The EASIX (Endothelial Activation and Stress Index) score has been shown to be associated with NRM and overall survival (OS) after reduced intensity alloHCT. We aimed to validate EASIX in patients ...who underwent a calcineurin-inhibitor (CNI)-free alloHCT using ex-vivo CD34-selection.
We included 364 adult patients who underwent first CD34-selected alloHCT between July 2006-December 2016 using the CliniMACS CD34 Reagent System (Miltenyi Biotech) as GVHD prophylaxis. The EASIX score (LDH*Creatinine/platelet counts) was calculated at several timepoints (pre-HCT day -30 to day -10, day 30, day 100 and onset of acute GVHD). For EASIX scores post-HCT, a landmark analysis was conducted at the given timepoint. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. The Kaplan-Meier and cumulative incidence methods were used to estimate OS and NRM/acute GVHD, respectively. Cox models (cause-specific for NRM and acute GVHD) were used to evaluate differences in outcomes. Relapse and death or relapse, were considered competing risks for NRM and acute GVHD, respectively.
Median age was 55 years (range 19-73). Most patients had myeloid diseases (47% AML, 28% MDS and 4% CML) and all patients received myeloablative conditioning (MAC). With a median follow-up among survivors of 4.7 years (range, 0.7-11.8), 1 and 3-year OS was 78.6% (95% confidence interval CI, 74.0-82.4) and 61.8% (95% CI, 56.5-66.7), respectively. The cumulative incidence of NRM at 1 and 3 years was 15.1% (95% CI, 11.7-19.0) and 24.2% (95% CI, 19.9-28.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4, and 3-4 acute GVHD were 40.1% (95% CI, 35.1-45.1), 29.4% (95% CI, 24.8-34.1) and 11.0% (95% CI, 8.0-14.5), respectively.
Pre-HCT EASIX was not significantly associated with OS, NRM, or acute GVHD. A higher day 30 EASIX score was significantly associated with increased risk of death (HR=1.35 95% CI, 1.19-1.52, p<0.001) and NRM (HR=1.56 95% CI, 1.35-1.80, p<0.001; Table 1, Figures 1-2). A higher day 100 EASIX score similarly resulted in an increased risk of NRM and death (p<0.001)
EASIX score at day 30 and at day 100 post-ex-vivo CD34-selected alloHCT is associated with higher NRM and inferior OS. Despite a CNI-free platform, endothelial injury is an important contributor to poorer outcomes after MAC. EASIX provides a simple, complimentary tool to predict allo-HCT outcomes in these patients.
The trajectory of functional decline and the prevalence of geriatric syndromes have not been examined among long-term survivors of older allo-HCT recipients. We previously described significant ...burden and adverse impact of post-transplant geriatric syndromes, delirium and fall, among older allogeneic recipients. We report here theprevalence and impact of geriatric syndromes in 2-year, progression-free survivors among this cohort of patients using our institutional database. Baseline characteristics, transplant outcomes, geriatric assessment domains, and geriatric syndromes were obtained and analyzed as previously described.
We identified 199 2-year, progression-free survivors of patients allografted at age ≥60 years from 2001 to 2016, including 111 out of 241 patients on the CD34+ selection platform (46%), and 88 out of 231 T-cell replete patients (38%). The median age at allo-HCT was 65.4 years (range 60 – 78.7); 73% had myeloid malignancies; 69% had high/very high risk HCT-CI/age; 14% had a mismatched donor; and 56% had a CD34+ selected graft. With a median follow-up of 5.7 years for survivors, the 3-yr OS and RFS from the 2-year landmark was 86% (95% CI, 80 – 91) and 83% (95% CI, 78 – 89). Thirty-three patients died, including 8 from relapse/disease progression, and 25 from non-relapse mortality (6 each from secondary neoplasm, organ failure, and infections). The 3-year cumulative incidence of new functional impairment (FI), defined as new admission to skilled nursing facility, fall, or assisted walking device from the 2-year landmark, was 20% (95% CI, 15 – 27). In addition, the 3-year cumulative incidence of new psychiatric illness and cognitive decline was 6% (95% CI, 3 – 11) and 5% (95% CI, 3 – 10), respectively (Figure 1). We examined factors associated with new FI and found that, among others, patients who were transplanted with a CD34+ selected graft had lower incidence of new FI in univariate (hazard ratio HR=0.49, 95% CI 0.28 – 0.86, P=0.014) and multivariate analysis with borderline significance (HR=0.53, 95% CI 0.27 – 1.02, P=0.056). In 2-year landmark analyses, both high/very high HCT-CI/age index and mismatched donor were significantly associated with inferior OS and RFS (Table 1).
While limited by the single institution, retrospective design, heterogenous transplant approach, and likely under-reporting, our findings nevertheless illustrate the high prevalence of FI among older allo-HCT survivors, which maybe attenuated by the CD34+ selection platform. In addition, the impact of graft-versus-host disease on the development of geriatric syndromes merits closer examination. While requiring prospective confirmation, long-term functional impairment should be considered as an important secondary outcome when comparing curative strategies to other less intense approaches in older patients with hematologic malignancies.
Patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have historically shown very poor ...post-relapse overall survival (prOS).
To study the factors and treatment strategies associated with the best prOS.
We conducted a retrospective analysis of all pts at our institution who received a first allo-HCT between 2010 and 2017 for AML or MDS but relapsed post-transplant. Bone marrow (BM) and peripheral blood stem cells (PBSC) grafts were included, either T-cell depleted (TCD) by ex-vivo CD34+ selection (Miltenyi CliniMACS) or unmodified. Univariate (UVA) Cox proportional hazards regression was used to examine the association between prOS and patient-, disease-, and transplant-related variables. Receipt of second cell therapy (sCT) after relapse was a time-dependent covariate.
Key characteristics of the study population are listed in Table 1.
Median time to relapse (TTR) was 6 months (range: 1-61) and median prOS was also 6 months (95%CI: 4.8-8.8) in the whole population. AML pts showed shorter median prOS compared with MDS pts (5.3 95%CI: 3.9-8 vs. 9.4 95%CI: 5.7-24 months, p=0.026).
No statistically significant associations were observed between prOS and conditioning intensity (reduced vs. ablative) or graft manipulation (TCD vs. unmodified). There was a significant association between TTR and prOS (Fig. 1).
Forty-five pts received sCT after relapse, either a second allo-HCT (28) or donor lymphocyte infusions (17). The hazard of death after relapse for these patients was lower (HR 0.53, 95%CI: 0.32-0.87, p=0.01) and 2-year survival after sCT was 44.9% (95%CI: 31.1-64.8, Fig. 2).
We used a 4-level categorization of TTR (</≥ 12 months) and receipt of sCT. Compared to the reference (TTR < 12 months and no sCT), the most favorable combination for prOS resulted TTR ≥ 12 months and receiving sCT (HR 0.28, 95%CI: 0.13-0.6, p=0.001, Fig. 3).
Although limited by the retrospective nature and potential selection bias, we show in a large, contemporary cohort that pts who relapse after ≥ 12 months from a first allo-HCT and receive sCT have the best prOS.
Cytokine release syndrome (CRS) and immune effector cells associated neurotoxicity syndrome (ICANS) are common CAR T cells toxicities. Various grading systems that attribute different grades of ...severity to symptoms are currently used, preventing comparisons of different products and possibly leading to management implications.
We included 53 patients (pts) with B acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T cells (NCT01044069) and 49 pts with diffuse large B cell lymphoma (DLBCL) who received axicabtagene ciloleucel (axi-cel, n=36) or tisagenlecleucel (tisa-cel, n=13) after FDA approval. CRS and ICANS were retrospectively graded according to the new ASTCT consensus grading system, for comparison with other available systems: Lee, Penn, Memorial Sloan Kettering Cancer Center, CARTOX and CTCAEv5.0 for CRS; CTCAEv4.03 and CARTOX for ICANS. We then used ASTCT grades to predict management according to current guidelines for DLBCL pts (axi-cel and tisa-cel insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our center.
According to the ASTCT grading, B-ALL pts had 87% CRS (28% grade ≥3), while DLBCL pts had 86% CRS (14% grade ≥3) with axi-cel, and 54% (no grade ≥3) with tisa-cel. B-ALL pts had 55% ICANS (45% grade ≥3), while DLBCL pts had 55% ICANS (33% grade ≥3) with axi-cel, and 15% with tisa-cel (no grade ≥3) (fig. 1). When comparing grading systems, agreement on CRS and ICANS diagnosis was found in 99% and 91% cases, respectively. However, when evaluating toxicities grade by grade, only 27% pts had the same grade in each system for CRS, and 55% for ICANS (fig. 2).
When predicting management for DLBCL pts, we found some relevant differences across current guidelines (fig. 3). At our center 58% and 13% of patients with CRS received tocilizumab (toci) and steroids, respectively, similarly to what predicted according to axi-cel's, CARTOX and NCCN guidelines, but differently from tisa-cel's label (10% and 5%). For ICANS, while tisa-cel's label does not provide any recommendations, other guidelines-based predictions were mostly overlapping. Indications for treatment vary across current guidelines, which were developed on single products and different grading systems, thus, should not be universally applied. This discrepancy becomes particularly relevant for cases with discordant CRS/ICANS grades. As such, we gave toci to 66% pts upgraded to grade 3 by Penn (grade 2 by ASTCT), while they would receive both toci and steroids according to axi-cel/CARTOX/NCCN guidelines, but would not be treated according to tisa-cel's.
Different grading systems provide inconsistent CRS/ICANS scores. To avoid discrepancies in assessing and managing toxicities of different products, a unified grading should be used and paired management guidelines with product-specific indications should be developed.
