Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation in a patient with chronic myelogenous leukemia.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
R Champlin
Publications and source records attributed to R Champlin.
Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients.
We reviewed the frequency and clinical course of parainfluenza virus (PIV) infections in 1,173 adult bone marrow transplant (BMT) recipients cared for at The University of Texas M.D. Anderson Cancer Center (Houston). Between January 1991 and September 1994, PIV was isolated from the respiratory secretions of 61 (5.2%) of these patients. Thirty-four (56%) of the 61 patients had uncomplicated upper respiratory tract illnesses and survived. The remaining 27 patients (44%) developed pneumonia, and the associated mortality was 37% (10 of 27 patients). Twenty-three (85%) of the patients with pneumonia had had preceding upper respiratory illnesses. Of the 10 patients who died, nine died within 100 days after transplantation. Histopathologic examination of lung tissue from seven patients revealed intracytoplasmic viral inclusions in six, a finding consistent with invasive PIV pneumonia, and viral changes in the seventh patient. Seven of the 10 patients who died had other serious concurrent infections. Of 42 patients who developed PIV infection early after transplantation (i.e., < 100 days), the frequency of pneumonia was higher among the 18 allogeneic BMT recipients (61%) than among the 24 autologous BMT recipients (42%), and the associated mortality was also higher (55% vs. 30%, respectively). PIVs are an important cause of life-threatening pneumonia in adult BMT recipients, particularly patients who have recently undergone allogeneic bone marrow transplantation.
Adult↗
Bone marrow transplantation from unrelated donors.
Unrelated donor bone marrow transplants provide the alternative to allogeneic transplants for patients lacking an HLA-matched related family member donor. Because the donor and recipient have greater immunogenetic disparity than related donor transplants, these transplants are associated with a higher rate of immunologic complications. This disparity has also translated into a lower risk of relapse relative to sibling donor transplants, enabling this treatment to offer a cure to advanced-disease patients.
Bone Marrow Transplantation↗
T cells, graft-versus-host disease and graft-versus-leukemia: innovative approaches for blood and marrow transplantation.
Allogeneic bone marrow transplantation is most commonly used as treatment for leukemia. Allotransplantation is associated with several interrelated immunologic processes, graft rejection, graft-versus-host disease (GvHD) and graft versus leukemia (GvL). Graft rejection can be overcome by intensive pretransplant immunosuppressive therapy. Following transplantation, immunoreconstitution must occur from donor-derived progenitors and GvHD may occur from reactivity of donor-derived immunocompetent cells against host tissues. In a related, but distinct process, donor immunocompetent cells may react against the recipient leukemia and recent data confirm that this GvL effect plays a critical role in preventing posttransplant relapse. This report summarizes present data regarding the mechanism of these processes. A major challenge is to separate the beneficial GvL effect from GvHD, the major complication of allogeneic marrow transplantation. We summarize data regarding innovative approaches to modify the composition of the transplanted marrow to optimize clinical outcome as well as use of donor lymphocyte infusions as a means to induce posttransplant GvL.
Bone Marrow Transplantation↗
Impact of preexisting CNS involvement on the outcome of bone marrow transplantation in adult hematologic malignancies.
PURPOSE: To determine the impact of prior or current CNS disease on the outcome of high-dose chemotherapy for patients with hematologic malignancies. PATIENTS AND METHODS: In a 54-month period, 373 patients with hematologic malignancies underwent allogeneic or autologous bone marrow transplantation (BMT) or blood stem-cell transplantation using high-dose thiotepa, busulfan, and cyclophosphamide (TBC) as the preparative regimen. Four patients with active CNS disease at BMT and 20 patients with a history of prior CNS disease were identified. The outcomes of those with a history of CNS disease were compared with those of a matched control group. RESULTS: Of four patients with active CNS disease at the time of BMT, two had CNS recurrences and one recurred in the bone marrow. One patient died of treatment-related toxicity. Four of 20 patients with prior CNS involvement currently remain free of disease. At 2 years, the disease-free survival (DFS) rate was 23% +/- 19%, and the DFS rate for the control group 39% +/- 24% (P = .053). An increased rate of treatment-related toxicity and especially grades II to IV CNS toxicity accounted for the poorer outcome of patients who had a history of CNS disease. Recurrence rates were not significantly different between the two groups. Prior radiation to the CNS correlated with CNS complications posttransplant (p = .01). CONCLUSION: Consolidation with TBC and BMT can induce prolonged DFS in a proportion of patients with a history of CNS disease. Such patients are at increased risk for CNS complications that lead to an inferior overall outcome when compared with a control group.
