with antivirals and have shed influenza virus for a prolonged period. Isolation procedures should be instituted for all immunocompromised patients with influenza, both during and after therapy with amantadine or rimantadine.
155 citations
TL;DR: The cause of the short survival of patients with monosomy or deletion of chromosome 13 was not clear, but further studies on the relationship with specific oncogenes are indicated.
Abstract: Karyotypic studies of bone marrow were conducted in 79 previously untreated patients with multiple myeloma who received a standard programme of chemotherapy. An abnormal karyotype was observed in 46% of patients, virtually all showing multiple abnormalities consistent with a long period of preclinical clonal evolution. Patients with an abnormal pattern showed various aberrations with hyperdiploidy in 64%, pseudodiploidy in 5% and hypodiploidy in 31%. The number of chromosomes affected ranged from two to 19 (median 10), with at least one trisomy in 83%, one monosomy in 75%, and one translocation in 42% of patients. Lymphoma-like karyotypes were present in 17% of patients with an abnormality but were not associated with atypical clinical features, such as an extramedullary mass, leukaemia, or increased serum lactate dehydrogenase. Monosomy or deletion of chromosome 13 was present in 47% of patients with an abnormal pattern, who lived for a shorter duration (median 10 months) than patients with other abnormalities (median 34 months) or with diploidy (median 35 months). The cause of the short survival of patients with monosomy or deletion of chromosome 13 was not clear, but further studies on the relationship with specific oncogenes are indicated.
138 citations
TL;DR: It was suggested that doses >5 x 10(6) CD34+ cells/kg were associated with more rapid engraftment and a lower probability of graft failure, and the risk of delayed recovery was inversely related toCD34+ cell dose.
135 citations
TL;DR: Clinical variables influencing platelet recovery should be considered in the design and interpretation of clinical strategies to accelerate recovery and could significantly decrease health care costs and potentially improve patient quality of life.
130 citations
TL;DR: IGF2 represents a novel type of genetic alteration in CML that appears to be specifically associated with disease progression, and LOI was found in all six cases of advanced disease.
82 citations
TL;DR: The results indicate that patients with PML may display an increased susceptibility to high-dose chemotherapy compared with other types of B-cell large-cell lymphoma, and this findings, if confirmed, may have implications for the initial management of patients withPML.
Abstract: PURPOSEThis study was performed to evaluate the outcome of high-dose chemotherapy and autologous transplantation in patients with diffuse B-cell large-cell lymphoma, and, specifically, to evaluate the impact of primary mediastinal localization on the outcome of high-dose chemotherapy.PATIENTS AND METHODSA retrospective review was performed of all patients with diffuse large B-cell lymphoma who underwent autologous marrow or peripheral-blood stem-cell transplantation at our institution between January 1 986 and December 1995.RESULTSNinety patients were identified, of whom 31 (34%) had a primary mediastinal B-cell large-cell lymphoma (PML). Cumulative probabilities of disease-free survival, overall survival, and disease progression are 40% (95% confidence interval [CI], 29 to 51), 42% (95% CI, 31 to 53), and 52% (95% CI, 40 to 64), respectively. By univariate analysis, low lactate dehydrogenase (LDH) level and low Ann Arbor stage at transplant were associated with improved survival and disease-free survival...
62 citations
Journal Article•
TL;DR: The data indicate that the alpha4beta1 integrin receptor (VLA-4) plays a central role in the apoptosis rescue function that results from the anchorage-dependent growth of the CD34-selected early hematopoietic cells on stromal cells.
