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Biomedical subjects

P I Warkentin

Publications and source records attributed to P I Warkentin.

At least 19 recordsLinked to original sources
PubMed2003

Voluntary accreditation of cellular therapies: Foundation for the Accreditation of Cellular Therapy (FACT).

Voluntary accreditation of cells, tissues, and cellular and tissue-based products intended for human transplantation is an important mechanism for improving quality in cellular therapy. The Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented programs of voluntary inspection and accreditation for hematopoietic cellular therapy, and for cord blood banking. These programs are based on the standards of the clinical and laboratory professionals of the American Society of Blood and Marrow Transplantation (ASBMT), the International Society for Cellular Therapy (ISCT), and NETCORD. FACT has collaborated with European colleagues in the development of the Joint Accreditation Committee in Europe (jACIE). FACT has published standards documents, a guidance manual, accreditation checklists, and inspection documents; and has trained as inspectors over 300 professionals active in the field. All inspectors have a minimum of 5 years' experience in the area they inspect. Since the incorporation of FACT in 1996, 215 hematopoietic progenitor cell facilities have applied for FACT accreditation. Of these facilities, 113 are fully accredited; the others are in the process of document submission or inspection. Significant opportunities and challenges exist for FACT in the future, including keeping standards and guidance materials current and relevant, recruiting and retaining expert inspectors, and establishing collaborations to develop standards and accreditation systems for new cellular products. The continuing dialogue with the Food and Drug Administration (FDA) is also important to ensure that they are aware of the accomplishments of voluntary accreditation, and keep FACT membership alerted to FDA intentions for the future. Other potential avenues of communication and cooperation with FDA and other regulatory agencies are being investigated and evaluated.

Accreditation↗
PubMed2001

Full hematopoietic engraftment after allogeneic bone marrow transplantation without cytoreduction in a child with severe combined immunodeficiency.

Bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) with human leukocyte antigen (HLA)-identical sibling donors but no pretransplantation cytoreduction results in T-lymphocyte engraftment and correction of immune dysfunction but not in full hematopoietic engraftment. A case of a 17-month-old girl with adenosine deaminase (ADA) deficiency SCID in whom full hematopoietic engraftment developed after BMT from her HLA-identical sister is reported. No myeloablative or immunosuppressive therapy or graft-versus-host disease (GVHD) prophylaxis was given. Mild acute and chronic GVHD developed, her B- and T-cell functions became reconstituted, and she is well almost 11 years after BMT. After BMT, repeated studies demonstrated: (1) Loss of a recipient-specific chromosomal marker in peripheral blood leukocytes (PBLs) and bone marrow, (2) conversion of recipient red blood cell antigens to donor type, (3) conversion of recipient T-cell, B-cell, and granulocyte lineages to donor origin by DNA analysis, and (4) increased ADA activity and metabolic correction in red blood cells and PBLs.

Adenosine Deaminase↗
PubMed2000

FAHCT accreditation: common deficiencies during on-site inspections.

