31 research outputs found
Establishing a Target Exposure for Once-Daily Intravenous Busulfan Given with Fludarabine and Thymoglobulin before Allogeneic Transplantation
AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD
Recommended from our members
Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.
HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P 5 .15), leukemia-free survival (P 5 .50), nonrelapse mortality (P 5 .16), relapse (P 5 .90), or grade II-IV acute GVHD (P 5 .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P, .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients. © 2019 American Society of Hematology. All rights reserved
Recommended from our members
Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study
Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat
Recommended from our members
Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study
The original version of this article unfortunately contained a mistake
Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study
Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat
Influence of Fludarabine Pharmacokinetics on Outcome of Allogeneic Stem Cell Transplantation with Fludarabine-Busulfan Conditioning
Recommended from our members
Maintenance tyrosine kinase inhibitors following allo-HCT for chronic myeloid leukemia: A CIBMTR Study.
It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myeloid leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML transplanted from 2007-2014 who received maintenance TKI following HCT (n=89) as compared to no TKI maintenance (n=301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy prior to HCT. The majority of patients had disease beyond CP1 at HCT (n=240, 62%). The study was conducted as a landmark analysis, excluding patients that died, relapsed, had chronic graft-versus-host disease or were censored prior to Day 100 following HCT. Of the 89 patients receiving TKI maintenance, 77 (87%) received a single TKI while 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n=50), imatinib (n=27) and nilotinib (n=27). As measured from Day 100, the adjusted estimates for 5-year relapse (maintenance, 35% vs. no maintenance, 26%; p=0.11), leukemia-free survival (LFS, maintenance, 42% vs. no maintenance, 44%; p=0.65) or overall survival (OS, maintenance, 61% vs. no maintenance, 57%; p=0.61) did not significantly differ between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by the status of disease prior to transplant. In conclusion, our data did not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes in a Day 100 landmark analysis. The optimal approach to TKI administration in the post-transplant setting in CML remains undetermined
Allogeneic Transplantation for Adult Acute Leukemia in First and Second Remission with a Novel Regimen Incorporating Daily Intravenous Busulfan, Fludarabine, 400 CGY Total-Body Irradiation, and Thymoglobulin
Recommended from our members
SWOG S1203: A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy Versus Idarubicin with High Dose Cytarabine (IA) with or without Vorinostat (IA+V) in Younger Patients with Previously Untreated Acute Myeloid Leukemia (AML)
Abstract
Background: A majority of younger pts with AML receive initial therapy with a 7+3 scheme. Escalated doses of daunorubicin (dauno) in combination with standard doses of ara-C may lead to improved outcomes (Fernandez; NEJM 2009). A phase II trial of idarubicin and high-dose ara-C (IA) in combination with the histone deacetylase inhibitor vorinostat (IA+V) resulted in historically high response rates compared to IA or 7+3 (Garcia-Manero; JCO 2011). SWOG 1203 tested whether a high-dose ara-C induction with or without vorinostat could result in improved outcomes for younger AML pts compared to 7+3.
Methods: The primary endpoints were comparison of event-free survival (EFS) of 7+3 vs IA vs IA+V and evaluating the frequency of allogeneic hematopoietic cell transplantation. Secondary endpoints included toxicity, remission rate, relapse-free survival (RFS), and overall survival (OS) according to treatment arm, and by cytogenetic and molecular subgroups. Because of the historical trend of cured pts in S0106, EFS was modeled with an exponential cure model, and it was assumed IA or IA+vorinostat increased the proportion of pts cured from 35% to 45% and increased median EFS among those not cured from 4.7 months to 7.1 months. Main inclusion criteria included a diagnosis of previously untreated non-APL AML by WHO criteria, age 15 to 60 years, and preserved cardiac function but no severe comorbidities. Pts with known CBF rearranged or FLT3 mutant leukemias were eligible if no other alternative clinical trials existed. Treatment was as follows: Induction: 7+3 arm: dauno 90 mg/m2 IV QD x 3 on days 1-3 with ara-C CI 100 mg/m2 QD x 7 days on days 1 to 7. IA arm: ida 12 mg/m2 QD x 3 on days 1 to 3 with 24 hours CI ara-C 1.5 gm/m2 QD for 4 days on days 1 to 4. IA+vorinostat was as IA but with vorinostat 500 mg orally TID for 3 days on days 1 to 3. Consolidation: 7+3 arm: standard high-dose ara-c at 3 gm/m2 over 3 hrs q12 hours x 6 doses for 1 to 4 cycles depending on transplant availability. IA arm: idarubicin 8 mg/m2 IV QD x 2 days on days 1 to 2 with ara-C 0.75 gm/m2 CI for 3 days on days 1 to 3 for 4 cycles. The number of consolidation cycles depended on transplant indication; a secondary aim of the study was to transplant all cytogenetically-determined high risk pts (presented in a different abstract).
Results: Of 754 pts randomized, 738 were eligible (261 to 7+3, 261 to IA, and 216 to IA+V). Baseline characteristics were well balanced among all three groups. Most (75%) pts were between 40 and 60 years, 51% were male, median (range) WBC and platelets were 10.8 (0.3-800) and 49 (3-3900), respectively; marrow blast percentage was 60% (0%-100%); cytogenetics were favorable in 13% of pts, intermediate in 63%, and high-risk in 22%; FLT-3 was mutated in 21% and unknown in 31%; NPM1 was mutated in 20% and was unknown in 37%. Complete remission (CR) rates were 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). Significantly more pts received reinduction with 7+3 (24%) versus 11% with IA and 9% with IA+V (p=0.001). 48% of intermediate and unfavorable risk pts received transplant in CR1, with no significant differences among arms (p=0.44). There were no significant differences in EFS, RFS or OS among all three arms (Figure 1, all p>0.5). By cytogenetic or molecular group, there were no differences in outcome for any standard risk subset (FLT-3, NPM1, or CEBPα or cytogenetic subset), although pts with favorable cytogenetics had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (Figure 2, all p≤0.015). 30% of pts received 1 consolidation cycle, 18% 2, 16% 3, and 37% 4 cycles. Grade 5 induction toxicity rates were 4% (7+3), 8% (IA), and 9% (IA+V) by arm (p=0.07), and for toxicities related to therapy, 2%, 7%, 8%, respectively (p=0.01). Grade 4 induction toxicity rates were similar across arms (p=0.38).
Conclusion: Treatment with IA is not more effective than 7+3 in younger pts with AML. Outcomes with IA or IA plus vorinostat are similar. In pts with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation.
Clinical Trials Registry: NCT #0180233
Support: NIH/NCI grants CA180888, CA180819, CA18020, CA180821, CA180863, CA077202;
CCSRI grant #021039
Disclosures
Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy; BMS: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; Baxalta: Consultancy; Cyclacel: Research Funding; Celator: Research Funding; Abbvie: Research Funding; Ambit: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Lundbeck: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Ariad: Consultancy; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Agios: Research Funding; Jannsen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Agios: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Ariad: Consultancy; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB