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Find video protocols related to scientific articles indexed in Pubmed.
Long-Term Survival after Transplantation of Unrelated Donor Peripheral Blood or Bone Marrow Hematopoietic Cells for Hematologic Malignancy.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-21-2014
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We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias.
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Maintenance therapy for multiple myeloma.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 07-22-2014
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Multiple myeloma (MM) is a neoplasm typical of the elderly, with median age at diagnosis of 70 years, and approximately 65% of patients older than 65 years. Many advances have been made thanks to the use of autologous hematopoietic stem cell transplantation (AHSCT) and the introduction of the immunomodulatory drugs and the proteasome inhibitors. Incorporation of novel agents into induction has resulted in improved overall survival. Optimal MM maintenance therapy should maintain or increase response after induction and, when possible, AHSCT. Optimal maintenance therapy must be effective with minimal toxicity and should be easily administered.
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Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT.
Blood
PUBLISHED: 06-30-2014
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Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.
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Effect of body mass in children with hematologic malignancies undergoing allogeneic bone marrow transplantation.
Blood
PUBLISHED: 04-07-2014
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The rising incidence of pediatric obesity may significantly affect bone marrow transplantation (BMT) outcomes. We analyzed outcomes in 3687 children worldwide who received cyclophosphamide-based BMT regimens for leukemias between 1990 and 2007. Recipients were classified according to age-adjusted body mass index (BMI) percentiles as underweight (UW), at risk of UW (RUW), normal, overweight (OW), or obese (OB). Median age and race were similar in all groups. Sixty-one percent of OB children were from the United States/Canada. Three-year relapse-free and overall survival ranged from 48% to 52% (P = .54) and 55% to 58% (P = .81) across BMI groups. Three-year leukemia relapses were 33%, 33%, 29%, 25%, and 21% in the UW, RUW, normal, OW, and OB groups, respectively (P < .001). Corresponding cumulative incidences for transplant-related mortality (TRM) were 18%, 19%, 21%, 22%, and 28% (P < .01). Multivariate analysis demonstrated a decreased risk of relapse compared with normal BMI (relative risk [RR] = 0.73; P < .01) and a trend toward higher TRM (RR = 1.28; P = .014). BMI in children is not significantly associated with different survival after BMT for hematologic malignancies. Obese children experience less relapse posttransplant compared with children with normal BMI; however, this benefit is offset by excess in TRM.
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Dextramer reagents are effective tools for quantifying CMV antigen-specific T cells from peripheral blood samples.
Cytometry B Clin Cytom
PUBLISHED: 04-04-2014
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The enumeration of antigen-specific T cells is increasingly relevant in clinical and research settings. This information is useful for evaluating immune responses to treatment, monitoring the efficacy of anticancer vaccines, and for detecting self-reactive T cells in autoimmune disorders. Quantifying antigen-specific T cells can be accomplished via IFN? ELISpot assay, the measurement of intracellular cytokine production by flow cytometry, or by lymphocyte proliferation assays in response to antigen. While robust, these technologies are labor-intensive and can take several days to obtain results. New technology has led to more powerful tools for quickly and accurately measuring antigen-specific T cells by flow cytometry via fluorescently-labeled TCR-specific multimers. In this study, we evaluated the use of an assay based on Dextramer reagents for enumerating cytomegalovirus (CMV) antigen-specific T cells (CASTs). Assay performance characteristics were assessed by establishing Dextramers' sensitivity (median?=?0.4; range?=?0.1-1.4 CASTs ?l(-1) ), determining their specificity (100%), evaluating assay robustness with different leukocyte sources and assay reproducibility via interlaboratory and interinstrument investigations. Furthermore, the levels of CASTs in 95 peripheral blood samples from 62 unique blood and marrow transplants recipients correlated well between Dextramers and Tetramers (R(2) ?=?0.9042). © 2014 International Clinical Cytometry Society.
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Dextramer reagents are effective tools for quantifying CMV antigen-specific T cells from peripheral blood samples.
Cytometry B Clin Cytom
PUBLISHED: 04-04-2014
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The enumeration of antigen-specific T cells is increasingly relevant in clinical and research settings. This information is useful for evaluating immune responses to treatment, monitoring the efficacy of anti-cancer vaccines, and for detecting self-reactive T cells in autoimmune disorders. Quantifying antigen-specific T cells can be accomplished via IFN? ELISpot assay, the measurement of intracellular cytokine production by flow cytometry, or by lymphocyte proliferation assays in response to antigen. While robust, these technologies are labor-intensive and can take several days to obtain results. New technology has led to more powerful tools for quickly and accurately measuring antigen-specific T cells by flow cytometry via fluorescently-labeled TCR-specific multimers. In this study, we evaluated the use of an assay based on Dextramer reagents for enumerating cytomegalovirus (CMV) antigen-specific T cells (CASTs). Assay performance characteristics were assessed by establishing Dextramers' sensitivity (median = 0.4; range = 0.1 - 1.4 CASTs µL(-1) ), determining their specificity (100%), evaluating assay robustness with different leukocyte sources and assay reproducibility via inter-laboratory and inter-instrument investigations. Furthermore, the levels of CASTs in 95 peripheral blood samples from 62 unique BMT recipients correlated well between Dextramers and Tetramers (R(2) = 0.9042). © 2014 Clinical Cytometry Society.
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Toxic tacrolimus levels after application of topical tacrolimus and use of occlusive dressings in two bone marrow transplant recipients with cutaneous graft-versus-host disease.
