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Find video protocols related to scientific articles indexed in Pubmed.
Race and ethnicity influences collection of G-CSF mobilized peripheral blood progenitor cells from unrelated donors, a CIBMTR analysis.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-27-2014
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Little information exists on the effect of race and ethnicity on collection of peripheral blood stem cells (PBSC) for allogeneic transplantation. We studied 10776 donors from the National Marrow Donor Program who underwent PBSC collection from 2006-2012. Self-reported donor race/ethnic information included Caucasian, Hispanic, Black/African American (AA), Asian/Pacific Islander (API), and Native American (NA). All donors were mobilized with subcutaneous filgrastim (G-CSF) at an approximate dose of 10 ?g/kg/d for 5 days. Overall, AA donors had the highest median yields of mononuclear cells (MNC)/L and CD34(+) cells/L blood processed (3.1 x 10(9) and 44 x 10(6) respectively) while Caucasians had the lowest median yields at 2.8 x 10(9) and 33.7 x 10(6) respectively. Multivariate analysis of CD34(+)/L mobilization yields using Caucasians as the comparator and controlling for age, gender, body mass index, and year of apheresis revealed increased yields in overweight and obese AA and API donors. In Hispanic donors, only male obese donors had higher CD34(+)/L mobilization yields compared to Caucasian donors. No differences in CD34(+)/L yields were seen between Caucasian and NA donors. Characterization of these differences may allow optimization of mobilization regimens to allow enhancement of mobilization yields without compromising donor safety.
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Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients.
Haematologica
PUBLISHED: 05-09-2014
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Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50-73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59-3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14-2.83; P=0.01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95%CI: 1.07-2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13-2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54-4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults.
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A prospective randomized wait list control trial of intravenous iron sucrose in older adults with unexplained anemia and serum ferritin 20-200ng/mL.
Blood Cells Mol. Dis.
PUBLISHED: 03-05-2014
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Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48m in the immediate intervention group and decreased a mean 11.45±49.46m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46g/dL in the immediate intervention group and declined a mean 0.39±0.85g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.
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Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant.
Leuk. Lymphoma
PUBLISHED: 02-26-2014
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We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for hematopoietic stem cell transplant (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration-time curve (AUC), maximum concentration and clearance, were measured, and patients were monitored for renal injury. All patients had normal pretreatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.
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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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Older patients/older donors: choosing wisely.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-10-2013
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Two lingering problems regarding transplantation in older adults have been how to select patients appropriately and whether to use older sibling donors. Allogeneic hematopoietic cell transplantation (HCT) of older patients may result in long-term survival due to GVL, but the data remain observational and mostly restricted to those 50 to 69 years of age. Patients with excellent performance status and low comorbidity have the best long-term survival after HCT. Novel measures of health status such as self-report or performance-based functional measures allow "staging the age" and may inform candidacy for less robust patients. Older matched sibling donors should be preferred over matched unrelated donors (MUDs) because outcomes are equivalent to superior for matched sibling donors compared with MUD. However, MUDs also achieve acceptable outcomes and long-term disease control. An alternative donor can be considered based on institutional protocols and expertise. Very limited information is available in patients or related donors 70 years of age and older. Future efforts to more completely characterize patient health status before transplantation will allow better application of HCT in older adults.
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Immune reconstitution after combined haploidentical and umbilical cord blood transplant.
Leuk. Lymphoma
PUBLISHED: 03-01-2013
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Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplant, but delayed myeloid and lymphoid immune reconstitution leads to increased risk of infections. We recently reported the clinical results of 45 patients enrolled on a pilot study combining UCB with a human leukocyte antigen (HLA)-haploidentical donor with reduced-intensity conditioning who showed rapid neutrophil and platelet recovery. We report here preliminary immune reconstitution data of these patients. Patients were assessed for lymphocyte subsets, T-cell diversity, Cylex ImmuKnow assay and serological response to pneumococcal vaccination. Natural killer (NK)-cell and B-cell reconstitution were rapid at 1 month and 3 months, respectively. T-cell recovery was delayed, with a gradual increase in the number of T-cells starting around 6 months post-transplant, and was characterized by a diverse polyclonal T-cell repertoire. Overall, immune reconstitution after haplo-cord transplant is similar to that seen after cord blood transplant, despite infusion of much lower cord blood cell dose.