BACKGROUND: The Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) was established in 1996 to develop and implement the inspection and accreditation program of the parent organizations, the International Society for Hematotherapy and Graft Engineering (ISHAGE) and the American Society of Blood and Marrow Transplant (ASBMT). Training of inspectors began in September 1996 and the first on-site inspections were conducted in September 1997. METHODS: The process of attaining FAHCT Accreditation includes the assessment of written application materials against uniform accreditation criteria and an on-site inspection of each of the sites in the applicant hematopoietic progenitor cell (HPC) transplantation program. Observations at each inspection are recorded by the inspector on a checklist, reviewed by the FAHCT Accreditation Chairman and/or Technical staff, and presented to the FAHCT Board of Directors for review. Each observation is determined to be in compliance with Standards, a deficiency, or a variance. The deficiencies observed in these inspections were tallied following Board review and entered into an electronic database. Those deficiencies occurring in > 25% of the transplant programs reviewed are described below. RESULTS: Significant deficiencies in the clinical programs included inadequate data management; incomplete or inadequate Quality Management Plan; and incomplete or absent standard operating policies and procedures. In the collection facilities, the most common significant deficiencies were incomplete or absent standard operating procedures; inadequate management of the results of donor evaluation findings and test results; lack of documentation of adverse reactions to collection; and deficiencies in the label applied to the HPC at the end of collection. Deficiencies in HPC laboratory services included validation procedures and/or records missing; ABO/Rh testing of the HPC component and/or the comparison of the results with prior test results not done or documented; labels in use did not meet Standards; incomplete quality control documentation; HPC infusion documents not available, or in use; HPC storage policies and procedures incomplete; adverse reactions to HPC infusion not documented, or tracked; and engraftment not tracked by the laboratory. DISCUSSION: Although all programs had a few to many deficiencies noted initially at the on-site inspection, 23 have successfully completed full accreditation. A few specific standards give problems to many programs. Participants, in general, believe the changes made in preparation for FAHCT accreditation have improved their HPC transplantation programs.

Accreditation↗
PubMed1999

Comparison of monocyte-dependent T cell inhibitory activity in GM-CSF vs G-CSF mobilized PSC products.

This study compares the immune properties of peripheral blood stem cell (PSC) products mobilized with different hematopoietic growth factors (HGFs) as well as apheresis products and peripheral blood leukocytes (PBL) from normal individuals. We found that monocytes in mobilized PSC products appear to inhibit T cell function independent of whether granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for mobilization. In addition, the GF used to mobilize the stem cell product may be less important to the CD4:CD8 ratio than the extent of prior chemotherapy, as we found an inverse correlation between chemotherapy and the CD4:CD8 ratio. In other observations, all apheresis products, whether mobilized or unmobilized, contained significantly more monocytes compared to normal PBL. The mononuclear cells (MNC) from G-CSF or GM-CSF mobilized PSC products had a similar T cell phytohemagglutinin (PHA) mitogenic response that was significantly lower (P = 0.001 and P = 0.005, respectively) than non-mobilized apheresis products. We also examined the T cell inhibitor (TI) activity of the MNC from the PSC products for allogeneic lymphocyte proliferation and found that PSC products significantly reduced the proliferation of allogeneic PBL to PHA. A significant correlation (P = 0.001, r = 0.517) between the frequency of monocytes and TI activity also was observed.

Adult↗
PubMed1998

Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies.

Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) >500/microl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8+ ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8+ cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.

Adult↗
PubMed1997

Allogeneic bone marrow transplantation for children with acute leukemia: long-term follow-up of patients prepared with high-dose cytosine arabinoside and fractionated total body irradiation.

High-dose therapy and allogeneic matched sibling bone marrow transplantation (BMT) is considered to be the treatment of choice for children with relapsed acute lymphoblastic leukemia (ALL), or for children with acute myeloid leukemia (AML) in first remission. However, the rate of bone marrow relapse after transplant for either of these diseases remains high. In this study, we assessed the efficacy and toxicity of high-dose cytosine arabinoside and total body irradiation (TBI) followed by allogeneic BMT, for children with acute leukemia or myelodysplastic syndrome (MDS). Sixty-five pediatric patients underwent allogeneic related (n = 57) or unrelated (n = 8) BMT. Twenty-seven were transplanted for ALL in second remission (CR2), and 16 for AML in first remission (CR1). The other 22 were high risk patients: six were transplanted for ALL in third remission (CR3), two for AML in CR2, two for myelodysplastic syndrome (MDS) and 12 for acute leukemia in relapse. Patients were prepared with cytosine arabinoside 3000 mg/m2 per dose twice daily for 6 days followed by 12000 cGy TBI as 200 cGy fractions twice daily for 3 days. Minimum follow-up is 21 months. Five-year event-free survival (EFS) and the actuarial relapse rate is 59 and 14% for patients with ALL in second remission, and 38 and 14+% for patients with AML in first remission. Twelve patients have relapsed (three are alive in remission after testicular or marrow relapse) and 28 have died of other causes. Acute GVHD with or without infection was the cause of death in 11 patients. Ten of the 11 patients who died of acute GVHD were considered at 'high risk' for GVHD (inadequate GVHD prophylaxis, or mismatched family donor or a matched unrelated donor). Toxicities in the immediate post-BMT period included diarrhea, oropharyngeal mucositis and conjunctivitis. Significant late toxicities included short stature, avascular necrosis of bone, and poor school performance (most often in patients who had received prior cranial irradiation). Our conclusions are that high-dose Ara-C and TBI followed by allogeneic bone marrow transplantation is effective therapy for children in second complete remission of their acute leukemia. However, significant late toxicities occur, and it is clear that more effective, less toxic therapies are necessary for these patients.