Adolescent↗
Integration of biological, procedural, apheresis principles of peripheral blood stem cell transplantation programs.
Collection and use of peripheral blood stem cells have rapidly replaced harvesting of pelvic bone marrow for transplant protocols. The mobilization of progenitor populations into the peripheral blood by chemotherapy and/or cytokine stimulation of marrow hematopoietic production has made it possible, in general, to collect larger quantities of progenitor populations than obtained in a single harvest of marrow. Technological advances through flow cytometry and generation of monoclonal antibodies to identify CD34 antigen expression on cells has provided a rapid means of assessing leukapheresis products for the presence of progenitor populations and has largely replaced the laborious 14 day culture assays' to measure colony forming units. Unlike apheresis platelet collection, where the yields are predictable through integration of donor biological variability, total volume of blood processed, and machine efficiency, CD34+ cell yields are not predictable. This has led to great diversity in stem cell collection procedures. Analyses of the same variables used to predict platelet yields, if applied to CD34+ cell collection, might lead to useful algorithms for development of standardized guidelines for stem cell collection.
Antigens, CD34↗
Purging: elimination of malignant cells from autologous blood or marrow transplants.
Explore the source record for details and available documents.
Antibodies, Monoclonal↗
Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia.
We report the case of a patient with chronic lymphocytic leukemia (CLL) with persistent lymphocytosis and lymphadenopathy after allogeneic bone marrow transplantation (BMT). After receiving a donor lymphocyte infusion on day 87 he achieved complete remission upon development of chronic graft-versus-host disease, suggesting that a graft-versus-leukemia effect is operative in this malignancy.
Adult↗
Allogeneic peripheral blood stem cell transplantation using normal patient-related pediatric donors.
Successful allogeneic peripheral blood progenitor cell (PBPC) transplantation has recently been reported by several transplant centers. This is a first report describing allogeneic PBPC transplantation in five patients using related pediatric donors between the ages of 4 and 13 years. Donors underwent 3 or 4 days of rhG-CSF treatment (6 micrograms/kg q 12 h) for stem cell peripheralization prior to PBPC collection, which was performed by continuous-flow apheresis on day 4 or 5. Venous access was exclusively by ante-cubital veins. A median of 2.2 times (range 1.4-3.6) the donor's total blood volume (TBV) was processed per procedure. In cases where the donor's TBV was < 2 liters, the blood cell separator was primed with human serum albumin (HSA-5%), and anticoagulation was performed using a combination of heparin (pre-apheresis bolus + continuous infusion (CI)) and/or ACD-A (CI at a reduced rate). The median number of CD34+ cells collected per kg of donor body weight (b.w.) and per liter of donor blood processed during each procedure was 128 x 10(4) (range 58 x 10(4)-314 x 10(4)). Between one and two aphereses were sufficient to collect a safe CD34+ cell engraftment dose of 3 or 4 x 10(6)/kg of recipient b.w. Two PBPC recipients were parents, and three were siblings. After freezing and thawing, the median number of CD34+ cells per kg of recipient b.w. thawed and transfused was 8.5 x 10(6) (range 3.2 x 10(6)-9.7 x 10(6)). The time to PMN > 1000/microliters was between 10 and 16 days (four out of five evaluable patients), and platelets > 20000/microliters were reached between day 13 and 14 post-transplantation (three out of five evaluable patients). Two out of three evaluable patients developed grades one and three acute GVHD, and one out of three developed chronic GVHD. Two patients died of sepsis and VOD at day 10 and 19, respectively. Two adult patients are alive and in cytogenetic and molecular remission of CML at +339 and +227 days post-allotransplantation. One 3-year-old girl with hemophagocytic lymphohistiocytosis is in remission at +304 days post-transplantation. Using pediatric donors for allogeneic PBPC transplantation appears to be safe, yields a sufficient amount of progenitors for prompt engraftment, and results in clinical outcome similar to adult PBPC allotransplantation.