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Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?
Blood
PUBLISHED: 01-29-2013
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Older patients are increasingly undergoing allogeneic hematopoietic transplantation. A relevant question is whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD). Accordingly, transplants in leukemia/lymphoma patients age ?50 years were analyzed comparing outcomes for recipients of MSD ?50 (n = 1415) versus MUD <50 years (n = 757). Risks of acute graft-versus-host disease (GVHD) grade 2 to 4 (hazard ratio [HR], 1.63; P < .001), 3 to 4 (HR, 1.85; P < .001), and chronic GVHD (HR, 1.48; P < .0001) were higher after MUD compared with MSD transplants. The effect of donor type on nonrelapse mortality (NRM), relapse, and overall mortality was associated with performance score. For patients with scores of 90 or 100, NRM (HR, 1.42; P = .001), relapse (HR, 1.45; P < .001), and overall mortality (HR, 1.28; P = .001) risks were higher after MUD transplants. For patients with scores below 90, NRM (HR, 0.96; P = .76), relapse (HR, 0.86; P = .25), and overall mortality (HR, 0.90; P = .29) were not significantly different after MUD and MSD transplants. These data favor an MSD over a MUD in patients age ?50 years.
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High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis.
J. Biol. Chem.
PUBLISHED: 01-10-2013
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Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome.
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Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions.
Blood
PUBLISHED: 10-05-2011
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We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34(+) stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.
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Phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for allogeneic hematopoietic cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-31-2011
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We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.
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Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic.
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 06-09-2011
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To accurately determine the causes of anemia and proportion of unexplained anemia in a racially diverse cohort of older adults after a comprehensive and standardized evaluation.
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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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Perceptions of disease state, treatment outcomes, and prognosis among patients with myelodysplastic syndromes: results from an internet-based survey.
Oncologist
PUBLISHED: 04-08-2011
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Myelodysplastic syndromes (MDSs) are a heterogenous group of clonal hematopoietic disorders affecting approximately 60,000 people in the U.S. Little information is available regarding how aware MDS patients are of their disease severity, prognosis, and treatment outcomes.
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Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.
Blood
PUBLISHED: 04-04-2011
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The success of reduced intensity conditioning (RIC) transplantation is largely dependent on alloimmune effects. It is critical to determine whether immune modulation with anti-T-cell antibody infusion abrogates the therapeutic benefits of transplantation. We examined 1676 adults undergoing RIC transplantation for hematologic malignancies. All patients received alkylating agent plus fludarabine; 792 received allografts from a human leukocyte antigen-matched sibling, 884 from a 7 or 8 of 8 HLA-matched unrelated donor. Using Cox regression, outcomes after in vivo T-cell depletion (n = 584 antithymocyte globulin [ATG]; n = 213 alemtuzumab) were compared with T cell- replete (n = 879) transplantation. Grade 2 to 4 acute GVHD was lower with alemtuzumab compared with ATG or T cell- replete regimens (19% vs 38% vs 40%, P < .0001) and chronic GVHD, lower with alemtuzumab, and ATG regimens compared with T-replete approaches (24% vs 40% vs 52%, P < .0001). However, relapse was more frequent with alemtuzumab and ATG compared with T cell-replete regimens (49%, 51%, and 38%, respectively, P < .001). Disease-free survival was lower with alemtuzumab and ATG compared with T cell-replete regimens (30%, 25%, and 39%, respectively, P < .001). Corresponding probabilities of overall survival were 50%, 38%, and 46% (P = .008). These data suggest adopting a cautious approach to routine use of in vivo T-cell depletion with RIC regimens.
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Gene mutations, epigenetic dysregulation, and personalized therapy in myeloid neoplasia: are we there yet?
Semin. Oncol.
