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Biomedical subjects

P McGlave

Publications and source records attributed to P McGlave.

At least 19 recordsLinked to original sources
PubMed2001

Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience.

The clinical importance of HLA class II gene disparity in unrelated stem cell transplantation is not entirely known. The impact was evaluated of matching donors and recipients for HLA-DR, HLA-DQ, and HLA-DP genes on clinical outcome after stem cell transplantation for chronic myeloid leukemia (CML) performed between 1988 and 1997. HLA-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1 alleles were identified in 831 transplant pairs using a combination of sequence-specific oligonucleotide probes, sequence-specific priming, and sequencing methods. Among the 831 pairs, 696 (84%) were HLA-A and -B serologically matched; of these, 565 (81%) were also matched for HLA-DRB1. HLA-DRB1 matching correlated with significantly improved survival (relative risk [RR], 1.29 [95% confidence interval (CI), 1.02-1.64; P =.04]) independently of HLA-DQA1 or HLA-DQB1 (RR, 1.01 [95% CI, 0.81-1.26; P =.94]) and HLA-DPA1 or HLA-DPB1 (RR, 1.11 [95% CI, 0.84-1.48; P =.46]). Single-locus HLA-DQ or HLA-DP disparity was not associated with significantly poorer survival. For patients who underwent transplantation in the first chronic phase (CP) from HLA-A, B matched donors, the presence of DRB1 allele mismatching was independently associated with increased incidence of grades III-IV acute graft-versus-host disease (GVHD). No significant associations of class II allele mismatching with risk for delayed engraftment or chronic GVHD disease were detected. This study clearly demonstrates the importance of precise matching of HLA-DRB1 alleles for successful transplantation. Furthermore, a good-risk population of patients whose transplantations were performed in the first CP of disease from HLA-A, B, DRB1 matched unrelated donors can be shown to have superior survival.

Alleles↗
PubMed2000

Hematopoietic stem-cell transplantation from an unrelated donor.

When an HLA-matched sibling is not available and nontransplant approaches have been ineffective, transplantation of hematopoietic stem cells from an unrelated donor can effect a cure in some patients with chronic myelogenous leukemia. Even when successful, however, transplantation is a rigorous and prolonged process whose complications include infection and graft-versus-host disease. Improvements in hematopoietic stem-cell transplantation as well as innovative nontransplant approaches may improve the outcome in these patients.

Adult↗
PubMed2000

A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease.

Glucocorticoids remain the standard approach to initial systemic management of acute graft-versus-host disease (aGVHD). For patients refractory to steroids, antithymocyte globulin (ATG) is frequently used as salvage therapy. We decided to test whether the combination of corticosteroids and equine ATG would improve the outcome of initial management of aGVHD, especially in high-risk patients such as recipients of unrelated donor (URD) transplants. One hundred patients with grade II to IV aGVHD having undergone a related or URD marrow transplant were enrolled in the study. Of the patients, 46 were randomly assigned to therapy with prednisone (60 mg/m2 per day x 7 days) and 50 received ATG/prednisone (15 mg/kg ATG bid plus 20 mg/m2 prednisone bid x 5 days, each followed by an 8-week prednisone taper). An intent-to-treat analysis of the overall response at day 42 revealed equivalent complete plus partial response rates of 76% in both the prednisone and ATG/prednisone therapy groups (P > .80). In univariate analysis, patient age, donor type, site of involvement, or aGVHD stage did not influence overall response to therapy (all P > .2). When treatment arms were studied separately, no single clinical feature predicted outcome in either group. Complications were more frequent in the ATG/prednisone arm; patients experienced more infections with cytomegalovirus (44% versus 22%; P = .02) and more frequent pneumonitis, both infectious and noninfectious (50% versus 24%; P < .01). Epstein-Barr virus lymphoproliferative disease was uncommon (4 cases) and comparable in both arms (P = .35). There was no significant difference in survival at day 100, 6 months, and 2 years between the 2 treatment arms. The more intensive immunosuppressive combination of ATG/prednisone failed to improve control of aGVHD and may have affected survival by causing more infectious complications. Combination therapy with ATG should thus be reserved as second-line therapy in the management of aGVHD.

Acute Disease↗
PubMed1999

B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome.

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic HSCT. Factors assessed were HLA-mismatching (> or = 1 antigen), T cell depletion (TCD), presence of acute GvHD (grades II-IV), donor type (related vs unrelated), age of recipient and donor, and underlying disease. Factors found to be statistically significant included patients transplanted for immune deficiency and CML, donor age > or = 18 years, TCD, and HLA-mismatching, with recipients of combined TCD and HLA-mismatched grafts having the highest incidence. Factors found to be statistically significant in a multiple regression analysis were TCD, donor age and immune deficiency, although 7/8 of the patients with immunodeficiencies and BLPD received a TCD graft from a haploidentical parent. The overall mortality was 92% (24/26). One patient had a spontaneous remission, but subsequently died >1 year later of chronic GVHD. Thirteen patients received therapy for BLPD. Three patients received lymphocyte infusions without response. The only patients with responses and longterm survival received alpha interferon (alphaIFN). Of seven patients treated with alphaIFN there were four responses (one partial and three complete). These data demonstrate that alphaIFN can be an effective agent against BLPD following HSCT, if a timely diagnosis is made.

Acyclovir↗
PubMed1998

Unrelated donor transplant therapy for chronic myelogenous leukemia.

Unrelated donor transplant therapy for chronic myelogenous leukemia is both feasible and effective. As discussed in this article, clinical outcome can be predicted based on several patient characteristics and transplant conditions. Highly selected subsets of patients experience outcomes not appreciably different from recipients of related donor transplants. In many cases, however, unrelated donor transplant is associated with significant peritransplant mortality and other complications. The impact of recent improvements in donor-recipient typing, marrow procurement, graft-versus-host disease prevention and treatment, medical support, and donor selection should soon become apparent.

Bone Marrow Transplantation↗
PubMed1998

Bone marrow transplantation for chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by an initial chronic phase of expanded clonal myelopoiesis followed by inevitable progression to accelerated phase and finally to fatal blast crisis. Although interferon therapy results in hematologic control of disease in most patients and major cytogenetic responses in 30% to 35%, resulting in better survival than with conventional therapy with hydroxyurea or busulfan, most patients have residual disease detectable by molecular methods. Allogeneic bone marrow transplantation may cure selected patients with CML and should be considered early in the course of disease. Newer approaches to therapy include autografting using mobilized peripheral blood stem cells. Selection and expansion of nonleukemic progenitors may improve outcome following autologous transplantation. Advances in understanding of mechanisms of action of antisense oligonucleotides, ribozymes, and tyrosine kinase inhibitors and the immunologic responses to CML cells are also likely to lead to novel approaches to therapy.

Bone Marrow Transplantation↗
PubMed1997

Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity.

Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lytic activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 x 10(6) (n = 6) or 0.5 x 10(6) (n = 6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 x 10(6) U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n = 2 at 0.25 x 10(6) U/m2/day, n = 4 at 0.5 x 10(6) U/m2/day) consisting of decreased performance status (n = 2), thrombocytopenia (n = 3, 1 at the lower dose), and mild neutropenia (n = 1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 x 10(6)/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.

Adjuvants, Immunologic↗
PubMed1997

Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs. G-CSF.

Autologous transplantation for non-Hodgkins lymphoma and Hodgkin's disease is widely used as standard therapy for those with high-risk or relapsed tumor. Peripheral blood stem cell (PBSC) collections have nearly completely replaced bone marrow stem cell (BMSC) harvests because of the perceived advantages of more rapid engraftment, less tumor contamination in the inoculum, and better survival after therapy. The advantage of PBSC, however, may derive from the hematopoietic stimulating cytokines used for PBSC mobilization. Therefore, we tested a randomized comparison of GM-CSF vs. G-CSF used to prime either BMSC or PBSC before collection for use in autologous transplantation. Sixty-two patients receiving transplants (31 PBSC; 31 BMSC) for non-Hodgkin's lymphoma (n = 51) or Hodgkin's disease (n = 11) were treated. All patients received 6 days of randomly assigned cytokine. Those with cellular marrow in morphologic remission underwent BMSC harvest, while those with hypocellular marrow or microscopic marrow tumor involvement had PBSC collected. Neutrophil recovery was similarly rapid in all groups (median 14 days; range 10-23 days), though two patients had delayed neutrophil recovery using GM-CSF primed PBSC (p = 0.01). Red cell and platelet recovery were significantly quicker after BMSC mobilized with GM-CSF or PBSC mobilized with G-CSF. This speedier hematologic recovery resulted in earlier hospital discharge as well. However, in multivariate analysis, neither the stem cell source nor randomly assigned G-CSF vs. GM-CSF was independently associated with earlier multilineage hematologic recovery or shorter hospital stay. Relapse-free survival was not independently affected by either the assigned stem cell source or the randomly assigned priming cytokine, though malignant relapse was more frequent in those assigned to PBSC (RR of relapse 3.15, p = 0.03). These data document that BMSC, when collected following cytokine priming, can yield a similarly rapid hematologic recovery and short hospital stay compared with cytokine-primed PBSC. Using primed BMSC, no difference in malignant relapse or relapse-free survival was observed. These findings suggest that despite widespread use of PBSC for transplantation, BMSC, when collected following hematopoietically stimulating cytokines, may remain a satisfactory source of stem cells for autologous transplantation. G-CSF and GM-CSF are both effective in priming autologous PBSC or BMSC for collection.

Adult↗
PubMed1996

Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.

We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect.

Adolescent↗
PubMed1995

Lupus inhibitors following bone marrow transplant.

Lupus inhibitors have been reported in a number of pathologic states in which there is a disruption of normal immunoregulation. We report here the development of new lupus inhibitors following bone marrow transplantation. Retrospective analysis of 1292 patients undergoing transplantation at the University of Minnesota over a 10 year period demonstrated newly recognized lupus inhibitors in 3% of the patients. These inhibitors were usually detected in the first 1-2 months after transplant. They occurred more frequently in children, with a particularly high incidence in patients with Hurler syndrome. The development of inhibitors was associated with the use of cyclosporine A (CsA) or T depletion for GVHD prophylaxis, with the use of busulfan/cytoxan as a preparative regimen (which includes phenytoin for seizure prophylaxis) and with the occurrence of viral infections. Lupus inhibitors were not associated with development of GVHD, or with any diagnosis other than Hurler syndrome. Thrombotic complications were rare as would be expected in this severely thrombocytopenic population. The incidence of lupus inhibitors that we recognized may substantially underestimate the true incidence as frequent routine coagulation studies were not performed in these patients. Prospective evaluation of lupus inhibitors during bone marrow transplant may provide insight into the pathogenesis of these inhibitors in other disease states.

Adolescent↗
PubMed1994

Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34+7+ NK progenitor.

We have recently described a marrow stroma-dependent long-term culture system that supports differentiation of CD34+ human marrow primitive progenitors into natural killer (NK) cells. We postulate that CD7 expression may be an early event in commitment of hematopoietic progenitors to the NK lineage. Here we compare the characteristics of CD34+7- and CD34+7+ marrow cells cultivated in the stroma-based NK culture system. These CD34+ populations were further compared with a marrow derived, more committed, CD34-7+ progenitor to emphasize the continuum of NK development and to highlight differences between progenitors in our assays. No progenitor proliferated when plated in media without stroma, underscoring the importance of stroma in NK differentiation. Plating progenitor populations in interleukin-2 containing media directly on preestablished, allogeneic, irradiated marrow stroma for 5 weeks resulted in CD56+CD3- NK cells; however, characteristics of the cultured populations differed. Fold expansion and cloning efficiency of the CD34+7+ population, determined by a functional limiting dilution assay was significantly higher than of the CD34+7- or CD34+7+ populations. This suggests that the CD34+7+ population is highly enriched for an NK progenitor and a possible intermediate in NK lineage differentiation. Further dividing the CD34+7+ population by the relative fluorescence of CD7 into CD34+7+dim and CD34+7+bright populations showed that the CD34+7+bright population exhibited a significantly higher cloning frequency than parallel experiments with CD34+7+dim cells (11.8% +/- 2.4% v 2.4% +/- 0.7%, n = 6; P = .005). Plating of the more primitive CD34+7- population in a transwell system (which separates progenitors from stroma by a microporous membrane) prevents differentiation into NK cells. In contrast, plating of CD34+7+ progenitors in transwells resulted in generation of NK cells. These data suggest that primitive, but not more mature NK progenitors may require direct contact with stroma for the initial differentiation steps. Finally, differentiation of the NK progenitors in this stroma-dependent model results in expression of CD2 not present on any of the starting populations. This observation suggests that marrow stroma can stimulate CD2 expression on NK progenitors in a previously undescribed fashion that may be analogous to the thymic effect on CD2 expression in immature T lymphocytes. These observations identify early steps in the commitment of primitive marrow CD34+ hematopoietic progenitors to a lymphoid lineage and underscore the importance of coexpression of CD7 with CD34 as an early lymphoid commitment characteristic and direct progenitor-stroma interactions in this process.