Abstract: Monoclonal antibodies to very late antigen 4 (VLA-4) recognize the alpha4beta1 integrin receptor. This monoclonal antibody blocks the adhesion between early hematopoietic progenitor cells (CD34-selected cells) and stromal cells when added to cultures of these cells. Addition of the VLA-4 monoclonal antibody to cultures of stromal cells and CD34-selected cells was shown to induce apoptosis of CD34-selected cells in these CD34-selected cell/stromal cell cocultures, as measured by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling method. In contrast to these experiments with early hematopoietic progenitor cells (CD34+), the level of adhesion between more differentiated cells (unfractionated hematopoietic cells) and stromal cells was not significantly altered by addition of the anti-VLA-4 monoclonal antibody. Similarly, the level of apoptosis of unfractionated hematopoietic cells was not significantly increased by the addition of anti-VLA-4 monoclonal antibody to cultures of the latter cells with stromal cells. The binding of the unfractionated cells is less than that of the CD34-selected cells. Given that there is no difference between the alpha4beta1 integrin expression level of the early and late myeloid cells, there may be a difference in the functional state of the integrin between the early and late myeloid cells. We also show that CD34+-selected precursor cells proliferate at a higher rate when these cells are plated on recombinant vascular cell adhesion molecule 1 molecules. These data indicate that the alpha4beta1 integrin receptor (VLA-4) plays a central role in the apoptosis rescue function that results from the anchorage-dependent growth of the CD34-selected early hematopoietic cells on stromal cells. The data suggest that these apoptosis rescue pathways have less significance as the cells mature and become anchorage independent in their growth. These data should assist in the design of systems for the ex vivo proliferation and transduction of early hematopoietic cells for genetic therapy.
57 citations
TL;DR: For patients with myeloproliferative disorders and evidence of accelerated disease, HLA‐identical marrow transplantation is well tolerated and can result in an extended disease‐free survival.
Abstract: The role of allogeneic marrow transplantation as treatment of myeloproliferative disorders other than chronic myelogenous leukemia is not yet determined. At our center, 1 patient with primary myelofibrosis, 1 with mastocytosis, and 4 with myeloid metaplasia have been transplanted using HLA-identical sibling donors. All patients engrafted with full donor chimerism, and morphologic and cytogenetic manifestations of disease in the marrow resolved posttransplant. Three patients died; two with relapse and one from infection. The other three patients are alive in remission at 24+, 28+, and 32+ months posttransplant. Including these cases, a total of 40 patients transplanted for myeloproliferative disorders have been reported. The most common indications for transplantation were cytopenias, increasing blasts in marrow or blood, uncontrolled counts on conventional therapy, poor prognosis cytogenetics, organ dysfunction, and consolidation after induction therapy for blast transformation. Using the outcome data published for these patients, the actuarial estimate of 3-year survival is 55% (95% C.I., 44-76%) with a median reported follow-up of survivors of 21 months (range, 4-158 months). For patients with myeloproliferative disorders and evidence of accelerated disease, HLA-identical marrow transplantation is well tolerated and can result in an extended disease-free survival.
53 citations
Journal Article•
TL;DR: Allogeneic transplantation of rhG-CSF-mobilized peripheral blood stem cells (PBSCs) is now being increasingly performed, but safety considerations for hematologically normal PBSC donors have not been fully addressed, and a consensus is gradually emerging on several issues.
Abstract: Allogeneic transplantation of rhG-CSF-mobilized peripheral blood stem cells (PBSCs) is now being increasingly performed, but safety considerations for hematologically normal PBSC donors have not been fully addressed. Experience in this area is rapidly accumulating, however, and on the basis of currently available data, a consensus is gradually emerging on several issues: (1) rhG-CSF treatment and PBSC collection seem to have an acceptable short-term safety profile in normal donors. There is a need for continued safety monitoring, however. (2) rhG-CSF doses up to 10 microg/kg/day show a consistent dose-response relationship with the mobilization (and collection) of CD34+ progenitor cells, and this dose is acceptable for routine clinical use. Whether higher doses are superior (or cost-effective) remains to be determined, and they may produce more severe side-effects. The potential risks of marked leukocytosis (arbitrarily defined as a leukocyte count of more than 70 x 10(9)/l) have been a concern, and rhG-CSF dose reduction is performed by many centers to maintain leukocyte counts below this level. (3) Transient post-donation cytopenias, involving granulocytes, lymphocytes and platelets, may occur and are at least partly related to the leukapheresis procedure. These are generally asymptomatic and self-limited; follow-up blood counts are not necessarily required. Reinfusion of autologous platelet-rich plasma should be considered for donors with expected post-donation thrombocytopenia (platelet count <80-100 x 10(9)/l). (4) Donors should meet the eligibility criteria which apply to donors of apheresis platelets, with the exception that pediatric (as well as elderly) donors may also be considered. There is insufficient information at this time to clearly establish definite contraindications for PBSC collection in a hematologically normal donor. Potential contraindications include the presence of inflammatory, autoimmune or rheumatologic disorders, as well as atherosclerotic or cerebrovascular disease. (5) The creation of an International PBSC Donor Registry is desirable to facilitate monitoring the long-term effects of the procedure. Individual institutions or donor centers are encouraged to establish their own PBSC donor follow-up system, preferably with a standardized approach to data collection.
TL;DR: Culture techniques similar to those used for CML are used to study the ability of AML cells to differentiate toward dendritic cells, and t-cell receptor studies provide evidence for an oligoclonal response implying a recognition of a limited number of antigens.
Abstract: The human myeloid leukemias are a diverse group of disorders characterized by massive clonal expansion of myeloid cells showing variable degrees of differentiation block. Leukemic dendritic cells were generated in culture from chronic myelogenous leukemia (CML). These were used to stimulate autologous T cells to develop leukemia-specific cytotoxicity. Available data suggest that the cells responsible for the cytolytic activity are at least in part CD8+ and HLA restricted in their function. Additional data suggest that some anti-CML cellular activity may be Fas mediated. T-cell receptor studies provide evidence for an oligoclonal response implying a recognition of a limited number of antigens. We have used culture techniques similar to those used for CML to study the ability of AML cells to differentiate toward dendritic cells. Four of five patients have shown acute leukemia-derived dendritic cells. This work offers an avenue for the development of novel strategies for the control of human myeloid leukemias.
TL;DR: The survey presents the main results obtained in the area of transplantation for chronic lymphocytic leukemia and critically discusses them in light of the current debate.
Abstract: Conventional therapies for chronic lymphocytic leukemia are not likely to provide a cure, prompting the use of more aggressive approaches. High-dose therapy with autologous and allogeneic bone marrow or blood stem cell transplantation appear to induce a prolonged period of disease-free survival in selected patients with this indolent disease. Significant questions were raised, however, in terms of survival benefit, the value of purging, the presence of graft-versus-leukemia effect, and the timing of transplantation. The survey presents the main results obtained in the area of transplantation for chronic lymphocytic leukemia and critically discusses them in light of the current debate.
TL;DR: It is concluded that filtered unscreened blood products as partial transfusion support for CMV-seronegative marrow transplant recipients were associated with a low incidence of CMV infection, justifying further evaluation of filteredBlood products as total transfusions support for this patient population.
Abstract: It has been suggested that leukoreduced unscreened blood products can be used as an alternative to components from cytomegalovirus (CMV)-seronegative donors in order to prevent transmission of CMV from transfusions for CMV-seronegative marrow transplant recipients with CMV-seronegative donors, but confirmatory data are lacking. A retrospective chart review was undertaken for patients undergoing allogeneic transplantation over a 4-year period during which blood products were filtered for CMV-seronegative patients with CMV-seronegative donors when CMV-seronegative components were not available. Forty-five CMV-seronegative patient-donor pairs were identified. Only one patient developed CMV disease (pneumonia) and no other patients developed an infection. In this group of patients, the rate of CMV infection was 2.7% (95% CI, 0-8%) by life-table analysis. We conclude that filtered unscreened blood products as partial transfusion support for CMV-seronegative marrow transplant recipients were associated with a low incidence of CMV infection, justifying further evaluation of filtered blood products as total transfusion support for this patient population. However, since CMV infections still occur, continued surveillance by periodic culture or other techniques is warranted.
TL;DR: To quantify subpopulations of CD34‐positive cells in peripheral blood stem cell (PBSC) collections of normal, colony‐stimulating factor‐granulocyte) (G‐CSF) primed donors that might represent megakaryocyte (MK) precursors, and to determine whether there is a statistical association between the dose transfused and the time course of the recovery.