PUBLISHED: 03-23-2011
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Myeloid neoplasms are characterized by acquired somatic mutations and epigenetic alterations in genes that are crucial for hematopoietic differentiation and cellular proliferation and survival pathways. The heterogeneity and genetic complexity of these disorders is daunting, but the improvement in our knowledge of the pathogenetic mechanisms underlying myeloid transformation, coupled with the increasing availability of agents that target these pathways, offers unique opportunities for improved therapy. This review will focus on common mutations that are of therapeutic or prognostic importance in acute myeloid leukemia (AML) and the classic Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-) MPNs), in the context of discussing the potential for risk-adapted and targeted therapeutic approaches for these diseases.
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Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401.
J. Clin. Oncol.
PUBLISHED: 02-28-2011
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Factors captured in a geriatric assessment can predict morbidity and mortality in older adults, but are not routinely measured in cancer clinical trials. This study evaluated the implementation of a geriatric assessment tool in the cooperative group setting.
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T-cell-depleted allogeneic transplant without donor leukocyte infusions results in excellent long-term survival in patients with multiply relapsed Lymphoma. Predictors for survival after transplant relapse.
Leuk. Lymphoma
PUBLISHED: 12-10-2010
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We analyzed 67 patients with lymphoma who received alemtuzumab-based conditioning regimens for allogeneic stem cell transplant and no post-transplant DLI. The median age was 54 (24-70), 43% had unrelated donors, 34% had chemotherapy refractory disease, and 25% had an elevated LDH. With a median follow-up for survivors of 35 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 30% and 47%, respectively. Chemosensitivity by CT and pre-transplant LDH were independent prognostic factors for both overall survival and progression-free survival. Patient age, performance status, donor type, lymphoma subtype, disease sensitivity by PET, and conditioning regimen did not correlate with PFS and OS. Patients who relapsed greater than 6 months after allogeneic transplant were frequently able to re-enter a subsequent durable remission. Our experience confirms the curative potential of alemtuzumab-containing RIC regimens for allogeneic HCT in patients with relapsed lymphoma without prophylactic DLI. An elevated pre-transplant LDH and chemorefractory disease prior to transplant confer a worse prognosis, while PET scan findings do not have this same implication. Patients who relapse greater than 6 months after their transplant are likely to achieve a subsequent remission with any of a variety of interventions, suggesting that GVL effects can be operative even after recurrence. Our outcomes challenge the utility of the common practice of prophylactic DLI after T-depleted transplant for lymphoma.
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Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease.
Leuk. Lymphoma
PUBLISHED: 10-04-2010
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Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.
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Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant.
Leuk. Lymphoma
PUBLISHED: 06-12-2010
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Few clinical protocols have focused on patients with therapy-related myeloid neoplasms (t-MN). Therefore, we enrolled 32 patients with previously untreated t-MN on a clinical trial testing the effectiveness of a unified induction regimen of high-dose cytarabine and mitoxantrone. The complete remission (CR) rate was 66% (95% CI 47-81%) and the partial remission (PR) rate was 16% (95% CI 5-33%), for an overall response rate of 82%. Day 30 treatment mortality was 9% (3/32), and the most serious induction toxicity was cardiac dysfunction. Among the patients with CR, 13 (62%) received consolidation therapy using an allogeneic hematopoietic cell transplant (HCT), four (21%) received an autologous HCT, and three (16%) received further chemotherapy. We observed long-term disease-free survival in patients who received all three types of consolidation therapy. The remission induction of high-dose cytarabine and mitoxantrone for t-MN is a well-tolerated efficacious combination, which allows aggressive consolidation and long-term disease-free survival.
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American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases.
J. Clin. Oncol.
PUBLISHED: 06-01-2010
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PURPOSE An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCOs membership following publication or presentation of potentially practice-changing information. This PCO addresses recommendations for chronic hepatitis B virus (HBV) infection screening in patients receiving cytotoxic or immunosuppressive chemotherapy for treatment of malignant diseases.
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Blood stem cell transplantation in older patients.
Biol. Blood Marrow Transplant.
PUBLISHED: 11-14-2009
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A serious dichotomy currently exists in hematopoietic stem cell transplantation (HSCT) and cancer research. Cancer is a disease that predominantly affects older people, yet there is a paucity of cancer research addressing the very unique needs of this population. Even basic biologic processes that exist in aging (decline in immune competency, increased sensitivities to therapies, etc.) are only beginning to be understood.Proportionally, the vast majority of cancer preclinical research does not involve the use of aged animals due to expense and time. This seriously hampers realistic extrapolation of preclinical findings to the general population affected by cancer. This report recommends research priorities that can help close the gaps in our understanding of aging as it relates to HSCT and cancer.