Pharmacotherapy
PUBLISHED: 04-03-2014
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Tacrolimus, a macrolide immunosuppressant, is used topically for the treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema. Despite the manufacturer's product information reporting minimal systemic effects of topical tacrolimus, this has not been evaluated in patients with cutaneous GVHD and with occlusive dressings. We describe two patients with cutaneous GVHD who developed toxic tacrolimus levels after receiving several applications of tacrolimus ointment along with occlusive dressings to enhance skin effectiveness. The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient's tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients' skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption. These case reports suggest that substantial use of topical tacrolimus with occlusive dressings in patients with cutaneous GVHD may contribute to increased systemic absorption resulting in toxic tacrolimus levels. Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.
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Early versus late preemptive allogeneic hematopoietic cell transplantation for relapsed or refractory acute myeloid leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-20-2014
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Many patients with relapsed or refractory acute myeloid leukemia (AML) do not receive allogeneic hematopoietic cell transplantation (alloHCT) because they are unable to achieve a complete remission (CR) after reinduction chemotherapy. Starting in January 2003, we prospectively assigned patients with AML with high-risk clinical features to preemptive alloHCT (p-alloHCT) as soon as possible after reinduction chemotherapy. High-risk clinical features were associated with poor response to chemotherapy: primary induction failure, second or greater relapse, and first CR interval <6 months. We hypothesized that any residual disease would be maximally reduced at the time of transplant, resulting in the best milieu and most lead time for developing a graft-versus-leukemia effect and in improved long-term overall survival (OS) without excess toxicity. This analysis studied the effect of transplant timing on p-alloHCT in 30 patients with high-risk clinical features of 156 consecutive AML patients referred for alloHCT. We compared early p-alloHCT within 4 weeks of reinduction chemotherapy before count recovery with late p-alloHCT 4 weeks after reinduction chemotherapy with count recovery. OS and progression-free survival (PFS) at 2 years were not significantly different for early versus late p-alloHCT (OS 23% versus 33%, respectively, P > .1; PFS 18% versus 22%, respectively, P > .1). Day 100 and 1-year transplant-related mortality were similar (33.3% versus 22.2%, P > .1; 44.4% versus 42.9%, P > .1, respectively). Preemptive alloHCT allowed 30 patients to be transplanted who would normally not receive alloHCT. Clinical outcomes for early p-alloHCT are similar to those for late p-alloHCT without excess toxicity. Early p-alloHCT is a feasible alternative to late p-alloHCT for maximizing therapy of AML that is poorly responsive to induction chemotherapy.
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Reprint of: Back to the future! The evolving role of maintenance therapy after hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-04-2014
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Relapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome.
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The emerging role of consolidation and maintenance therapy for transplant-eligible multiple myeloma patients.
Expert Rev Hematol
PUBLISHED: 01-29-2014
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Multiple myeloma (MM) is an incurable malignant cancer of plasma cell origin. It is highly treatable with glucocorticoids, alkylating drugs, and novel agents including the proteasome inhibitors (bortezomib and carfilzomib) and the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide. Induction regimens incorporating the newer agents have resulted in deeper responses that have translated into prolonged response and survival for transplant eligible and transplant-ineligible MM patients. For the transplant-eligible patient, the current approach to those patients requiring therapy is induction, hematopoietic stem cell (HSC) collection, autologous HSC transplant (AHSCT) which may be followed by consolidation. Maintenance therapies with bortezomib or lenalidomide prolong response and appear to improve overall survival. For very high risk patients, allogeneic (alloHSCT) is an alternative therapy that may improve survival for selected patients. Incorporation of new therapies in combination with existing agents should lead increased response and improved survival of the MM patient with the ultimate goal of development of curative approaches for this disease.
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Fludarabine and cyclophosphamide provides a nonmyeloablative alternative conditioning regimen with low transplant-related mortality and control of high risk disease.
Leuk Res Rep
PUBLISHED: 01-01-2014
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Non-myeloablative allogeneic transplant (NMAT) has a curative potential for patients who are not myeloablative allogeneic transplant (MAT) candidates. We report a phase II trial of a NMAT regimen with cyclophosphamide and fludarabine in 40 patients; 21 of whom had a prior MAT. Day +100 and 1-year transplant-related mortality (TRM) post-NMAT were 13% and 34%, respectively. Day +100 and 1-year Overall/Progression-Free Survival (OS/PFS) were 80%/65% and 43%/25%, respectively. OS was higher in patients with KPS?90 and lower in recipient/donor CMV+/- vs. other combinations. FluCy has low TRM and is curative in about 20% of high-risk patients.
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Remestemcel-L for acute graft-versus-host disease therapy.
Expert Opin Biol Ther
PUBLISHED: 12-19-2013
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Introduction: Remestemcel-L (Prochymal®, Osiris) is an off-the-shelf adult mesenchymal stromal cell product that has been applied to acute graft-versus-host disease (aGvHD) for its immunomodulatory properties. Areas covered: This article discusses preclinical and clinical studies supporting the use of remestemcel-L in aGvHD as well as the current regulatory status. This information was based upon a PubMed and Internet search. Expert opinion: Phase II studies suggest remestemcel-L may have clinical activity in aGvHD and confirm tolerability. However, these results must be interpreted cautiously with any use of remestemcel-L optimally occurring in the context of a clinical trial. Further clarity will be obtained when the results of a completed Phase III study are published. There is a small market for remestemcel-L in aGvHD. A possible future scenario is that a more prevalent indication is found and remestemcel-L is approved for that indication, but use continues for aGvHD.
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Strategies for induction, autologous hematopoietic stem cell transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma patients.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-10-2013
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There have been major advances in the past decade in the continuum of therapy for transplantation-eligible multiple myeloma patients. For patients requiring therapy, recommended induction treatment consists of triple drug regimens followed by the collection of hematopoietic stem cells. The question of early versus delayed transplantation is under investigation and may identify patients for whom early transplantation is optimal therapy and those for whom it may be delayed. For transplantation-eligible patients, high-dose melphalan remains the standard regimen. After transplantation, consolidation can be considered for patients with less than a complete remission. Maintenance therapy with bortezomib or lenalidomide (or both in very-high-risk patients) is a reasonable option for long-term disease control and improvement in overall survival. Incorporation of new agents into the continuum of multiple myeloma care should result in improved outcomes and long-term disease control.
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Back to the Future! The Evolving Role of Maintenance Therapy after Hematopoietic Stem Cell Transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 11-21-2013
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Relapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome.
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New developments in post-transplant maintenance treatment of multiple myeloma.
Semin. Oncol.
PUBLISHED: 10-19-2013
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Treatment of multiple myeloma (MM) has evolved significantly over the past two decades with high-dose chemotherapy and autologous stem cell transplant (ASCT), incorporating novel therapies such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) during induction and post-transplant maintenance therapies. We reviewed the evolution of maintenance therapy from traditional chemotherapy, interferon (IFN), and prednisone to the current use of thalidomide, lenalidomide, and bortezomib in the post-transplant maintenance setting. Based on existing literature, either thalidomide or lenalidomide can be recommended for maintenance therapy post-transplant resulting in improved progression- free survival (PFS) and overall survival (OS). Thalidomide is less tolerated than lenalidomide and does not improve survival in patient subgroups who had achieved at least a very good partial response (VGPR) or who had chromosome 13 deletion. Thalidomide maintenance may be even detrimental in patients with high-risk cytogenetics. Alternatively, lenalidomide maintenance improves PFS in all subgroups of patients including those achieving at least a VGPR and those with high-risk cytogenetics, and improves OS in one other study. Bortezomib maintenance improves PFS and OS as part of induction and maintenance when compared to thalidomide maintenance and it is uncertain as to whether this improvement was due to bortezomib used during induction. The future research in maintenance therapy may include incorporation of current novel agents and testing new oral agents such as pomalidomide, or ixazomib or antibody therapy with elotuzumab.
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Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation.
Blood
PUBLISHED: 09-30-2013
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We conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N = 1025; TBI, N = 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval [CI]), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P = .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P = .03) and TBI, respectively. Corresponding incidences of transplant-related mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P = .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P = .08). The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.
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Unrelated donor allogeneic hematopoietic cell transplantation is underused as a curative therapy in eligible patients from the United States.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-18-2013
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Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for hematologic disorders including acute lymphoblastic and myeloid leukemia, chronic lymphocytic and myeloid leukemia, Hodgkins and non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndrome. To determine the utilization of alloHCT from unrelated donors (URDs) in the United States, we calculated the number of patients diagnosed with hematologic disorders age 20 to 74 years based on 2004 to 2008 Surveillance, Epidemiology and End Results and 2007 US Census data, estimated the percentage of patients who would be eligible for URD alloHCT after discounting the mortality rate during induction therapy and the rate of severe comorbidities, and compared these with the actual 2007 alloHCTs facilitated by the National Marrow Donor Program. We found that the number of URD alloHCT as a percentage of the estimated potential transplantations ranged from 11% for multiple myeloma to 54% for chronic myeloid leukemia, with an average percentage of 26% for all the disorders considered. In an analysis stratified by age groups (20 to 44, 45 to 64, and 65 to 74 years), the utilization of URD alloHCT was higher in younger patients than in older patients for all disorders. Of acute lymphoblastic and myeloid leukemia patients, approximately 66% underwent URD alloHCT later in the course of their disease (in second or greater complete remission). URD alloHCT is likely underused for potentially curable hematologic disorders, particularly in older patients. Understanding the reasons for low use of alloHCT may lead to strategies to expand the use of this curative therapy for more patients with hematologic disorders.
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Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors.
J. Clin. Oncol.
PUBLISHED: 05-28-2013
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Over the past four decades, allogeneic hematopoietic cell transplantation (alloHCT) has evolved as a curative modality for patients with hematologic diseases. This study describes changes in use, technique, and survival in a population-based cohort.
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Simplified validated prognostic model for progression-free survival after autologous transplantation for hodgkin lymphoma.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-20-2013
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Hodgkin lymphoma (HL) prognostic models based on factors measured at time of autologous hematopoietic cell transplantation (AHCT) are limited by small sample sizes. Models based on information at diagnosis are often not uniformly collected or available at transplantation. We propose an easily implementable prognostic model for progression-free survival (PFS) post-AHCT based on factors available at transplantation in a large international cohort of HL patients. The outcomes of 728 AHCT recipients for relapsed/refractory HL were studied. Patients were randomly selected for model development (n = 337) and validation (n = 391). The multivariate model identified 4 major adverse risk factors at the time of AHCT with the following relative weights: Karnofsky performance score <90 and chemotherapy resistance at AHCT were each assigned 1 point, whereas at least 3 chemotherapy regimens pre-AHCT and extranodal disease at AHCT were each assigned 2 points. Based on the total score summed for the 4 adverse risk factors, 3 risk groups were identified: low (score = 0), intermediate (score = 1 to 3), or high (score = 4 to 6). The 4-year PFS for the low- (n = 176), intermediate- (n = 261), and high- (n = 283) risk groups were 71% (95% confidence interval [CI], 63% to 78%), 60% (95% CI, 53% to 66%), and 42% (95% CI, 36% to 49%), respectively. The prognostic model was validated in an independent cohort. The Center for International Blood and Marrow Transplant Research model is based on factors easily available at the time of AHCT and discriminates patients with favorable post-AHCT outcomes as well as an intermediate-risk group. This model should assist in the prospective evaluation of alternative treatment strategies.