Acute Disease↗
PubMed1997

Ex vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome.

Effective ex vivo purging techniques can decrease the likelihood of infusing bone marrow contaminated with leukemic cells during autologous transplantation. In preliminary studies, OL(1)p53, a 20-mer phosphorothioate oligonucleotide directed against p53 mRNA, decreased the number of acute myelogenous leukemia (AML) cells in vitro, suggesting a possible role for OL(1)p53 in purging bone marrow harvests of leukemia cells. To demonstrate that OL(1)p53 was nontoxic to hematopoietic progenitor cells, normal bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h, and hematopoietic progenitor cell survival was determined by in vitro colony assays. OL(1)p53 had no toxic effect on the growth of either myeloid (CFU-GM) or erythroid (BFU-E) progenitor cells. OL(1)p53 was then used to ex vivo purge bone marrow harvests from nine patients with either AML or myelodysplastic syndrome (MDS). Bone marrow cells were incubated with 10 microM OL(1)p53 for 36 h before transplantation. The median times posttransplantation for the patient to recover an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet transfusion independence were 30 days and 56 days, respectively. Incubation of bone marrow cells with OL(1)p53 had no detrimental effect on the growth of hematopoietic progenitor cells, and transplantation of autologous bone marrow cells treated with the phosphorothioate oligonucleotide, OL(1)p53, resulted in successful recovery of circulating neutrophils following high-dose therapy in patients with AML or MDS. The data show that OL(1)p53 can be used safely to purge autologous bone marrow harvests from patients with leukemia.

Adult↗
PubMed1997

Allogeneic-blood stem-cell collection following mobilization with low-dose granulocyte colony-stimulating factor.

PURPOSE: The optimal dose of granulocyte colony-stimulating factor (G-CSF) for mobilization of allogeneic-blood stem cells (AlloBSC) has yet to be determined. As part of a prospective trial, 41 related human leukocyte antigen (HLA)-matched donors had blood cells mobilized with G-CSF at 5 micrograms/kg/d by subcutaneous administration. The purpose of this trial was to monitor adverse effects during G-CSF administration and stem-cell collection, to determine the optimal timing for stem-cell collection, and to determine the cellular composition of stem-cell products following G-CSF administration. PATIENTS AND METHODS: The median donor age was 42 years. Apheresis began on day 4 of G-CSF administration. At least three daily 12-L apheresis collections were performed on each donor. A minimum of 1.0 x 10(6) CD34+ cells/kg (recipient weight) and 8.0 x 10(8) mononuclear cells/kg were collected from each donor. All collections were cryopreserved in 5% dimethyl sulfoxide and 6% hydroxyethyl starch. RESULTS: Toxicities associated with G-CSF administration and the apheresis process included myalgias/arthralgias (83%), headache (44%), fever (27%), and chills (22%). The median baseline platelet count of 242 x 10(4)/ mL decreased to 221, 155, and 119 x 10(6)/mL on days 4, 5, and 6 of G-CSF administration, respectively. Median numbers of CD34+ cells in collections 1, 2, and 3 were 1.99, 2.52, and 3.13 x 10(6)/kg, respectively. The percentage and total number of CD4+, CD8+, and CD56+/CD3- cells remained relatively constant during the three collections. Median total numbers of cells were as follows: CD34+, 7.73 x 10(6)/kg; and lymphocytes, 6.93 x 10(8)/kg. CONCLUSION: Relatively low doses of G-CSF can mobilize sufficient numbers of AlloBSC safely and efficiently.