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Patterns and kinetics of T-cell chimerism after allo transplant with alemtuzumab-based conditioning: mixed chimerism protects from GVHD, but does not portend disease recurrence.
Leuk. Lymphoma
PUBLISHED: 10-14-2009
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We analyzed the kinetics of CD3 chimerism in 120 consecutive allogeneic hematopoietic cell transplantation (HCT) recipients receiving alemtuzumab-based conditioning. Fifty-two received fludarabine/melphalan, 44 received fludarabine/busulfan, and 24 received clofarabine/melphalan in addition to alemtuzumab. Post-transplant GVHD prophylaxis consisted of tacrolimus. No prophylactic donor lymphocyte infusion or other interventions were used for mixed donor chimerism (MDC). Bone marrow (BM) and/or peripheral blood (PB) samples were obtained at 30 days, 100 days, 180 days, and 1 year following HCT. On Day 30, 15% of assessable patients had MDC in the CD3 compartment. This had increased to 50% by Day 100, and to 63% by Day 180. MDC predicted for a lower risk of acute (p = 0.08) and particularly of chronic GVHD (p = 0.01). MDC was not associated with subsequent relapse or TRM (p = 0.67 and 0.72, respectively). A decline of more than 15% in CD3 chimerism between Day 30 and Day 180 predicted for a 40% risk of subsequent disease recurrence. The observation of MDC after alemtuzumab conditioning does not by itself constitute a risk factor for relapse and should not be used to guide therapeutic intervention. By contrast, declining donor chimerism between Day 30 and Day 180 is associated with a somewhat increased risk of disease recurrence. The high incidence of MDC after alemtuzumab containing conditioning contributes to the low risk of acute and chronic GVHD.
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Older age but not donor health impairs allogeneic granulocyte colony-stimulating factor (G-CSF) peripheral blood stem cell mobilization.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-06-2009
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We evaluated stem cell mobilization in 195 consecutive sibling donors who underwent a uniform mobilization regimen of granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg/day divided into twice daily dosing. On day 5, peripheral blood (PB) CD34 cells/microL were measured immediately prior to peripheral blood stem cell (PBSC) apheresis. Failed mobilization was defined as <20 CD34 cells/microL on day 5. The median age was 52 years and 73 (37%) were 55 years or greater. Comorbid conditions by the Charlson Comorbidity Index (CCI) occurred in 13%, but only 3% had Karnofsky performance status (PS) <100%. Eight (4%) failed mobilization, defined as <20 CD34 cells/microL on day 5. Older age was associated with fewer CD34 cells/microL (P=.002). In addition, 6/73 (8.2%) older donors failed mobilization compared to 2/122 (1.6%) younger donors (P=.054). Comorbidity, sex, race, and donor weight did not influence mobilization. Although low PS was very uncommon, it was associated with reduced mobilization (P=.021), but not mobilization failure. A small fraction of older donors mobilize poorly, and this is not explained by standard measures of comorbidity or PS.
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Diminished quality of life and physical function in community-dwelling elderly with anemia.
Medicine (Baltimore)
PUBLISHED: 03-14-2009
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The occurrence of anemia in older adults has been associated with adverse outcomes including functional decline, disability, morbidity, and mortality. It is not clear to what extent these outcomes are the result of the anemia or concurrent illness. We performed a cross-sectional, observational study to determine whether lower hemoglobin concentrations in older adults are associated with reduced health-related quality of life, functional status, depression, disability, and physical strength, independent of chronic disease. Three sites participated in this research: an academic geriatric practice, a hospital-based geriatric outpatient unit, and a community-based multispecialty internal medicine group. Health-related quality of life and functional status were measured using the Short Form-36 Health Survey (SF-36) and the Functional Assessment of Chronic Illness Therapy-Anemia (FACIT-An). Disability and depression were assessed using the Instrumental Activities of Daily Living (IADL) and the Geriatric Depression Scale (GDS) questionnaires, respectively. Handgrip strength was used as a physical performance measure. Anemia was defined as hemoglobin <13 g/dL for men or <12 g/dL for women. The mean SF-36 physical health component summary scores were 38.9 (with anemia) and 44.1 (without anemia) (p<0.001). Anemia was associated with greater fatigue (p < 0.001), lower handgrip strength (p = 0.014), increased number of disabilities (p=0.005), and more depressive symptoms (p = 0.002). Multivariate regression analysis, adjusted for demographic and clinical characteristics, demonstrated strong associations for reduced hemoglobin, even within the "normal" range, and poorer health-related quality of life across multiple domains. Thus, anemia was independently associated with clinically significant impairments in multiple domains of health-related quality of life, especially in measures of functional limitation. Mildly low hemoglobin levels, even when above the World Health Organization (WHO) anemia threshold, were associated with significant declines in quality of life among the elderly.