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Trends in use of and survival after autologous hematopoietic cell transplantation in North America, 1995-2005: significant improvement in survival for lymphoma and myeloma during a period of increasing recipient age.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-29-2013
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Autologous hematopoietic cell transplantation (auto-HCT) is performed to treat relapsed and recurrent malignant disorders and as part of initial therapy for selected malignancies. This study evaluated changes in use, techniques, and survival in a population-based cohort of 68,404 patients who underwent first auto-HCT in a US or Canadian center between 1994 and 2005 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The mean annual number of auto-HCTs performed was highest during 1996-1999 (6948), and decreased subsequently 2000-2003 (4783), owing mainly to fewer auto-HCTs done to treat breast cancer. However, the mean annual number of auto-HCTs increased from 5278 annually in 1994-1995 to 5459 annually in 2004-2005, reflecting increased use for multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Despite an increase in the median recipient age from 44 to 53 years, there has been a significant improvement in overall survival (OS) from 1994 to 2005 in patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma (day +100 OS, from 85% to 96%; 1-year OS, from 68% to 80%; P < .001) and chemotherapy-sensitive multiple myeloma (day +100 OS, from 96% to 98%; 1-year OS, from 83% to 92%; P < .001). This improvement in OS was most pronounced in middle-aged (>40 years) and older (>60 years) individuals.
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Part I: the role of maintenance therapy in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation.
J Natl Compr Canc Netw
PUBLISHED: 01-12-2013
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Multiple myeloma remains a highly treatable but incurable disease. New agents with improved efficacy have increased the response to induction treatment. These agents have been adapted for use in maintenance therapy strategies to improve responses and delay relapse/progression with the ultimate goal of improved overall survival. Recent trials have shown that the immunomodulatory drugs thalidomide and lenalidomide; the proteasome inhibitor bortezomib; and the bisphosphonate zoledronate improve time to progression and overall survival. Introduction of new therapies, alone or in combination with existing agents, may lead to increased improvement and prolongation of disease control after autologous hematopoietic stem cell transplantation for transplant-eligible patients.
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Risk factors for acute GVHD and survival after hematopoietic cell transplantation.
Blood
PUBLISHED: 10-18-2011
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Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.
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Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-17-2011
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Clinical research published since the first evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of pediatric acute lymphoblastic leukemia (ALL) is presented and critically evaluated in this update. Treatment recommendations are provided by an expert panel. Allogeneic SCT is recommended for children who: are in second complete remission (CR2) after experiencing an early marrow relapse for precursor-B ALL; experienced primary induction failure, but subsequently achieved a CR1; have T-lineage ALL in CR2; or have ALL in third or greater remission. Although the 2005 pediatric ALL evidence-based review (EBR) recommended allogeneic SCT for children with Philadelphia chromosome positive (Ph+) ALL in CR1, preliminary tyrosine kinase inhibitor (TKI) data demonstrate that early outcomes are comparable for allogeneic SCT and chemotherapy + imatinib. Based on the evidence, autologous SCT is not recommended for ALL in CR1. Allogeneic SCT is not recommended for: T-lineage ALL in CR1; mixed-lineage leukemia (MLL)+ ALL when it is the sole adverse risk factor; isolated central nervous system (CNS) relapse in precursor-B ALL. Based on expert opinion, allogeneic SCT may be considered for hypodiploid ALL and persistent minimal residual disease [corrected] (MRD) positivity in ALL in CR1 or greater, although these are areas that need further study. Treatment recommendations pertaining to various transplantation techniques are also provided, as are areas of needed future research.
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Abandonment of high-dose chemotherapy/hematopoietic cell transplants for breast cancer following negative trial results.
Health Serv Res
PUBLISHED: 07-25-2011
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In 1999, three randomized controlled trials concluded that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDC/HCT) is no better than conventional chemotherapy for women with breast cancer. This study documents the impact of the trials on use of HDC/HCT and describes how hospitals reacted to the trials.
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Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-26-2011
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Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.
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Common genetic variants are associated with accelerated bone mineral density loss after hematopoietic cell transplantation.
PLoS ONE
PUBLISHED: 05-19-2011
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Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT.
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The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukemia: update of the 2006 evidence-based review.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-17-2011
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Clinical research published since the first evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of acute lymphoblastic leukemia (ALL) in adults is presented and critically evaluated in this update. Treatment recommendations changed or modified based on new evidence include: (1) myeloablative allogeneic SCT is an appropriate treatment for adult (<35 years) ALL in first complete remission for all disease risk groups; and (2) reduced-intensity conditioning may produce similar outcomes to myeloablative regimens. Treatment recommendations unchanged or strengthened by new evidence include: (1) allogeneic SCT is recommended over chemotherapy for ALL in second complete remission or greater; (2) allogeneic is superior to autologous SCT; and (3) there are similar survival outcomes after related and unrelated allogeneic SCT. New treatment recommendations based on new evidence include: (1) in the absence of a suitable allogeneic donor, autologous SCT may be an appropriate therapy, but results in a high relapse rate; (2) it is appropriate to consider cord blood transplantation for patients with no HLA well-matched donor; and (3) imatinib therapy before and/or after SCT (for Ph+ ALL) yields significantly superior survival outcomes. Areas of needed research in the treatment of adult ALL with SCT were identified and presented in the review.
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Effect of obesity on outcomes after autologous hematopoietic stem cell transplantation for multiple myeloma.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-16-2011
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Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 who received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or nonrelapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS. Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients.
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The bit in the middle and why its important: a computational analysis of the linguistic features of body paragraphs.