Adult↗
GM-CSF accelerates neutrophil recovery after autologous hematopoietic stem cell transplantation.
Patients with non-myeloid hematologic malignancies (including Hodgkin's and non-Hodgkin's lymphomas, myeloma and acute lymphoid leukemia) or solid tumors underwent cytoreductive conditioning regimens followed by either autologous bone marrow transplantation (ABMT) (n = 343) or transplantation of peripheral blood stem cells (PBSC) with (n = 44) or without bone marrow (BM) (n = 16). In a randomized double-blind phase III multi-center trial, patients received either granulocyte-macrophage colony-stimulating factor (GM-CSF, 10 micrograms/kg/day) or placebo by daily i.v. infusion beginning 24 h after bone marrow infusion and continuing until the absolute neutrophil count (ANC) had recovered to > or = 1000/mm3, or for a maximum of 30 days. Median time to neutrophil recovery was significantly shorter in the GM-CSF group (18 vs 27 days, P < 0.001), and more GM-CSF patients had neutrophil recovery by day 30 (70 vs 48%). Median duration of hospitalization was significantly shorter in the GM-CSF group (29 vs 32 days, P = 0.02). GM-CSF significantly reduced the median time to neutrophil recovery in patients receiving bone marrow only (19 vs 27 days, P < 0.001) or PBSC with or without bone marrow (14 vs 21 days, P < 0.001). The overall incidence of adverse events was comparable in the two groups, although more patients in the GM-CSF group discontinued treatment due to adverse events (17 vs 9%, P < 0.001). No difference was noted in infection incidence or time to platelet independence. GM-CSF had no negative impact on time to relapse or long-term survival. These data indicate the positive influence of GM-CSF on neutrophil recovery and hospital stay in patients receiving ABMT for a variety of clinical indications.
Adolescent↗
Delayed effects of rhG-CSF mobilization treatment and apheresis on circulating CD34+ and CD34+ Thy-1dim CD38- progenitor cells, and lymphoid subsets in normal stem cell donors for allogeneic transplantation.
Allogeneic transplantation of peripheral blood progenitor cells (PBPC) is emerging as a new stem cell transplant modality. Rather than undergoing general anesthesia for bone marrow harvest, normal blood stem cell donors are subjected to rhG-CSF mobilization treatment followed by single or multiple apheresis. Whereas the effects of cytokine treatment and apheresis on stem cell peripheralization and collection have been described, little is known about delayed effects of rhG-CSF treatment and apheresis on a normal hematopoietic system, and there are no long-term data that address safety issues. Ten normal, patient-related donors underwent a 3 or 4 day rhG-CSF (filgrastim) treatment (12 micrograms/kg/day) followed by single or tandem apheresis. We monitored peripheral blood (PB) cellularity including CD34+ and lymphoid subsets at baseline, during cytokine treatment, prior to apheresis, and at days 2, 4, 7, 30 and 100 post-apheresis. The PB progenitor cell concentration peak prior to apheresis was followed by a nadir by day 7 and normalized by day 30, with the exception of the most primitive CD34+ Thy-1dim CD38- progenitor subset that reached a nadir by day 30. Lymphoid subsets such as CD3, 4, 8, suppressor cells (CD3+ 4- 8- TCR+ alpha beta), and B cells (CD19+) showed a similar pattern with a nadir concentration by day 7, followed, except for B cells, by a rebound by day 30 and subnormal counts at day 100. The PB concentrations of hemoglobin and platelets dropped mainly due to the apheresis procedure itself, and normalized by day 30. With cytokine treatment, the PB alkaline phosphatase and lactate dehydrogenase concentrations increased 2.2- and 2.8-fold, respectively, over baseline, and returned to normal range by day 30. Based on the preliminary nature of this study, the clinical relevance of these findings is still unclear.
ADP-ribosyl Cyclase↗
CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation.
Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft-versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus-leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.
Acute Disease↗
Myeloablative therapy for primary resistant multiple myeloma.
