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Find video protocols related to scientific articles indexed in Pubmed.
Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation.
Blood
PUBLISHED: 08-26-2014
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We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated.
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Long-term Survival and Late Effects among 1-year Survivors of Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Acute Leukemia and Myelodysplastic Syndromes.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-19-2014
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We analyzed the outcomes of patients who survived disease-free for 1-year or more following second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant following disease relapse; among these 325 survived relapse-free at 1-year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplant in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least one year were 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status prior to second HCT was significantly associated with higher risk for overall mortality (HR 1.71 for patients with disease not in complete remission prior to second HCT, P<0.01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults following second transplant. Chronic GVHD was the leading cause of non-relapse mortality followed by organ failure and infection. The cumulative incidence of developing at least one of the studied late effects at 10-years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence 22%) and cataracts (20%), and in adults were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease-free for at least 1-year, many can be expected to survive long term. However, they continue to be at risk for relapse and non-relapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplant morbidity in this population.
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Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation.
Cochrane Database Syst Rev
PUBLISHED: 07-26-2014
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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis.
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Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease.
Haematologica
PUBLISHED: 07-04-2014
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The National Institutes of Health global score for chronic graft-versus-host disease was devised by experts but was not based on empirical data. We hypothesized that analysis of prospectively collected data would enable derivation of a more accurate model for estimating mortality risk. We analyzed 574 adult patients with chronic graft-versus-host disease enrolled in a multicenter, observational study, using multivariate time-varying analysis accounting for serial changes in severity of involvement of eight individual organ sites over time. In the training set, severity of skin, mouth, gastrointestinal tract, liver and lung involvement were independently associated with the risk of non-relapse mortality. Weighted mortality points were assigned to individual organs based on the hazard ratios and were summed. The population was divided into three risk groups based on the total mortality points. The three new risk groups were validated in an independent validation set, but did not show better discriminative performance than the National Institutes of Health global score. As compared to a moderate or mild global score, a severe global score was associated with increased risks of non-relapse and overall mortality across time but not with a decreased risk of recurrent malignancy. The National Institutes of Health global score predicts patients' mortality risk throughout the course of their chronic graft-versus-host disease. Further research is required in order to improve outcomes in patients with severe chronic graft-versus-host disease, since their risk of mortality remains elevated.
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Assessment of joint and fascia manifestations in chronic graft-versus-host disease.
PUBLISHED: 04-24-2014
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To investigate the usefulness of various scales for evaluating joint and fascia manifestations in patients with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, and to compare the scales in terms of simplicity of use and ability to yield reliable and clinically meaningful results.
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Sleep disruption in hematopoietic cell transplantation recipients: prevalence, severity, and clinical management.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-09-2014
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Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of recipients experiencing sleep disruption pre-transplant, with up to 82% of patients experiencing moderate to severe sleep disruption during hospitalization for transplant and up to 43% after transplant. These rates of sleep disruption are substantially higher than what we see in the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption and disorders (ie, insomnia, obstructive sleep apnea, restless legs syndrome) as a clinical problem in HCT in order to facilitate patient education, intervention, and research. We identified 35 observational studies published in the past decade that examined sleep disruption or disorders in HCT. Most studies utilized a single item measure of sleep, had small sample size, and included heterogeneous samples of patients. Six studies of the effects of psychosocial and exercise interventions on sleep in HCT have reported no significant improvements. These results highlight the need for rigorous observational and interventional studies of sleep disruption and disorders in HCT recipients..
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Impact of age on quality of life, functional status, and survival in patients with chronic graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-17-2014
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Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) and survival outcomes for older compared with younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N = 522, 1661 follow-up visits, a total of 2183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult, "AYA," 18 to 40 years; "middle-aged," 41 to 59 years; and "older," ? 60 years) and QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]), physical functioning (Human Activity Profile [HAP]), functional status (2-minute walk test [2MWT]), nonrelapse mortality, and overall survival. Because of multiple testing, P values < .01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status (shorter 2MWT [P < .001] and lower HAP scores [P < .001]) relative to AYA and middle-aged patients, older patients reported better QOL (FACT-BMT, P = .004) compared with middle-aged patients and similar to AYA patients (P = .99). Nonrelapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and nonrelapse mortality when compared with younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD.
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Allotransplantation for patients age ?40 years with non-Hodgkin lymphoma: encouraging progression-free survival.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-30-2014
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Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ?40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ?65; P = .0008). Fewer patients aged ?65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ?65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ?65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ?55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ?55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.
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Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-21-2014
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Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.
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Quality of life associated with sirolimus for prevention of graft versus host disease: results from a randomized trial.