Behav Res Methods
PUBLISHED: 02-03-2011
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This study examines the relationship between the linguistic characteristics of body paragraphs of student essays and the total number of paragraphs in the essays. Results indicate a significant relationship between the total number of paragraphs and a variety of linguistic characteristics known to affect student essay scores. These linguistic characteristics (e.g., semantic overlap, syntactic complexity) contribute to two underlying factors (i.e., textual cohesion and difficulty) that are used as dependent variables in mixed-effect models. Results suggest that student essays with 5-8 paragraphs tend to be more linguistically consistent than student essays with 3, 4, and 9 paragraphs. Essays with totals of 5-8 paragraphs, considered by many educators to contain an optimal number of paragraphs, may include functionally and structurally similar paragraphs. These findings could aid writing researchers and educators in obtaining a clearer view of the relationship between the total number of paragraphs comprising an essay and the linguistic characteristics that affect essay evaluation. Consequently, writing interventions may become better equipped to pinpoint student difficulties and facilitate student writing skills by providing more detailed and informed feedback.
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Outcome of patients with IgD and IgM multiple myeloma undergoing autologous hematopoietic stem cell transplantation: a retrospective CIBMTR study.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 12-16-2010
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Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined.
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One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-07-2010
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Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen-mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele-matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT.
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Reduced-intensity conditioning allogeneic hematopoietic cell transplantation for patients with hematologic malignancies who relapse following autologous transplantation: a multi-institutional prospective study from the Cancer and Leukemia Group B (CALGB t
Biol. Blood Marrow Transplant.
PUBLISHED: 06-02-2010
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We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m(2) plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.
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The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-20-2010
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Clinical research published since the 2001 evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of diffuse large B cell lymphoma (DLBCL) in adults is presented and critically evaluated in this update. Treatment recommendations that remain unchanged from the original review include: (1) autologous SCT as salvage therapy is recommended for patients with chemosensitive relapsed DLBCL; and (2) autologous SCT is not recommended for patients who achieve a partial response to an abbreviated induction regimen. New treatment recommendations based on new published data include: (1) autologous SCT as first-line therapy is not recommended for any IPI group; (2) planned tandem or multiple sequential autologous SCT is not recommended; (3) peripheral blood is the standard stem cell source for autologous SCT; (4) age is not a contraindication for autologous SCT, although outcomes in older adults are not as good as in younger adults. There are insufficient data to make recommendations on the routine use of rituximab maintenance after autologous SCT, autologous versus allogeneic SCT, fewer versus more cycles of induction therapy prior to autologous SCT, or the use of reduced intensity versus myeloablative conditioning regimens. Areas of needed research in the treatment of DLBCL with SCT were identified and are presented in the review.
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MTLD, vocd-D, and HD-D: a validation study of sophisticated approaches to lexical diversity assessment.
Behav Res Methods
PUBLISHED: 05-19-2010
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The main purpose of this study was to examine the validity of the approach to lexical diversity assessment known as the measure of textual lexical diversity (MTLD). The index for this approach is calculated as the mean length of word strings that maintain a criterion level of lexical variation. To validate the MTLD approach, we compared it against the performances of the primary competing indices in the field, which include vocd-D, TTR, Maas, Yules K, and an HD-D index derived directly from the hypergeometric distribution function. The comparisons involved assessments of convergent validity, divergent validity, internal validity, and incremental validity. The results of our assessments of these indices across two separate corpora suggest three major findings. First, MTLD performs well with respect to all four types of validity and is, in fact, the only index not found to vary as a function of text length. Second, HD-D is a viable alternative to the vocd-D standard. And third, three of the indices--MTLD, vocd-D (or HD-D), and Maas--appear to capture unique lexical information. We conclude by advising researchers to consider using MTLD, vocd-D (or HD-D), and Maas in their studies, rather than any single index, noting that lexical diversity can be assessed in many ways and each approach may be informative as to the construct under investigation.
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Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR).
Biol. Blood Marrow Transplant.
PUBLISHED: 05-11-2010
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Preservation of fertility after hematopoietic cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N = 99) and nonmalignant disorders (N = 79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative (MA) allogeneic HCT (12 women, 50 men), and nonmyeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were MA in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5 to 10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or MA conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility, and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.
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The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission.
Blood
PUBLISHED: 04-19-2010
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We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.
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Multiparameter flow cytometry for the diagnosis and monitoring of small GPI-deficient cellular populations.
Cytometry B Clin Cytom
PUBLISHED: 02-22-2010
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Glycosyl-phosphatidylinositol (GPI)-negative blood cells are diagnostic for Paroxysmal Nocturnal Hemoglobinuria (PNH). Marrow failure states are often associated with GPI-negative cell populations. Quantification of small clonal populations of GPI-negative cells influences clinical decisions to administer immunosuppressive therapy in marrow failure states (aplastic anemia or myelodysplastic syndrome) and to monitor minimal residual disease after allogeneic blood or marrow transplantation (BMT). We studied the reliability of high-resolution flow cytometry markers operating at the limits of detection.
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Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in adults.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-16-2010
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The incidence of excessive adiposity is increasing worldwide, and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myelogenous leukemia (AML) who underwent autologous (auto, n = 373), related donor (RD, n = 2041), or unrelated donor (URD, n = 1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using bone marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2004. Four weight groups by BMI (kg/m(2)) were defined: underweight <18 kg/m(2); normal 18-25 kg/m(2); overweight >25-30 kg/m(2); and obese >30 kg/m(2). Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (relative risk [RR], 1.92; 95% confidence interval [CI], 1.28-2.89; P = .002), but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, although this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT.