Adult↗
PubMed1996

Phase I trial of recombinant fusion protein PIXY321 for mobilization of peripheral-blood cells.

PURPOSE: Mobilization of peripheral-blood cells (PBC) with cytokines alone results in rapid hematopoietic recovery and avoids the potential morbidity associated with mobilization by chemotherapy. PIXY321, a fusion protein that consists of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), has enhanced hematopoietic colony-forming activity as compared with individual or equimolar combinations of the two cytokines. A phase I trial of PIXY321 for mobilization of PBC in patients with malignant lymphoma was performed. PATIENTS AND METHODS: Thirteen patients with malignant lymphoma who were eligible for high-dose therapy (HDT) were enrolled onto the trial. All patients were ineligible for autologous bone marrow transplantation due to overt metastatic disease in the marrow or to severe marrow hypocellularity. PIXY321 was administered at three dose levels of 250, 500, and 750 micrograms/m2/d by continuous infusion until completion of PBC collections. Collections were initiated when the WBC count was greater than 10 x 10(9)/L or 4 days after the initiation of PIXY321, whichever came first. Collections were continued until a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg patient weight were obtained. RESULTS: PIXY321 was generally well tolerated. Side effects associated with PIXY321 administration did not exceed grade 2 and included fever (85%), chills/sweats (54%), myalgias (38%), fatigue (31%), nausea/vomiting (31%), headache (31%), edema (23%), and rhinorrhea (23%). The median numbers of colony-forming units-granulocyte/macrophage (CFU-GM) in the graft products for the three dose levels were 0.31, 2.94, and 2.88 x 10(4)/kg, respectively; the median numbers of burst-forming units-erythroid (BFU-e) were 0.20, 6.94, and 12.78 x 10(4)/kg, and the median numbers of CD34+ cells were 2.30, 0.74, and 0.39 x 10(6)/kg. Following transplantation, the median times to an absolute neutrophil count (ANC) > 0.5 x 10(9)/L were 12, 15, and 12 days, respectively, and the median times to platelet transfusion independence were 30, 19, and 15 days. CONCLUSION: PIXY321 can be safely administered and effectively mobilizes PBC in patients with bone marrow defects. PIXY321-mobilized PBC autotransplants result in rapid and sustained hematopoietic recovery.

Adult↗
PubMed1995

Comparison of subcutaneous and intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor for peripheral blood stem cell mobilization.

In an effort to determine whether subcutaneous or continuous intravenous infusion administration of rhGM-CSF results in better hematopoietic progenitor mobilization, the findings of two sequential clinical trials were reviewed. Patients who had received prior chemotherapy for leukemia, lymphoma, multiple myeloma, breast cancer, or other solid tumors and were candidates for high-dose therapy received rhGM-CSF, 250 micrograms/m2/day, either as a continuous intravenous infusion (trial 1) or subcutaneously (trial 2) for stem cell mobilization. At least five apheresis collection procedures were performed to collect a target number of 6.5 x 10(8) mononuclear cells (MNC)/kg. For the 37 patients in trial 1, the collections contained a median of 7.99 x 10(8) MNC/L (range 6.42-21.36) and a median of 5.27 x 10(4) CFU-GM/kg (range 0.28-19.35). In trial 1, 25 patients were autografted with their cells and recovered 0.5 x 10(9) granulocytes/L at a median of 12 days (range 6-16). For the 33 patients in trial 2, the autograft product contained a median of 7.63 x 10(8) MNC/kg (range 6.51-22.66) and 6.31 x 10(4) CFU-GM/kg (range 0.06-60.4). In trial 2, 25 patients were autografted. The median time to reach 0.5 x 10(9) granulocytes/L was 11 days (range 9-26). All patients received rhGM-CSF after peripheral stem cell transplant. No significant differences in the collected products or the time to hematopoietic recovery was found between the two trials (p > 0.05). The mobilization effects of subcutaneous rhGM-CSF in these pretreated patients were similar to those of intravenous rhGM-CSF.