Haematologica
PUBLISHED: 11-15-2013
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Several studies have examined sirolimus-based immune suppression for the prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation, but little is known regarding its effects on quality of life. The current study reports on changes in quality of life to day 360 in a randomized phase II trial of sirolimus and tacrolimus versus methotrexate and tacrolimus. Quality of life was assessed prior to transplant and on days 30, 90, 180, 270, and 360 with the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Trial Outcome Index. Random effects models examined the effects of study arm on change in Trial Outcome Index scores from day 30 to 360, controlling for baseline Trial Outcome Index. The sirolimus/tacrolimus arm (n=37) showed less improvement in Trial Outcome Index scores over time compared to the methotrexate/tacrolimus arm (n=34) (p=.02). Patients receiving sirolimus and tacrolimus were more likely to endorse a lack of energy and nausea over time (ps?.01). These data suggest that sirolimus-based immune suppression is associated with less improvement in quality of life in the first year post-transplant compared to methotrexate/tacrolimus. Quality of life differences may be due to increased fatigue and nausea in patients treated with sirolimus. These findings should be considered in the clinical management of patients treated with sirolimus. Clinical trial registration: NCT00803010.
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STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity.
J. Leukoc. Biol.
PUBLISHED: 09-25-2013
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Alloreactivity negatively influences outcomes of organ transplantation or HCT from allogeneic donors. Standard pharmacologic immune suppression impairs T-cell function and jeopardizes the beneficial reconstitution of Tregs. Murine transplantation models have shown that STAT3 is highly expressed in alloreactive T cells and may be therapeutically targeted. The influence and effects of STAT3 neutralization in human alloreactivity, however, remain to be elucidated. In this study, S3I-201, a selective small-molecule inhibitor of STAT3, suppressed human DC-allosensitized T-cell proliferation and abrogated Th17 responses. STAT3 blockade significantly enhanced the expansion of potent iTregs and permitted CD8(+) cytolytic effector function. Mechanistically, S3I-201 polarized the ratio of STAT phosphorylation in favor of STAT5 over STAT3 and also achieved a significant degree of Foxp3 demethylation among the iTregs. Conversely, selective impairment of STAT5 phosphorylation with CAS 285986-31-4 markedly reduced iTregs. STAT3 represents a relevant target for achieving control over human alloresponses, where its suppression facilitates STAT5-mediated iTreg growth and function.
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Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors.
Haematologica
PUBLISHED: 09-20-2013
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Allogeneic hematopoietic cell transplantation has an established role in treating adult acute lymphoblastic leukemia with survival using adult unrelated donors approaching those of sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood, 546 peripheral blood progenitor-cells and 140, bone marrow. Patient and disease characteristics of recipients were similar except cord blood recipients were younger, more likely to be non-Caucasians and to have low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match between the donor sources. Most adult donor transplants were matched at the allele-level considering human leukocyte antigen-A, -B, -C and DRB1. In contrast, most cord blood transplants were mismatched and considered antigen-level match; 57% were mismatched at 2- and 29% at 1-loci whereas only 29% of adult donor transplants were mismatched at 1 locus and none at 2-loci. There were no differences in the 3-year probabilities of survival between cord blood (44%), matched (44%) and mismatched (43%) adult donor transplants. Cord blood transplants had slower engraftment, less grade 2-4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. Cord blood grafts achieved similar survival to matched or mismatched unrelated donor grafts and should be considered a valid alternative stem-cell source for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor.
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Pulmonary Symptoms Measured by the National Institutes of Health Lung Score Predict Overall Survival, Nonrelapse Mortality, and Patient-Reported Outcomes In Chronic Graft-Versus-Host Disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-07-2013
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The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.
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Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality.
Blood
PUBLISHED: 08-27-2013
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HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death.
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Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease.
Blood
PUBLISHED: 08-01-2013
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Alloreactive donor T cells against host minor histocompatibility antigens (mHAs) cause graft-versus-host disease (GVHD) after marrow transplantation from HLA-identical siblings. We sought to identify and expand regulatory CD4 T cells (Tregs) specific for human mHAs in numbers and potency adequate for clinical testing. Purified Tregs from normal donors were stimulated by dendritic cells (DCs) from their HLA-matched siblings in the presence of interleukin 2, interleukin 15, and rapamycin. Male-specific Treg clones against H-Y antigens DBY, UTY, or DFFRY-2 suppressed conventional CD4 T cell (Tconv) response to the specific antigen. In the blood of 16 donors, we found a 24-fold (range, 8-fold to 39-fold) excess Tconvs over Tregs reactive against sibling mHAs. We expanded mHA-specific Tregs from 4 blood samples and 4 leukaphereses by 155- to 405-fold. Cultured Tregs produced allospecific suppression, maintained demethylation of the Treg-specific Foxp3 gene promoter, Foxp3 expression, and transforming growth factor ? production. The rare CD4 T conv and CD8 T cells in the end product were anergic. This is the first report of detection and expansion of potent mHA-specific Tregs from HLA-matched siblings in sufficient numbers for application in human transplant trials.
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Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.
J. Clin. Oncol.
PUBLISHED: 06-24-2013
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Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ? 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk.
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Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies.
Immunotherapy
PUBLISHED: 05-04-2013
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There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure.
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The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors.