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The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: an evidence-based review.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-14-2010
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Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of follicular non-Hodgkin lymphoma in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations reached unanimously by a panel of follicular lymphoma experts are: (1) autologous SCT is recommended as salvage therapy based on pre-rituximab data, with a significant improvement in overall survival (OS) and progression-free (PFS) survival; (2) autologous SCT is not recommended as first-line treatment for most patients because of no significant improvement in OS; (3) autologous SCT is recommended for transformed follicular lymphoma patients; (4) reduced intensity conditioning before allogeneic SCT appears to be an acceptable alternative to myeloablative regimens; (5) an HLA-matched unrelated donor appears to be as effective an HLA-matched related donor for reduced intensity conditioning allogeneic SCT. There are insufficient data to make a recommendation on the use of autologous SCT after rituximab-based salvage therapy. Eleven areas of needed research in the treatment of follicular lymphoma with SCT were identified and are presented in the review.
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Accelerated bone mineral density loss occurs with similar incidence and severity, but with different risk factors, after autologous versus allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-13-2010
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Bone mineral density (BMD) loss occurs commonly in patients after allogeneic hematopoietic cell transplantation (HCT), primarily because of steroid use, but little is known about BMD change post-autologous HCT. In a prospective study of 206 consecutive first HCT patients, we measured acute BMD change at the lumbar spine and dual femur between baseline and day +100, and evaluated risk factors for bone loss. Accelerated BMD loss in this 4-month period occurred after both autologous and allogeneic HCT with similar severity (median, 0.03 g/cm(2) versus 0.03 g/cm(2) at the spine; 0.03 g/cm(2) versus 0.05 g/cm(2) at the femur, respectively). This is equivalent to 7 to 17 years worth of bone loss by aging. Risk factors for BMD loss were different between autologous and allogeneic HCT patients: lymphoma was associated with greater bone loss after autologous HCT than myeloma, whereas higher steroid dose was the most significant risk factor after allogeneic HCT. Multivariable risk models explained 11% to 30% of the variation in HCT-related BMD change. Surprisingly, BMD loss post-autologous HCT occurred with similar incidence and severity to allogeneic HCT, even in the absence of steroid use. Evaluation of clinical strategies to prevent and reverse HCT-related BMD loss is necessary in both autologous and allogeneic HCT patients.
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A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-05-2010
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Toxicity after blood and marrow transplantation (BMT) has interindividual variability that may be explained by common genetic polymorphisms in critical pathways. The glutathione-S-transferase (GST) isoenzymes detoxify the reactive oxygen species generated by chemotherapy agents and radiation. We investigated whether deletion polymorphisms in 2 GST genes (GSTM1 and GSTT1) were associated with toxicity after autologous or allogeneic BMT. The study population was selected from 699 consecutive BMT patients from 2 centers in Buffalo, NY, and Moscow, Russia, of whom 321 (203 autologous, 118 allogeneic BMT) had available banked samples and amplifiable DNA. Fifty percent of patients were homozygous null for GSTM1, which did not vary by center; however, the GSTT1 homozygous null deletion polymorphism occurred more frequently in patients treated in Moscow (38% versus 18%, P < .001). Overall grade 2-4 regimen-related toxicity occurred in 56%, with nearly 1 in 5 patients having 2 or more organ systems affected. Among autologous BMT patients, a deletion polymorphism in 1 or both genes was significantly associated with increased occurrence of overall toxicity (71% versus 56%, P = .034) and mucositis (74% versus 55%, P = .006). GSTM1 and/or GSTT1 deletion polymorphisms were not associated with toxicity after allogeneic BMT. Future studies may allow for individualized genetic risk stratification.
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Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia.
Blood
PUBLISHED: 12-23-2009
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Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation.
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Race and outcomes of autologous hematopoietic cell transplantation for multiple myeloma.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-11-2009
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Blacks are twice as likely to develop and die from multiple myeloma (MM), and are less likely to receive an autologous hematopoietic-cell transplant (AHCT) for MM compared to Whites. The influence of race on outcomes of AHCT for MM is not well described. We compared the probability of overall survival (OS), progression-free survival (PFS), disease progression, and nonrelapse mortality (NRM) among Black (N=303) and White (N=1892) recipients of AHCT for MM, who were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2005. The Black cohort was more likely to be female, and had better Karnofsky performance scores, but lower hemoglobin and albumin levels at diagnosis. Black recipients were younger and more likely to be transplanted later in their disease course. Disease stage and treatment characteristics prior to AHCT were similar between the 2 groups. Black and White recipients had similar probabilities of 5-year OS (52% versus 47%, P=.19) and PFS (19% versus 21%, P=.64) as well as cumulative incidences of disease progression (72% versus 72%, P=.97) and NRM (9% versus 8%, P=.52). In multivariate analyses, race was not associated with any of these endpoints. Black recipients of AHCT for MM have similar outcomes compared to Whites, suggesting that the reasons underlying lower rates of AHCT in Blacks need to be studied further to ensure equal access to effective therapy.
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Outcome of transplantation for myelofibrosis.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-10-2009
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Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.
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The components of paraphrase evaluations.
Behav Res Methods
PUBLISHED: 07-10-2009
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Two sentences are paraphrases if their meanings are equivalent but their words and syntax are different. Paraphrasing can be used to aid comprehension, stimulate prior knowledge, and assist in writing-skills development. As such, paraphrasing is a feature of fields as diverse as discourse psychology, composition, and computer science. Although automated paraphrase assessment is both commonplace and useful, research has centered solely on artificial, edited paraphrases and has used only binary dimensions (i.e., is or is not a paraphrase). In this study, we use an extensive database (N=1,998) of natural paraphrases generated by high school students that have been assessed along 10 dimensions (e.g., semantic completeness, lexical similarity, syntactical similarity). This study investigates the components of paraphrase quality emerging from these dimensions and examines whether computational approaches can simulate those human evaluations. The results suggest that semantic and syntactic evaluations are the primary components of paraphrase quality, and that computationally light systems such as latent semantic analysis (semantics) and minimal edit distances (syntax) present promising approaches to simulating human evaluations of paraphrases.