Adult↗
PubMed1995

Erythropoietin for mobilization of circulating progenitor cells in patients with previously treated relapsed malignancies.

A trial to determine the usefulness of recombinant human erythropoietin (rhEpo) as a mobilizing cytokine for patients with previously treated relapsed malignancies was performed. An initial peripheral stem cell apheresis collection was conducted during steady-state hematopoiesis for each patient to provide baseline data. rhEpo, 200 U/kg/day, was administered subcutaneously until the last apheresis procedure was completed. Immediately after the fourth daily dose of Epo, apheresis procedures were resumed and continued beyond five collections, when necessary, to accrue a total of 6.5 x 10(8) mononuclear cells (MNCs)/kg. Eight female and four male patients (median age = 44 years) were evaluated. Five to 14 (median = 8) apheresis procedures were performed for each patient. Toxicity attributable to Epo administration was negligible. Mobilization effects, as determined by an increase in the number of colony-forming units granulocyte/macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E) in the apheresis products after Epo administration, were observed in all patients. Nine patients received high-dose chemotherapy and Epo-mobilized peripheral stem cell transplantation (PSCT). Beginning the day of the transplant, GM-CSF was administered until neutrophil recovery was satisfactory. The median time to recover 0.5 x 10(9)/L granulocytes was 16 days after PSCT. Epo appears to have mobilization properties. Further studies are needed to determine the clinical usefulness of Epo as a mobilizing cytokine. The addition of Epo to other mobilizing cytokines may provide increased effectiveness without adding toxicity.

Adult↗
PubMed1994

High-dose therapy and peripheral blood progenitor cell transplantation: effects of recombinant human granulocyte-macrophage colony-stimulating factor on the autograft.

Between June 1989 and June 1992, 144 patients participated in sequential clinical trials using peripheral blood progenitor cells (PBC) as their sole source of hematopoietic rescue following high-dose chemotherapy. All patients had received prior extensive combination chemotherapy and had marrow defects that precluded autologous bone marrow transplantation (ABMT). PBC were collected according to a single apheresis protocol. The initial 86 patients (group 1) had PBC collected without mobilization. Beginning in April 1991, PBC were mobilized solely with recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). Thirty-four patients (group 2) received rHuGM-CSF at a dose of 125 micrograms/m2/d by continuous intravenous infusion, and 24 patients (group 3) received rHuGM-CSF at a dose of 250 micrograms/m2/d by continuous intravenous infusion. Patients underwent at least six aphereses and had a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg collected. Cytokines were not routinely administered immediately after transplantation. A median of nine aphereses were required to collect PBC in group 1 and seven aphereses for groups 2 and 3 (P = .03). The time required to recover 0.5 x 10(9)/L granulocytes after transplant was significantly shorter (P = .0004) for the mobilized groups; the median time to recovery was 26 days for group 1, 23 days for group 2, and 18 days for group 3. Transplantation of PBC mobilized with rHuGM-CSF resulted in a shorter time to platelet (P = .04) and red blood cell (P = .01) transfusion independence. Mobilization with rHuGM-CSF alone resulted in efficient collection of PBC, that provided rapid and sustained restoration of hematopoietic function following high-dose chemotherapy. Mobilization of PBC with rHuGM-CSF alone is an effective method for patients who have received prior chemotherapy and have bone marrow abnormalities.

Adolescent↗