Blood
PUBLISHED: 05-01-2013
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The impact of HLA homozygosity at mismatched (MM) loci on the outcome of 2687 myeloablative unrelated donor hematopoietic cell transplantations performed for malignant disease was evaluated among 4 groups: 7/8 bidirectional MM transplants (donor and recipient heterozygous MM, n = 1393), 7/8 host-versus-graft (HVG) vector MM (recipient homozygous, n = 112), 7/8 graft-versus-host (GVH) vector MM (donor homozygous, n = 119), and 8/8 matches (n = 1063). Multivariate analyses found 7/8 GVH (P = .001) and bidirectional MM groups (P < .0001) had significantly worse transplant-related mortality and overall and disease-free survival than the 8/8 match group, a difference not observed with the 7/8 HVG MM group (P > .01). The 3 7/8 groups differed only for grades III-IV acute GVH disease (GVHD), where HVG MM had less GVHD than the 7/8 bidirectional MM (hazard ratio [HR] 0.52, P = .0016) and GVH MM (HR 0.43, P = .0009) groups but not the 8/8 group (HR 0.83, P = .39). There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment, or graft failure. GVH MM have the same risk as 7/8 bidirectional MM. 7/8 HVG MM confer a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared with a 7/8 bidirectional MM.
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Hand grip strength and 2-minute walk test in chronic graft-versus-host disease assessment: analysis from the Chronic GVHD Consortium.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-07-2013
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Hand grip strength (HGS) and the 2-minute walk test (2MWT) have been proposed as elements of chronic graft-versus-host disease (GVHD) assessment in clinical trials. Using all available data (n = 584 enrollment visits, 1689 follow-up visits, total of 2273 visits) from a prospective observational cohort study, we explored the relationship between HGS and 2MWT and patient-reported measures (Lee symptom scale, MOS 36-Item Short-Form Health Survey [SF-36], and Functional Assessment of Cancer Therapy [FACT]-Bone Marrow Transplantation quality of life instruments and Human Activity Profile [HAP]), chronic GVHD global severity (National Institutes of Health global score, clinician global score, and patient-reported global score), calculated and clinician-reported chronic GVHD response, and mortality (overall survival, nonrelapse mortality, and failure-free survival) in multivariable analyses adjusted for significant covariates. 2MWT was significantly associated with intuitive domains of the Lee Symptom Scale (overall, skin, lung, energy), SF-36 domain and summary scores, FACT summary and domain scores, and HAP scores (all P < .001). Fewer associations were detected with the HGS. The 2MWT and HGS both had significant association with global chronic GVHD severity. In multivariable analysis, 2MWT was significantly associated with overall survival, nonrelapse mortality, and failure-free survival, whereas no association was found for HGS. 2MWT and HGS were not sensitive to National Institutes of Health or clinician-reported response. Based on independent association with mortality, these data support the importance of the 2MWT for identification of high-risk chronic GVHD patients. However, change in 2MWT is not sensitive to chronic GVHD response, limiting its usefulness in clinical trials.
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Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-05-2013
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One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ?50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/?L and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) ?mol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ?50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.
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Analysis of gastrointestinal and hepatic chronic grant-versus-host disease manifestations on major outcomes: a chronic grant-versus-host disease consortium study.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-01-2013
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Although data support adverse prognosis of overlap subtype of chronic grant-versus-host disease (GVHD), the importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Using data from the Chronic GVHD Consortium observational cohort study (N = 567, total of 2115 visits), we examined whether the site of GI (esophageal, upper GI, or lower GI) and type of hepatic (bilirubin, alkaline phosphatase, alanine aminotransferase) involvement are associated with overall survival (OS) and nonrelapse mortality (NRM), symptoms, quality of life (QOL) and functional status measures. In multivariate analysis utilizing data from enrollment visits only, lower GI involvement (HR, 1.67; P = .05) and elevated bilirubin (HR, 2.46; P = .001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR, 1.69; P = .02) and elevated bilirubin (HR, 3.73; P < .001) were associated with OS; results were similar for NRM. Any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL, whereas elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, alkaline phosphatase, alanine aminotransferase, or NIH liver score add prognostic value for survival, overall symptom burden, or QOL. These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD-affected patients and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches.
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Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study.
Haematologica
PUBLISHED: 11-04-2011
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The National Institutes of Health Consensus Conference proposed the term "overlap" graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present.
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Graft-vs-host disease following allogeneic hematopoietic cell transplantation.
Cancer Control
PUBLISHED: 10-07-2011
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Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy with proven efficacy in the management of hematologic malignancies. However, it is complicated by the syndromes of acute and chronic graft-vs-host disease (GVHD).
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Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission.
Cochrane Database Syst Rev
PUBLISHED: 10-07-2011
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Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT) and allogeneic HCT represent potential treatment alternatives for post-remission therapy in adult acute lymphoblastic leukemia (ALL), but there is genuine uncertainty regarding the optimal approach.
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Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly.
Blood
PUBLISHED: 09-23-2011
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Adoptive transfer of regulatory T cells (Tregs) prevents GVHD in experimental animals. Because antigen activation drives Treg function, we measured the frequency, growth requirements, and function of alloantigen-specific (allospecific) Tregs from human blood. When alloantigen was presented directly, the precursor frequency of allo-specific Tregs in normal individuals was 1.02% (95% confidence interval [95% CI]: 0.65-1.59) and non-Tregs 1.56% (95% CI: 0.94-2.55). When alloantigen was presented indirectly, the frequency of specific Tregs was approximately 100-fold less. Purified Tregs were expanded with APCs, rapamycin, IL-2, and IL-15. In 12 days, allo-specific Tregs expanded 793-fold (95% CI: 480-1107), with duplication approximately every 24 hours. Purified allo-specific Tregs suppressed responses to specific alloantigen selectively and were approximately 100-fold more potent than polyspecific Tregs and nonexpanded Tregs. Allo-specific Tregs maintained high expression of Foxp3, Bcl-2, lymphoid homing receptor CD62L, and chemokine receptor CCR7, predicting sustained function and migration to lymphoid tissues in vivo. Allo-specific Tregs produced TGF-? and IL-10 and expressed more cytoplasmic CTLA-4 compared with non-Tregs. These data provide a platform for the selective expansion of Tregs against major and possibly minor histocompatibility antigens and predict the feasibility of adoptive immunotherapy trials using Tregs with indirect allo-recognition for preventing GVHD while sparing GVL effects.
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Have we improved in preventing and treating acute graft-versus-host disease?
Curr. Opin. Hematol.
PUBLISHED: 09-14-2011
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Acute graft-versus-host disease (GVHD) is a considerable source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Accordingly, progress in the prevention and primary therapy of this complication is needed to improve patient outcomes.
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Clinical predictors of cognitive function in adults treated with hematopoietic cell transplantation.
Cancer
PUBLISHED: 08-15-2011
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Studies suggest that patients with cancer who undergo hematopoietic cell transplantation (HCT) are at risk for cognitive deficits. To date, little research has investigated the cumulative effects of clinical risk factors on cognitive function in patients who undergo HCT.
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Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 07-29-2011
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Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 ?M-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ?70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 ?M-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 ?M-min (level 2) and 220 mg/m(2)/day for AUC 9,000 ?M-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 ?M-min × 4 days) was the maximally tolerated AUC. Within the confines of the trials small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 ?M-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.
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The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality.
Haematologica
PUBLISHED: 07-26-2011
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The 2005 National Institutes of Health Consensus Development Conference on chronic graft-versus-host disease proposed major changes in the classification and grading of severity of chronic graft-versus-host disease.
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Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria.
Blood
PUBLISHED: 07-26-2011
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In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.
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Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: results from the Chronic Graft-versus-Host Disease Consortium.
Haematologica
PUBLISHED: 06-17-2011
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The 2005 National Institute of Health Chronic Graft-versus-Host Disease Consensus Conference recommended collection of patient-reported outcomes in clinical trials on chronic graft-versus-host disease. We assessed whether changes in chronic graft-versus-host disease severity, determined using National Institute of Health criteria, clinicians assessment or patients self-evaluation, correlated with patient-reported quality of life as measured by the Short Form-36 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) instruments.
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Validation of measurement scales in ocular graft-versus-host disease.
Ophthalmology
PUBLISHED: 06-02-2011
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To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes.
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Variation in management of immune suppression after allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-04-2011
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Practice variation in transplant physician management of immune suppression (IS) after allogeneic hematopoietic cell transplantation (HCT) is anticipated to have important consequences, but has not been characterized to date. We conducted a national survey of transplant physician members of the American Society for Blood and Marrow Transplantation to discern variation in IS management, characterize the burden of graft-versus-host disease (GVHD) emerging in the setting of IS taper, and describe the proportion of HCT recipients who successfully discontinue IS by 2 and 5 years post-HCT. There was marked heterogeneity in IS discontinuation practice, with variation in initiation of taper, sequence of agents tapered, frequency of changes, and strategy utilized. Twenty-five percent reported no consistent strategy in their usual practice. Confidence in therapeutic decision making was limited. The majority indicated that they could not predict who would develop GVHD on taper of IS, and reported a resultant burden of both acute and chronic GVHD (aGVHD, cGVHD) emerging or recurring in the setting of IS taper. HCT physicians projected rates of IS discontinuation that increased from 2 to 5 years post-HCT, and differed significantly according to donor relation and stem cell source utilized. The marked variation in practice, burden of GVHD emerging in the setting of IS taper, and limited confidence in therapeutic decision making all highlight shortcomings in an essential component of HCT physicians scope of practice. These data argue for more rigorous study of IS management post-HCT so that evidence-based practice guidelines can be developed.
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Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium.
Blood
PUBLISHED: 02-25-2011
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Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.
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Fludarabine and pharmacokinetic-targeted busulfan before allografting for adults with acute lymphoid leukemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-25-2011
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We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CR1] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and 1 in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplant-related mortality (TRM) was 2% (95% confidence interval [CI] 0%-16%) at 100 days and 18% (95% CI 10%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-41%) for those transplanted in CR1, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: 15-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.
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Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications.
Int. J. Hematol.