Abstract: Platelet engraftment, the time course and magnitude of platelet recovery (PR) post-transplant, is imprecisely defined but is most often reported as the time to transfusion (tx) independence and/or a platelet count ⩾20,000/μl. While correlations between engraftment time for granulocytes (PMN) and the dose of CD34-positive cells per kilogram are established, such associations have not been established for platelet engraftment. The objective of this study was to quantify subpopulations of CD34-positive cells in peripheral blood stem cell (PBSC) collections of normal, colony-stimulating factor-granulocyte) (G-CSF) primed donors that might represent megakaryocyte (MK) precursors, and to determine whether there is a statistical association between the dose transfused and the time course of the recovery. Based on previously published data of the sequential expression of CD34, HLA-DR, and CD61, among others, during MK maturation, a combination of corresponding antibodies for the detection of various antigen coexpressions by flow cytometry fluorescence-activated cell sorting [FACS] was chosen. CD34-positive cells were further subdivided into CD34++ (bright) and + (dim). Ploidy of density-gradient separated cells was examined in subsequent donor samples by FACS.
For the entire group of patients, there was no strong correlation between any of the studied subpopulations and time to PR. Only in a selected groups of patients whose platelet counts showed a sustained increase during the first 6 days after engraftment, there was a weak correlation between the time to PR and the quantity of CD34+/+CD61+ (r = −0.57) and CD34++HLA-DR-CD61+ (r = −0.62) cells infused. The magnitude of platelet production in these pt., a product of the peripheral blood platelet count and the patient's blood volume, was correlated with the time to PR (r = −0.73).
We conclude from this study that subpopulations within CD34+ cells are making some contribution to PR in allogeneic peripheral blood stem cell transplantation, but the correlations are not sufficiently strong because there are probably too many unpredictable and unknown variables in the allogeneic setting that influence the pattern of engraftment. J. Clin. Apheresis 13:7–15, 1998. © 1998 Wiley-Liss, Inc.
TL;DR: Almost all patients with metastatic breast cancer succumb to their disease, and conventional cytotoxic chemotherapy is mainly used for palliation, but high doses of chemotherapy with hematopoietic progenitor cell support and growth factors have been extensively studied for treatment of breast cancer.
TL;DR: Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia, which can mandate a decrease in the dose intensity of cytotoxic therapy by causing either delays or dose reductions in therapy administration.
Abstract: Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia. This can be associated with significant bleeding; currently, it is treated with supportive platelet transfusions. Frequent platelet transfusions can cause alloimmunization which requires HLA-matched donors and more frequent blood transfusions, and transmission of both viral and bacterial infections via platelet transfusions remains a concern. Furthermore, thrombocytopenia can mandate a decrease in the dose intensity of cytotoxic therapy by causing either delays or dose reductions in therapy administration. An intervention that reduces the risk or shortens the duration of severe thrombocytopenia would represent an important medical advance. Thrombopoietin (TPO), a naturally occurring, glycosylated polypeptide that was cloned by Genentech in 1994, is capable of inducing differentiation of stem cells into megakaryocytes and accelerating the maturation of megakaryocytes, thereby increasing the platelet count. Recombinant human TPO (rHuTPO) is currently undergoing testing in phase 1 and 2 studies in patients receiving myelosuppressive or myeloablative therapy. For the purposes of illustration, preliminary safety and activity data from one ongoing phase 1 myelosuppression trial (rHuTPO in women with advanced gynecologic malignancies receiving carboplatin) and one ongoing phase 1 myeloablation trial (rHuTPO for peripheral blood progenitor cell mobilization prior to myeloablative chemotherapy for high risk breast cancer) will be presented.
Journal Article•
01 Jan 1998
TL;DR: Majority of studies have documented that autologous transplantation of peripheral blood progenitors results in rapid hematopoietic recovery leading to an almost preferential consideration of peripheralBlood progenitor cells over bone marrow as a source of hematopolietic cells for autOLOGous and allogeneic transplantation.
Abstract: Traditionally, hematopoietic support for high dose chemotherapy and radiation therapy has been harvested from bone marrow from either the posterior iliac crests, sternum or tibia (in small children). With the clinical use of hematopoietic colony-stimulating factors, substantial increases in hematopoietic progenitors and stem cells capable of reestablishing hematopoiesis after myeloablative therapy can be obtained in peripheral circulation. By apheresis, these cells can be collected and use as a source of hematopoietic cellular reconstitution after autologous or allogeneic transplantation. Numerous studies have documented that autologous transplantation of peripheral blood progenitors results in rapid hematopoietic recovery leading to an almost preferential consideration of peripheral blood progenitor cells over bone marrow as a source of hematopoietic cells for autologous and allogeneic transplantation.