Myeloablative therapy supported by autologous bone marrow or blood stem cell transplantation was assessed in 41 patients who had multiple myeloma resistant to vincristine-doxorubicin by continuous infusion with high-dose dexamethasone (VAD) or other high-dose dexamethasone regimens. In patients who had high or intermediate tumor mass, the myeloma cell mass was reduced by more than 75% in 56% of patients and the survival time quadrupled in comparison with that of a matched control group. Later treatment resulted in a lower response rate and shorter remission. Current myeloablative regimens supported by autologous stem cells provided a useful treatment for patients who had advanced primary resistant multiple myeloma. Such treatment should be given early in the disease course to provide the best chance for remission, collecting blood stem cells with facility, and preventing complications that would increase the risk of the procedure.
Adult↗
Recent advances in the application of gene therapy to human disease.
PURPOSE: To review the recent advances in the application of genetic modification strategies to the therapy of human diseases for which a molecular defect is known. METHODS: A computerized data bank search, the minutes of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee published in the Federal Record, and reports of human clinical trials were used as data sources for this review. Clinical trials included in this review were published in the literature or approved by the NIH Recombinant DNA Advisory Committee. STUDY SELECTION: Evaluations of the efficacy of genetic modification strategies in clinical trials in human and in animal models are summarized. The design and outcome of the genetic modification strategies employed are reviewed for 16 marking trials, 16 gene replacement trials for molecular deficiency diseases, 3 chemoprotection and 4 chemotherapy sensitization trials, 11 cancer vaccine trials, 2 antisense oligonucleotide trials, and 3 molecular immunotherapy trials. DATA SYNTHESIS: The marking trials have shown that residual leukemia cells in the infused autologous marrow can contribute to relapse following autologous bone marrow transplants. The use of genetic modification for the replacement of missing or deficient genes in severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis has been associated with encouraging results so far. Clinical genetic therapy trials involving cancer vaccines, antisense oligonucleotides, adoptive immunotherapy with genetically modified T cells, delivery vectors containing interleukin-1 receptor inhibitor for arthritis, replacement strategies for storage diseases, and genetic suppression of human immunodeficiency viral replication are just commencing. CONCLUSIONS: The clinical application of genetic modification techniques has thus far been successful in the beginning phases of this field. These early results suggest that continuation of gene therapy trials designed to correct the molecular changes that lead to disease states in humans is warranted. Evaluation of such clinical trials in the future may be based on the analysis of assays for short-term surrogate endpoints, as well as on the therapeutic outcomes of the trial, such as survival or remission.
Bone Marrow Transplantation↗
Optimizing the composition of bone marrow for allogenic transplantation.
Graft versus host disease, graft failure, and disease relapse remain significant impediments to successful allogeneic transplantation. Ex vivo engineering of the graft offers the opportunity to modify the cellular composition to overcome these problems. This review describes recent developments that employ this approach.
Blood Cells↗
Separation of graft-vs.-host disease and graft-vs.-leukemia effect against chronic myelogenous leukemia.
Explore the source record for details and available documents.
Bone Marrow Transplantation↗
Treatment of leukemia relapse after bone marrow transplantation with interferon-alpha and interleukin 2.
A 16-year-old girl with refractory AML received unmanipulated BMT from an unrelated donor. Leukemia relapse occurred 82 days later. The patient was then treated with IL-2 1.8 x 10(6) U/m2 for 5 days per week and 2.5 MU/m2 IFN-alpha three times per week. Toxicities included fever, skin rash, somnolence and a generalized seizure. Treatment was stopped after 2 weeks. Acute GVHD developed at the end of therapy and the patient's leukemia went into remission. She died of fungal pneumonia 30 days later. We conclude that a combination of cytokines may be useful in treating relapsed leukemia after BMT.
Adolescent↗
High-dose melphalan allows durable engraftment of allogeneic bone marrow.
Conditioning regimens for allogeneic bone marrow transplantation are designed to eradicate malignant cells and to provide sufficient immunosuppression for engraftment of donor marrow. Total body irradiation and high-dose cyclophosphamide are the most established immunosuppressive agents used for this purpose. It is uncertain whether other alkylating agent-based conditioning regimens are sufficiently immunosuppressive to allow engraftment of allogeneic marrow. We report four patients who had prompt engraftment after conditioning with melphalan-based chemotherapy regimens (BEAM or busulfan/melphalan). Two patients survived without disease for a prolonged period, indicating that these melphalan regimens are sufficiently immunosuppressive to allow sustained engraftment and donor hematopoiesis.
Adult↗