PUBLISHED: 01-19-2011
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We examined pharmacokinetic-targeted IV busulfan (75-170 mg/m(2), with target AUC of 3500-6000 ?mol min) and fludarabine (40 mg/m(2)) × 4 days with rituximab (t-IV Bu/Flu + rituximab) 375 mg/m(2) on days +1 and +8 followed by allogeneic hematopoietic cell transplantation in 19 patients (median age 56, range 35-68 years) with CD20+ lymphoid malignancies. Median time to neutrophil and platelet engraftment was 15 and 12 days. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 58% (95% confidence interval, CI 39-85%), and chronic GVHD was 50% (95% CI 28-88%). With a median follow up of 7 (range 1-31) months, overall response was observed in 15, and stable or progressive disease in 4. Overall survival at 1 year was 67%. Engraftment, chimerism, and infectious complications did not differ significantly from a contemporaneous non-rituximab containing comparator group. The addition of rituximab 375 mg/m(2) to t-IV Bu/Flu does not appear to adversely affect engraftment, donor chimerism, or increase the risk of infectious complications.
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ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-06-2011
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Severe acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following mismatched unrelated donor hematopoietic cell transplantation (HCT). Through a retrospective analysis, we investigated the efficacy of GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) 7.5 mg/kg (1 mg/kg given on day -3, then 3.25 mg/kg/day on days -2 and -1 before stem cell infusion) followed by standard tacrolimus plus methotrexate in a consecutive series of 45 HLA partially matched unrelated donor HCT recipients. The cumulative incidence of grade III-IV aGVHD was 11% by 100 days (95% confidence interval [CI] 5%-25%). Moderate to severe chronic GVHD (per NIH consensus criteria) was 19% (95% CI 10%-36%) at 1 year, and 28% (95% CI 16%-48%) at 2 years. With a median follow-up time for surviving patients of 12 months (range: 5-39 months), overall survival was 55% (95% CI 39%-71%) at 1 year, and 45% (95% CI 27%-63%) at 2 years. Nonrelapse mortality was 11% (95% CI 5%-25%) by 100 days post-HCT, 26% (95% CI 16%-44%) by 1 year, and 30% (95% CI 18%-50%) by 2 years. The cumulative incidence of primary disease relapse was 23% (95% CI 13%-41%) at 1 year, and 33% (95% CI 20%-56%) by 2 years after HCT. Cytomegalovirus (CMV) infection or reactivation varied according to recipient and donor CMV serostatus. Epstein-Barr Virus (EBV) reactivation occurred in 54% (95% CI 40%-71%) of patients. Preemptive rituximab therapy was administered for EBV reactivation, however, posttransplant lymphoproliferative disorder was diagnosed in 5 (11%) cases, and was fatal in 1. A regimen of ATG 7.5 mg/kg total ending on day -1 effectively decreased the occurrence of grade III-IV aGVHD and severe chronic GVHD.
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Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease.
Ann. Transplant.
PUBLISHED: 12-25-2010
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Despite scientific advances in hematopoietic cell allografting, glucocorticoid-refractory acute (aGVHD) and chronic graft-versus-host disease (cGVHD) represent major sources of transplant-related morbidity and mortality. We aimed to characterize the activity of pentostatin as rescue therapy for refractory GVHD.
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Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia.
J Hematol Oncol
PUBLISHED: 09-13-2010
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Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV × 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 ?M/L*min per day × 4 days) and fludarabine (40 mg/m2 × 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered.
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Dysglycemia following glucocorticoid therapy for acute graft-versus-host disease adversely affects transplantation outcomes.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-03-2010
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Disordered glucose metabolism is a common complication of glucocorticoid therapy for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). We aimed to examine the impact of dysglycemia on outcomes in 173 recipients of HCT treated with glucocorticoids for aGVHD. A total of 147 of these patients contributed data to a landmark analysis performed at 12 weeks post-HCT. Median aGVHD onset was 21 days (range: 5-79) after transplant. Median duration of glucocorticoid therapy was 381 days (range: 15-1632). Glucose values were obtained from glucocorticoid initiation date to death or last follow-up, resulting in 11,588 total values. The median (range) for each parameter were: maximum 292 mg/dL (128-694), minimum 75 mg/dL (34-142), average 142 mg/dL (86-327), and standard deviation 46 mg/dL (12-108). Baseline diabetes mellitus predicted significantly greater maximum, mean, and standard deviation. With median follow-up of 20 months (range: 3-55), median overall survival (OS) was 33.7 months (95% confidence interval [CI] 16.4-not reached). On multivariable analysis, maximum, average, or standard deviation of glucose values predicted OS and maximum or average glucose values predicted nonrelapse mortality (NRM). Minimum glucose values of (0-60 mg/dL) were associated with worsened OS and increased NRM. Those patients treated with insulin or oral agents suffered significantly worse OS and increased NRM compared to patients who did not need therapy. Finally, those with sustained maximum values >200 mg/dL despite treatment suffered worse OS and increased NRM. These data suggest an independent adverse effect of dysglycemia in patients treated with glucocorticoids for aGVHD, and argue for stringent glycemic control in this setting.
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Glucocorticoid-refractory acute graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-13-2010
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Acute graft-versus-host disease (aGVHD) is a major cause of hematopoietic cell transplant (HCT) associated morbidity and mortality. Those who fail first-line therapy with ?1 mg/kg of glucocorticoids achieve limited complete responses to salvage agents, and suffer inferior outcomes compared to those who respond to glucocorticoids. The literature to date in salvage therapy for refractory aGVHD suffers from a number of methodologic limitations, and the near absence of data on comparative effectiveness of alternative salvage agents limits conclusions and application to clinical practice. This review examines the current literature on salvage therapy for glucocorticoid-refractory aGVHD, identifies barriers to progress in the field, calls for consensus in definitions and response criteria in the conduct of refractory aGVHD trials, and explores the scientific and therapeutic implications of molecular insights into glucocorticoid responsiveness realized in allied investigation.
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Can antigen-specific regulatory T cells protect against graft versus host disease and spare anti-malignancy alloresponse?
Haematologica
PUBLISHED: 12-16-2009
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Allogeneic hematopoietic cell transplantation provides effective control of hematopoietic malignancies, but with an associated risk of graft-versus-host disease (GVHD) related morbidity and mortality. Several advances in hematopoietic cell transplantation including high resolution HLA typing, development of reduced intensity conditioning regimens, infectious prophylaxis and treatment, and novel immunosuppressive agents have resulted in improved outcomes and improved access to transplantation, but GVHD remains a major obstacle. This clinico-pathological syndrome, mediated by donor alloreactive T cells, occurs often despite prophylactic immunosuppressive therapy. Regulatory T cells, a suppressive subset of the T-cell repertoire, may offer promise as a novel cellular therapy for more effective prevention of GVHD. While advances have been made in pre-clinical experimental animals, several challenges remain in the translation of this work to human trials. Strategies to effectively produce ex vivo expanded alloantigen-specific regulatory T cells specific for ubiquitous alloantigens but sparing hematopoietic- or tumor-associated antigens hold promise to prevent GVHD while allowing a preserved graft versus malignancy effect.
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Health-related quality of life following haematopoietic cell transplantation: patient education, evaluation and intervention.
Br. J. Haematol.
PUBLISHED: 11-16-2009
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Health-related quality of life (QOL) is a vital concern in the pre-treatment consent process and post-treatment care of recipients of haematopoietic cell transplantation (HCT). We propose that comprehensive care of such patients requires an integration of knowledge of the impact of HCT on QOL, assessment of QOL, as well as resources available for intervention. This knowledge may significantly improve patient care when incorporated into daily clinical practice in the transplant setting. As a framework for this approach, this article reviews the literature on QOL after allogeneic and autologous HCT for adults with haematological malignancies. We then discuss evidence in support of the beneficial impact of clinical QOL assessment, and finally evaluate behavioural interventions that show promise to maintain or improve QOL after HCT.
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Biomarkers to discern transplantation tolerance after allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-11-2009
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Although it is commonly accepted that allogeneic hematopoietic cell transplant (HCT) recipients develop transplantation tolerance and can quickly discontinue all immunosuppressive drugs, existing data does not support this concept. Most patients will require a prolonged duration of immunosuppression, lasting commonly several years. This has even greater importance, as the majority of transplants are now performed utilizing peripheral blood mobilized stem cells, which are associated with an increased risk of chronic graft-versus-host disease (cGVHD) and prolonged duration of immunosuppression. Despite these challenges, the approach to liberation from immunosuppression after HCT is empiric, and biomarkers of operational tolerance after HCT are lacking. Conversely, investigators in solid organ allografting have begun to examine tolerance associated gene expression in renal and hepatic allograft recipients. Significant challenges in the design and interpretation of these studies potentially limit comparisons. However, a relatively unified model is beginning to emerge, which largely recapitulates previously established mechanisms of immune tolerance. This evidence supports a state of immune quiescence with reduced expression of costimulation and immune response genes, and upregulation of cell cycle control genes. Data indirectly supports the importance of tumor growth factor (TGF)-beta, supports the role of CD4(+)CD25(+) regulatory T cells, and offers new insights into the role of natural killer (NK) cells. Distinct in hepatic allograft tolerance, emerging evidence highlights the importance of gammadeltaT cells, and selection of the Vgammadelta1+ subtype among the gammadeltaT cell population. The deficiencies in the current understanding of transplantation tolerance after HCT, as well as the inadequacies evident in the current empiric approach to immunosuppressive medication (IS) management after HCT make clear the rationale for investigation aimed at elucidating tolerance associated biomarkers after HCT.
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Decision analysis of peripheral blood versus bone marrow hematopoietic stem cells for allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-10-2009
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Peripheral blood stem cells (PBSCs) and bone marrow (BM) hematopoietic stem cells represent therapeutic alternatives in allogeneic hematopoietic cell transplantation. Randomized controlled trials and an individual patient data meta-analysis (IPDMA) have demonstrated a decreased risk of disease relapse and an increased risk of acute and chronic graft-versus-host disease (aGVHD, cGVHD) in patients receiving PBSCs compared with those receiving BM stem cells. Decision modeling provides quantitative integration of the risks and benefits associated with these alternative treatments, incorporates survival discounts for lower quality of life in patients with aGVHD or cGVHD and post-transplantation relapse, and allows sensitivity analyses for all model assumptions. We have constructed an externally validated Markov model to represent and analyze the decision to use PBSC or BM, estimating post-transplantation state transition probabilities (eg, GVHD and relapse) and quality-of-life discounts from the IPDMA and relevant literature; importantly, this IPDMA synthesized data from primarily adult patients treated with myeloablative (MA) conditioning regimens with T cell-replete matched sibling donors. In this setting, the model demonstrates the superiority of PBSC over BM in both overall and quality-adjusted life expectancy, with a 7-month advantage for PBSC. Sensitivity analyses support this conclusion through a range of values for each variable supported by the IPDMA and quality-of-life discounts, as supported by the literature. However, BM is the optimal strategy in conditions in which the 1-year relapse probability is < 5%. PBSC is the optimal stem cell source in terms of both overall and quality-adjusted life expectancy, except in conditions with a very low relapse probability, in which BM provides optimal outcomes.
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Quality of life after allogeneic hematopoietic cell transplantation.
Blood
PUBLISHED: 03-31-2009
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High-dose therapy with allogeneic hematopoietic cell transplantation (HCT) offers effective control and potential cure of hematopoietic malignancies, but with the cost of associated morbidity that includes adverse effects on quality of life (QOL). A growing body of literature has characterized this impact. Longitudinal studies suggest early moderate impairments that largely return to pretransplantation levels by day 100; the majority of studies suggest that greater than 60% of patients report good to excellent QOL in years 1 to 4 after HCT. Comparisons of allogeneic HCT with autologous HCT and standard-dose chemotherapy suggest impairments in QOL and a different trajectory of recovery in allogeneic HCT, but these conclusions are limited by confounding variables. Cross-sectional studies suggest larger and more persistent decrements in QOL in comparison with matched noncancer controls and population normative data. Acute and chronic graft-versus-host disease (GVHD) are significant threats to QOL. Behavioral interventions show promise to maintain or improve quality of life after allogeneic HCT. The review concludes with recommendations to investigators and clinicians as the state of this research advances.
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Infliximab for managing steroid-refractory acute graft-versus-host disease.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-25-2009
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Infliximab has demonstrated activity in the treatment of steroid-refractory acute graft-versus-host disease (aGVHD). We aimed to confirm the effectiveness of infliximab as a salvage therapy for steroid-refractory aGVHD. In a series of 52 patients, 71% of whom had grade III-IV aGVHD, only 15% achieved complete remission (CR) with the use of infliximab alone as salvage therapy. CR of aGVHD differed according to overall aGVHD grade at salvage (grade II, 5/15; grade III, 2/17; grade IV, 1/20; P=.03). Median overall survival (OS) was only 1.7 months (95% confidence interval [CI]=0.99 to 2.3 months). CR of aGVHD was significantly associated with OS, with a hazard ratio of 8.4 for death in those without CR (95% CI=3.6 to 19.6; P < .0001). This series demonstrates the limited activity of infliximab in patients with high-grade aGVHD. Further work is needed to identify effective therapy for aGVHD.
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Granulocyte Macrophage Colony Stimulating Factor Treatment is Associated with Improved Cognition in Cancer Patients.
Brain Disord Ther
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BACKGROUND: Endogenous Granulocyte Macrophage Colony Stimulating Factor (GMCSF) is released in rheumatoid arthritis patients, who are largely protected from Alzheimers disease (AD). Introducing exogenous GMCSF into an AD mouse model reduced amyloid deposition by 55% and restored normal cognition. No published studies have examined exogenous GMCSF and cognitive functioning in humans. OBJECTIVES/DESIGN: The goal of the current study was to examine the association between receipt of GMCSF and cognitive functioning in patients receiving colony stimulating factors as part of routine supportive care for hematopoietic cell transplantation (HCT). SETTING AND PARTICIPANTS: Archived neuropsychological data were examined from a longitudinal study of cognitive functioning in 95 patients receiving HCT at the Moffitt Cancer Center. INTERVENTION: Receipt of GMCSF and/or Granulocyte Colony Stimulating Factor (GCSF) was ascertained through patient billing records. MEASUREMENTS: Patients were assessed with a battery of neuropsychological tests prior to transplant and 6 and 12 months post-transplant. RESULTS: Patients treated with GMCSF and GCSF (n=19) showed significantly greater improvement in total neuropsychological functioning (TNP) at 6 months than patients treated with GCSF only (n=76) (p=.04). There was no group difference in TNP at 12 months (p=.24). Improvement in TNP from baseline to 6 months post-HCT was significant in the GMCSF+GCSF group (p=.01) but not the GCSF only group (p=.33). Improvement in TNP from baseline to 12 months post-HCT was significant in both groups (ps<.01). CONCLUSION: Preliminary data from this study of humans receiving colony stimulating factors suggest that receipt of GMCSF+GCSF was associated with greater cognitive improvement than GCSF alone. Randomized controlled trials of the effects of GMCSF on cognitive functioning in humans are warranted and underway to confirm these findings.
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Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the late effects working committee of the center for international blood and marrow transplant research.
Biol. Blood Marrow Transplant.
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With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.