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BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoetic stem cell transplants.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-04-2009
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BK virus (BKV) is an important pathogen and cause of nephropathy in renal transplant recipients, but its significance following hematopoetic stem cell transplantation (HSCT) is less well described. We measured blood and urine BKV in 124 allogeneic HSCT patients (67 had undergone prior HSCT [surveillance cohort]; 57 were monitored from transplant day 0 [prospective cohort]). BK viruria was manifest in 64.8% of the patients; 16.9% developed viremia. In the prospective cohort, the median time from transplantation to BK viremia development (128 days) was longer than for viruria (24 days; P < .0001). Among clinical factors (sex, disease, transplant type, alemtuzumab use, cytomegalovirus [CMV] viremia, graft-versus-host disease [GVHD], donor HLA C7 allele), only CMV viremia was more common in patients with BKV infection (P < or = .04). There was a direct relationship between blood and urine BKV levels and the occurrence, and degree, of hematuria (P < or = .03). Finally, BKV infection was analyzed along with other clinical factors in relation to the development of post-HSCT renal impairment. On multivariate analysis, only BK viremia (P=.000002) and alternative-donor transplantation (P=.002) were independent predictors of development of post-HSCT renal impairment, with BK viremia associated with a median 1.62mg/dL rise in creatinine from the pretransplant baseline. Among 8 patients in the surveillance cohort with BK viremia, 2 developed biopsy-proven BKV nephropathy requiring hemodialysis. Investigation of whether prophylaxis against, or treatment of, BKV in the post-HSCT setting mitigates the associated morbidities, especially kidney injury, warrants prospective evaluation.
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Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting long-term outcomes.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-27-2009
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The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.
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Allogeneic stem cell transplantation with alemtuzumab-based conditioning for patients with advanced chronic myelogenous leukemia.
Leuk. Lymphoma
PUBLISHED: 01-15-2009
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for patients with chronic myelogenous leukemia (CML) who have failed or are intolerant to tyrosine kinase inhibitors (TKI). Myeloablative conditioning regimens have been associated with high treatment-related mortality (TRM) rate in such patients, and reduced-intensity conditioning (RIC) regimens are often preferred but have high rates of disease recurrence and graft-versus-host-disease (GVHD). We report our experience with nine CML patients (four chronic phase and five with accelerated phase or blast crisis) who failed TKI and underwent allo-HSCT using an alemtuzumab-based RIC regimen. The conditioning regimen was well tolerated and induced engraftment in all patients, and complete cytogenetic remission (CCyR) in eight of nine. Four patients, all with a history of accelerated phase or blast crisis, died. Four of the five remaining patients had a cytogenetic relapse a median of 10 months after transplantation. Donor lymphocyte infusion (DLI), TKI or both induced a CCyR in all cases. With a median follow-up of 47 months, five patients, including all those transplanted in first or second chronic phase, are alive and in remission. Allo-HSCT with an alemtuzumab-based conditioning regimen induces remission in patients with CML that have failed TKI therapy and has a low incidence of GVHD. Disease recurrence is frequent but responds to DLI. In some cases, restoration of susceptibility to TKI was observed. Outcomes may improve with the routine administration of post-transplant TKI.
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Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients.
Biol. Blood Marrow Transplant.