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A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report from the CIBMTR.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-29-2009
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We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.
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Race and socioeconomic status influence outcomes of unrelated donor hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-20-2009
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Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 141), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT. Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [CI] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% CI 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% CI 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.
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The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation.
Blood
PUBLISHED: 05-02-2009
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Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]-matched, n=941) or HLA-identical sibling donor (n=3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P< .001) and relapse (RR, 1.50; P< .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P< .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.
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Sibling versus unrelated donor allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia: refined HLA matching reveals more graft-versus-host disease but not less relapse.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-06-2009
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Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor-recipient histoincompatibility can augment the graft-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA matching. Here, we used our recently refined HLA-matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new matching criteria identifies substantially more frequent mismatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-matching scheme in analyzing retrospective data sets when fully informative, allele-level typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD, but does not improve protection against relapse; thus the best donor remains the most closely matched donor.
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The effect of smoking on allogeneic transplant outcomes.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-11-2009
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Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we compared the transplant outcomes of patients with chronic myelogenous leukemia (CML) who were nonsmokers (NS) and past or current smokers (PCS). There were 2193 NS and 625 PCS who received matched sibling and unrelated donor allografts for CML in first chronic phase. We looked for dose effects and identified low and high dose smoking groups (>10 pack years, >1 pack per day). Outcomes were adjusted for known prognostic variables including the European Group for Blood and Marrow Transplant (EBMT) risk score. In multivariate analyses of sibling allograft recipients, relapse risk (RR) was higher (RR=1.67, P=.003) in smokers than NS, but the dose effects were not consistent. High-dose smokers experienced a 50% treatment-related mortality (TRM) versus 28% in the NS group at 5 years on univariate analysis, and the RR was 1.57 (P=.005) on multivariate analysis. Overall survival (OS) at 5 years was 68% in NS versus 62% in the low-dose smoking group versus 50% in the high-dose smoking group (P < .001). Smoking did not significantly affect outcomes in unrelated donor recipients, but numbers were smaller. High-dose smoking is associated with a reduction in OS in patients having sibling allografts for CML. A prospective study with detailed demographic, pulmonary function, and quality-of-life data would improve our understanding of this issue.
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Treatment with plerixafor in non-Hodgkins lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: implications for the heavily pretreated patient.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-27-2009
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We investigated the efficacy and toxicity of combining granulocyte-colony stimulating factor (G-CSF) at standard doses with plerixafor, a CXCR4 inhibitor, to mobilize stem cells in patients with non-Hodgkins lymphoma (NHL) and multiple myeloma (MM). Patients with NHL and MM underwent mobilization with G-CSF (10 microg/kg/day) for up to 9 days and plerixafor (240 microg/kg/day), which started on the evening of day 4. Apheresis began on day 5 and continued daily until either >or= 5 x 10(6) CD34/kg were collected or to a maximum of 5 aphereses. Toxicities, increase in circulating CD34 cells/microL before and after the first dose of plerixafor, percentage of patients collecting >or= 5 x 10(6) CD34/kg, total CD34 cells/kg collected, engraftment, and exploratory efficacy analyses in heavily pretreated patients were examined. Six sites enrolled 49 patients (NHL, 23; MM, 26). All completed mobilization and 47 of 49 (96%) underwent transplant. Circulating CD34 cells/microL increased by 2.5-fold (1.3-6.0-fold) after the first plerixafor dose. The median CD34 cells/kg collected was 5.9 x 10(6) (1.5-22.5) in 2 (1-5) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (8-16) and 14.5 (7-39) days, respectively. Adverse events primarily were mild nausea and diarrhea (n=24). Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34 cells/microL was 2.5 (1.4-5.0) after plerixafor, similar to minimally pretreated patients. Plerixafor and G-CSF increased circulating CD34 cells/microL and led to the adequate collection of stem cells for autotransplant in 96% of the patients. This combination may have particular value in heavily pretreated patients.
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The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-27-2009
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Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of myelodysplastic syndromes (MDS) in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in Table 3, and were reached unanimously by a panel of MDS experts. The identified priority areas of needed future research in MDS include: (1) the benefit of using alternative donor sources (eg, cord blood; haploidentical family donors) for patients without matched sibling or unrelated donors; (2) the role and appropriate timing of allogeneic SCT in combination with hypomethylating and immunomodulatory treatment regimens; (3) randomized trials comparing the safety and efficacy of various novel agents for treating MDS; and (4) the influence of the various MDS treatment modalities on patient-reported quality-of-life outcomes.
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A comparison of measured creatinine clearance versus calculated glomerular filtration rate for assessment of renal function before autologous and allogeneic BMT.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-22-2009
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Common blood and marrow transplantation (BMT) eligibility criteria include a minimum glomerular filtration rate (GFR) that may vary by regimen intensity. GFR is often estimated by measurement of creatinine clearance in a 24-hour urine collection (24-hr CrCl), an inconvenient and error-prone method that overestimates GFR. The study objectives were to determine which of 6 GFR calculations: Cockroft-Gault (CG), modified CG (mCG), Modification of Diet in Renal Disease 1 (MDRD1), MDRD2, Jelliffe, and Wright, consistently underestimated measured 24-hr CrCl pre-BMT. We retrospectively analyzed 98 consecutive allogeneic (n = 48) or autologous (n = 50) adult BMT patients from January 2006 to April 2007. All 6 formulas were significantly (P < .001) correlated with 24-hr CrCl with R = 0.64 (Wright), 0.63 (CG), 0.61 (mCG), 0.61 (Jelliffe), 0.54 (MDRD2), and 0.50 (MDRD1). When compared to the measured 24-hr CrCl, MDRD2 consistently underestimated it in the highest proportion of patients (66%, P < .001), compared with MDRD1 (65%, P < .001), Jelliffe (61%, P = NS), mCG (55%, P = NS), Wright (34%, P < .001), and CG (34%, P = .001). Measured 24-hr CrCl, pre-BMT serum Cr, and all 6 equations were not predictive of renal regimen-related toxicity (RRT) post-BMT. The Wright and CG formulas are closest to, but overestimate 24-hr CrCl in 66% of patients. In comparison, MDRD2 consistently underestimates 24-hr CrCl in 66%. Although MDRD2 is the most conservative formula, all 6 formulas gave reasonable estimates of GFR and any of the 6 equations can replace the measured 24-hr CrCl. Larger analyses and transplantation of patients with GFR <50 mL/min may better define subgroups at risk for renal RRT.
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Seeing whats out of sight: wireless capsule endoscopys unique ability to visualize and accurately assess the severity of gastrointestinal graft-versus-host-disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-21-2009
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Early recognition of gastrointestinal graft-versus-host disease (GI GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) is vital to initiation of therapy. However, the most common location, the small bowel (SB), is difficult to access with upper and lower endoscopy (UGE/LGE). Wireless capsule endoscopy (WCE) is a noninvasive technology allowing complete SB evaluation. The capsule location can also be tracked to identify motility derangements. From August 2006 to July 2007, 11 alloHSCT patients with GI symptoms underwent WCE, and visual grading was performed. UGE and LGE with biopsies were done when clinically indicated. All patients had evidence of probable acute GVHD (aGVHD) on WCE. WCE revealed lesions of greater severity than those seen by UGE or LGE in most patients. WCE demonstrated that 45% of patients had delayed gastric transit time. WCE is an excellent, noninvasive method for assessing GI GVHD, with the ability to more accurately assess the severity of GVHD, evaluate clinical symptoms, and follow response to treatment.
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Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect.
J. Immunol.
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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and other malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the treatment. Using multiple tumor models and diverse donor-host combinations, we have studied the role of granzyme B (GzmB) in GVT effect. We first confirmed previous findings that GzmB deficiency diminished the ability of a high dose of CD8(+) T cells to cause lethal graft-versus-host disease. However, when GVT studies were performed using a moderate cell dose that the hosts could tolerate, GzmB(-/-) CD8(+) T cells demonstrated a significantly enhanced GVT effect. GzmB-mediated, activation-induced cell death in wild-type CD8(+) T cells was found responsible for their reduced GVT activity. Conversely, GzmB(-/-) CD8(+) T cells exhibited enhanced expansion, skewed toward an effector or effector memory phenotype, and produced higher amounts of IFN-? and Fas ligand that might contribute to GzmB-independent tumor control. These findings demonstrate for the first time, to our knowledge, that GzmB-mediated damage of CD8(+) T cells impairs the desired GVT effect. This study suggests that inhibiting donor-derived GzmB function may represent a promising strategy to improve GVT effect without exacerbating graft-versus-host disease.
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Progressive chronic lymphocytic leukemia after allogeneic hematopoietic cell transplantation.
J Natl Compr Canc Netw
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This case report presents a patient with poor-prognosis chronic lymphocytic leukemia (CLL) who was treated with chemotherapy and underwent allogeneic hematopoietic cell transplant (alloHCT) but ultimately progressed. The application of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL and the impact of alloHCT on secondary therapy for progressive CLL are discussed.
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A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease.
J. Immunol.
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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8(+) T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the allogeneic CD8(+) T cells. Moreover, mechanistic analyses showed that CBLB502 stimulates CD8(+) T cell proliferation and enhances their tumor killing activity mainly indirectly through a mechanism that involves the IL-12 signaling pathway and the CD11c(+) and CD11b(+) populations in the bone marrow cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating graft-versus-host disease.
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Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1-, IL-17-, and G-CSF-dependent manner.
Blood
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Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1?, and IL-1? concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF-, IL-17-, and IL-1-dependent mechanism.
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Phase II trial of parathyroid hormone after double umbilical cord blood transplantation.
Biol. Blood Marrow Transplant.
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Transplantation of 1 or 2 umbilical cord blood products is a useful alternative stem cell source. However, the limited number of stem cells in each infusion results in slow engraftment. In mouse models, administration of parathyroid hormone (PTH) is an effective way to enhance the ability of limited numbers of hematopoietic stem cells to support hematopoiesis. In this study, patients received either a myeloablative or a reduced-intensity double umbilical cord blood transplantation, followed by PTH at 100 ?g/day for 28 days. Thirteen patients (median age, 42 years) were enrolled. All patients engrafted; the median time to neutrophil and platelet engraftment of >20 × 10(9) cells/L was 30 days and 61 days, respectively. The incidence of grade II-IV acute GVHD was 38.5% at day 100. Four deaths occurred before day 100, prompting early study closure. No patient who received a myeloablative regimen relapsed. Overall survival at 6 months after transplantation was 62%, and disease-free survival at 2 years was 39%. At the dose and schedule studied, there was no evidence that PTH influenced blood count recovery.
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Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia.
Biol. Blood Marrow Transplant.
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Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.
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IMWG consensus on maintenance therapy in multiple myeloma.
Blood
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Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.