Adolescent↗
PubMed1994

Recommended guidelines for the management of autologous and allogeneic bone marrow transplantation. A report from the Eastern Cooperative Oncology Group (ECOG)

OBJECTIVE: To define the basic state-of-the-art medical care of the patients after bone marrow transplantation as practiced by the Eastern Cooperative Oncology Group. DATA IDENTIFICATION: Studies examining the role of bone marrow transplantation in the care of neoplastic disorders identified using computer and bibliographic searches. STUDY SELECTION: More than 500 articles, book chapters, and abstracts from meetings, covering all therapeutic and diagnostic aspects of the patient having bone marrow transplantation were critically reviewed; information from over 200 publications is included. RESULTS OF DATA ANALYSIS: Enormous progress has been made in understanding the biology, therapy, and prophylaxis strategies of bone marrow transplantation and in extending the range of potential marrow donors to include unrelated persons. Dramatic advances have occurred in the prevention of serious infection, including cytomegalovirus infection, formerly a cause of a high rate of mortality. The advent of newer-combination, high-dose chemotherapy regimens and advances in cryopreservation and in vitro marrow purging techniques have led to increased use and greater efficacy of autologous transplantation. Recent advances using recombinant hematopoietic growth factors and autologous peripheral stem cells are likely to reduce morbidity and mortality and significantly shorten the length of hospitalization and the cost of bone marrow transplantation. CONCLUSIONS: Bone marrow transplantation now is a common procedure done throughout the world. Cooperative groups have assumed a major role in conducting clinical trials. A standardized approach defining basic standards of care will assure uniformity of management, better interpretation of data, and continued progress in the care of the patient who has had a bone marrow transplantation. Basic research and clinical trials are ongoing to define better methods for the treatment and prevention of graft-versus-host disease and hepatic veno-occlusive disease.

Bone Marrow Transplantation↗
PubMed1994

Expansion and activation of human natural killer cells for autologous therapy.

Ex vivo depletion of lymphocytes has been used to decrease the incidence of acute graft-versus-host disease following the allogeneic bone marrow transplantation. Many depletion techniques also remove natural killer (NK) cells that may mediate a beneficial graft-versus-leukemia effect. In this paper we review our studies on ex vivo expansion and activation of NK cells for use in the therapy of chronic myelogenous leukemia.

Bone Marrow Transplantation↗
PubMed1994

Large scale ex vivo expansion and activation of human natural killer cells for autologous therapy.

Immunotherapy with recombinant interleukin-2 (rIL-2) activated natural killer cells (ANK) may be useful in the treatment of malignancies. Difficulties in large scale cultivation of purified ANK have hampered clinical trials. In a first set of experiments designed to characterize ANK precursors in blood we demonstrated that both FACS purified CD56+/CD3- and CD56-/CD3- cultured with rIL-2 give rise to an expanded cell population bearing the CD56+(bright)/CD3- phenotype and having both NK and lymphokine-activated killer (LAK) activity. Cultivation of NK was markedly enhanced by autologous monocytes. We next demonstrated that panning of peripheral blood stem cells on CD5/CD8 coated flasks yielded a starting population enriched for monocytes and NK precursors which after cultivation resulted in production of 4 x 10(10) highly cytotoxic ANK adequate for in vivo clinical trials. Finally, we demonstrated that ANK generated in high dose IL-2 maintain NK and LAK activity for up to 6 days when cultured in as little as 1 U/ml rIL-2. This may allow infusion of ANK with a rIL-2 dose achievable in vivo that does not produce significant systemic toxicity. We plan to test the efficacy of ANK to prevent relapse in a minimal residual disease state following autologous bone marrow transplant.

Adult↗
PubMed1994

Bone marrow transplantation for chronic myelogenous leukemia: clinical outcomes.

Marrow transplant is potentially curative therapy for CML. Allogeneic sibling-donor marrow transplant may be the therapy of choice for younger patients early in the course of disease. Early transplant is an important influence on disease-free survival and relapse after related-donor transplant therapy, although additional patient characteristics influencing outcome can be identified and may have cumulative adverse effects. The 5-year disease-free survival of patients transplanted within one year of diagnosis and without signs of advanced disease is greater than 65%. Significant problems remain, however, including early mortality (primarily from infection, pneumonia, and pneumonitis) and relapse of CML following transplant, including late relapse occurring more than 5 years posttransplant. For patients without a matched, related donor, unrelated-donor marrow transplant may be a treatment option and can result in successful outcome for patients with CML. Relapse following unrelated-donor marrow transplant is rare. However, the use of an unrelated donor is associated with significant toxicity, including early mortality, engraftment failure, and ongoing morbidity and mortality associated with acute and chronic graft-versus-host disease. For patients who lack an available matched-related or -unrelated donor, autologous marrow transplant has been developed as an alternative approach to therapy. Long-term survival following autologous marrow transplant is possible and may even approach the survival for allogeneic related-donor recipients, although cure of disease is not achieved.

Actuarial Analysis↗