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Comprehensive geriatric assessment (CGA) is frequently used in oncology to measure the health status of older adults with cancer, but it has not been studied in allogeneic hematopoietic cell transplantation (HCT). We conducted a prospective pilot study of CGA in allogeneic HCT recipients aged ?50 years to examine the prevalence of vulnerabilities in this population. Patients aged ?50 years eligible for HCT were enrolled. CGA consisted mainly of self-reported, performance-based, and chart-extracted measures evaluating domains of comorbidity, physical and mental function, frailty, disability, and nutrition. Of 238 eligible patients, 166 completed CGA and underwent HCT. Only 1% had a Zubrod Performance Status score >1; 44% had high comorbidity defined by the Hematopoietic Cell Transplantation Comorbidity Index, and 66% had high comorbidity defined by the Cumulative Illness Rating Scale-Geriatrics. The presence of additional vulnerability was frequent. Disability was present in 40% by Instrumental Activities of Daily Living. Self-reported physical and mental function were significantly lower than population age group norms, 58% were pre-frail, and 25% were frail. Among those with Zubrod Performance Status score of 0, 28% demonstrated disability, 58% were pre-frail, 15% were frail, 35% reported low physical function, and 55% reported low mental function. CGA uncovers a substantial prevalence of undocumented impairments in functional status, frailty, disability, and mental health in older allogeneic HCT recipients.
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Umbilical cord blood transplantation supported by third-party donor cells: rationale, results, and applications.
Biol. Blood Marrow Transplant.
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Low incidence of graft-versus-host disease provides the major rational for pursuing umbilical cord blood (UCB) stem cell transplantation (SCT). Considerable evidence also suggests a lower rate of recurrence after UCB SCT than after transplantation from adult donors. Recent advances in understanding of the human fetal immune development provide a rational underpinning for these clinical outcomes. The fetal immune system is geared toward maintaining tolerance to foreign antigens, particularly to the maternal antigens to which it is exposed throughout gestation. To this purpose it is dominated by a unique population of peripheral T regulatory cells that actively maintain tolerance. This and other features of the UCB lymphoid system explains the low incidence of graft-versus-host disease and superior outcomes of UCB SCT with noninherited maternal antigen-matched grafts. At the same time, highly sensitized maternal microchimeric cells are frequently detected in UCB and likely contribute to superior graft-versus-leukemia effects and low rates of disease recurrence in inherited paternal antigen-matched UCB recipients. However, historically erratic and slow hematopoietic recovery after UCB SCT leads to increased early morbidity and mortality, excessive hospitalization, and increased costs. This has held up the widespread utilization of UCB SCT in adults. Here we summarize recent data on UCB SCT with an emphasis on studies of co-infusion of adult CD34 selected hematopoietic stem cells with UCB SCT. This procedure, through transient engraftment of adult hematopoietic stem cells, largely overcomes the problem of delayed engraftment. It also results in predictable engraftment of a UCB with the desired characteristics. We also briefly discuss unresolved issues and possible future applications of this technology.
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Influence of related donor age on outcomes after peripheral blood stem cell transplantation.
Cytotherapy
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The rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34(+)cell dose, has not been well-characterized.
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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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Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant.
Leuk. Lymphoma
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Most cases of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occur <21 days after allogeneic hematopoietic stem cell transplant (HCT). Rarely, however, VOD/SOS can occur later, and can be confused with other causes. We report the clinicopathologic features of eight patients with advanced hematologic malignancies developing VOD/SOS >30 days after dose-escalated busulfan/fludarabine/alemtuzumab and HCT. Median time to diagnosis was 52 days (range: 33-77). For seven patients, VOD/SOS was confirmed by liver biopsies showing classical features including reticulin deposition within sinusoids, central vein occlusions, hepatocyte atrophy/necrosis, sinusoidal/perivenular hemorrhage and sparing of portal tracts. VOD/SOS risk was directly related to higher busulfan plasma exposures. Two patients died from VOD/SOS, and in another two patients VOD/SOS was contributory to death. Late-onset VOD/SOS may be underrecognized and should be considered in the differential diagnosis of patients undergoing HCT, particularly after high dose busulfan. Liver biopsy should be entertained even late in the course if appropriate signs/symptoms exist.
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