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Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium.
Blood
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There are no validated criteria to measure skin response in chronic GVHD. In a prospectively assembled, multicenter cohort of patients with chronic GVHD (N = 458), we looked for correlation of change in several different scales recommended by the National Institutes of Health (NIH) Consensus with clinician and patient perception of change and overall survival. Of the clinician scales, the NIH composite 0-3 skin score was the only one that correlated with both clinician and patient perception of improvement or worsening. Of the patient-reported scales, the skin subscale of the Lee Symptom Scale was the only one that correlated with both clinician and patient perception of improvement or worsening. At study entry, NIH skin score 3 and Lee skin symptom score > 15 were both associated with worse overall survival. Worsening of NIH skin score at 6 months was associated with worse overall survival. Improvement in the Lee skin symptom score at 6 months was associated with improved overall survival. Our findings support the use of the NIH composite 0-3 skin score and the Lee skin symptom score as simple and sensitive measures to evaluate skin involvement in clinical trials as well as in the clinical monitoring of patients with cutaneous chronic GVHD.
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Poor agreement between clinician response ratings and calculated response measures in patients with chronic graft-versus-host disease.
Biol. Blood Marrow Transplant.
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In 2005, a National Institutes of Health consensus conference was held to refine methods for research in patients with chronic graft-versus-host disease, including proposed objective response measures and a provisional algorithm for calculating organ-specific and overall response. In this study, we used weighted kappa statistics to evaluate the level of agreement between clinician response ratings and calculated response categories in patients with chronic graft-versus-host disease. The study included 290 patients who had paired enrollment and follow-up visits. Based on a set of objective measures, 37% of the patients had an overall complete or partial response, whereas clinicians reported an overall complete or partial response rate of 71% (slight to fair agreement, weighted kappa 0.20). Agreement rates between calculated organ-specific responses and clinician-reported changes in skin, mouth, and eyes were fair to moderate (weighted kappa, 0.28-0.54). We conclude that for both overall and organ-specific comparisons, clinician response ratings did not agree well with calculated response categories. Possible reasons for this discrepancy include a high clinical sensitivity for detecting response, a clinical predisposition to recognize selective improvements as overall response, the large change in objective measures proposed to define response, and the high incidence of progressive disease based on new manifestations. Conclusions from prior literature reporting high overall response rates based on clinician judgment would not be supported if the provisional algorithm had been applied to calculate response. Our analysis also highlights the need to define an overall response measure that incorporates both patient-reported and objective measures and accurately reflects the outcome in patients with a mixed response in which one organ or site improves, whereas another shows new involvement.
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A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation.
Haematologica
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There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells.
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Clinical benefit of response in chronic graft-versus-host disease.
Biol. Blood Marrow Transplant.
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To determine whether changes in objective response measures proposed by the National Institutes of Health correlate with clinical benefit, such as symptom burden, quality of life, and survival outcomes, we analyzed data from a multicenter prospective cohort of 283 patients with chronic graft-versus-host disease requiring systemic treatment. The median follow-up time of survivors was 25.1 months (range, 5.4-47.7 months) after enrollment. Symptom measures included the Lee symptom scale and 10-point patient-reported symptoms. Quality-of-life measures included the Short Form-36, Functional Assessment of Cancer Therapy-Bone Marrow Transplantation, and Human Activities Profile. Overall and organ-specific responses were calculated by comparing manifestations at the 6-month visit and those at the enrollment visit using a provisional algorithm. Complete or partial responses were considered "response," and stable or progressive disease was considered "no response." Overall response rate at 6 months was 32%. Organ-specific response rates were 45% for skin, 23% for eyes, 32% for mouth, and 51% for gastrointestinal tract. Response at 6 months, as calculated according to the provisional response algorithm, was correlated with changes in symptom burden in patients with newly diagnosed chronic graft-versus-host disease, but not with changes in quality of life or survival outcomes. Modification of the algorithm or validation of other more meaningful clinical endpoints is warranted for future clinical trials of treatment for chronic graft-versus-host disease.
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Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma.
Br. J. Haematol.
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We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m(2) per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4·35 mg/l (range: 1·8-11·4); albumin was 37 g/l (range: 3·1-4·9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m(2) was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (?partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0·0072) and FANCF (P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma.
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Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era.
Blood
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Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMA HCT from 2001 to 2007: 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The majority (74%) had treatment with imatinib before HCT. At HCT, most patients aged 40 to 49 years were in chronic phase (CP) 1 (74%), compared with 31% aged 60 years or older. Siblings were donors for 56% aged 40 to 49 years; older cohorts had more unrelated donors. The majority received peripheral blood grafts and RIC across all age groups. 3 year overall survival (54%, 52%, and 41%), day + 100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. The 3-year relapse incidence (36%, 43%, and 66%) and disease-free survival (35%, 32%, and 16%) were inferior in the oldest cohort. Importantly, for CP1 patients, relapse and disease-free survival were similar across age cohorts. Allogeneic RIC HCT for older patients with CML can control relapse with acceptable toxicity and survival in TKI-exposed CML, especially if still in CP1.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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

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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.