The BMT CTN 0901 phase 3 trial showed improved relapse-free survival (RFS) in patients with AML or MDS with myeloablative-conditioning (MAC) vs. Reduced intensity conditioning (RIC) allogeneic ...hematopoietic cell transplantation (allo-HCT). However, overall survival (OS) increase was not statistically significant because of higher non-relapse mortality (NRM) compared to RIC allo-HCT. HCT-CI ≥ 3 also predicts for poor OS related to high NRM in patients undergoing MAC CD34+ selected allo-HCT.
We aimed to evaluate impact on OS, NRM and RFS of MAC CD34+ selected vs. RIC allo-HCT in patients with high comorbidity burden.
We retrospectively compared the outcomes of 221 patients with AML or MDS with HCT-CI ≥ 3 who underwent MAC CD34+ selected (n=157) vs. RIC allo-HCT (n=64) at our institution from 2009 to 2017. The indication for MAC CD34+ vs. RIC allo-HCT was based on multidisciplinary consensus and primary physician's choice.
Patients in the RIC group were older, had a higher proportion of high disease risk index (DRI), and higher use of matched unrelated donors compared to the MAC CD34+ group. HCTCI grades were balanced between the two cohorts, but the RIC group had a higher though non-significant proportion of patients with HCTCI > 5 (Figure 1). When comparing the MAC CD34+ vs. unmodified RIC cohorts, respectively, no difference was seen in OS 43% (95% CI 32-59) vs. 53% (95% CI 46-52), p=0.37, NRM 31% (95% CI 19-44) vs. 30% (95% CI 23-38), p=0.74, and relapse-free survival (RFS) 34% (95% CI 23-49) vs. 48% (95% CI 41-57) p=0.1, even when adjusting for age, DRI, and donor differences (Figure 2). However, incidence of acute and chronic graft versus host disease (GVHD) was lower for MAC CD34+ allo-HCT. When evaluating outcomes by HCT-CI subgroups (3, 4-5 and >5), MAC CD34+ allo-HCT resulted in higher 3-year estimated RFS 54% (95% CI 44-68) vs. 28% (95% CI 14-58), p=0.03 in patients with HCT-CI = 3, though this did not translate into an OS advantage 44% (95% CI 27-73) vs 59% (95% CI 48-72), p=0.26, possibly related to higher though non-significant NRM 16% (95% CI 4-35) vs. 28% (95% CI 18-39), p=0.26 (figure 3). When adjusting for differences in age, DRI, and donor, the difference in RFS was no longer statistically significant (p=0.13).
Though limited by their retrospective nature, our data suggest that CD34+ selected allografts after myeloablative conditioning can be feasible in selected patients with comorbidity scores over 3 with low rates of acute and chronic GVHD. However, further prospective studies are needed to reduce NRM and optimize this treatment platform in older patients with comorbidities.
The present study describes the harnessing of revalued cow milk (denoted as waste milk) for fabricating casein fibers (CAS) with enhanced mechanical performance and antibacterial properties by the ...electrospinning method. For this purpose, polyethylene oxide (PEO) was employed (10 and 20 wt%) as a binder for the appropriate electrospun CAS fibers. Different amount of tannic acid (TA) was incorporated into casein/polyethylene oxide fibers (CAS/PEO) as a crosslinker agent, bringing filaments with a diameter of ca. 2 µm. The incorporation of 4 wt% of TA promotes the fibers' reticulation, forming a stable three-dimensional network. Also, the mechanical performance of CAS/PEO fibers was improved, where the tensile strength was increased from 0.91 MPa to 1.88 MPa with 4 % of TA, while the breaking elongation was increased from 93.74 % to 274.56 %. This behavior benefits the processing of fibers by electrospinning. Furthermore, the TA addition during the electrospun of CAS/PEO fibers enhances fibers' wettability properties and thermal stability induced by the crosslinker agent. Additionally, the antibacterial activity (AA) test demonstrates that CAS fibers can inhibit the growth of Gram-positive S. aureus and Gram-negative E. coli after 0.5 h, 1.5 h, 3 h, and 24 h of contact, which is generated by the TA addition. Our results suggest that the electrospun fabrication of CAS/PEO fibers with TA as a crosslinker agent represents an innovative harnessing of waste milk to produce functional textiles with potential biological application.
Laura Gochicoa-Rangel, Santiago C. Arce, Carlos Aguirre-Franco, Wilmer Madrid-Mejía, Mónica Gutiérrez-Clavería, Lorena Noriega-Aguirre, Patricia Schonffeldt-Guerrero, Agustín Acuña-Izcaray, Arturo ...Cortés-Telles, Luisa Martínez-Valdeavellano, Federico Isaac Hernández-Rocha, Omar Ceballos-Zúñiga, Rodrigo Del Rio Hidalgo, Sonia Sánchez, Erika Meneses-Tamayo, and Iván Chérrez-Ojeda; and on Behalf of the Respiratory Physiology Project in COVID-19 (FIRCOV). Effect of altitude on respiratory functional status in COVID-19 survivors: results from a Latin American Cohort-FIRCOV.
24:37-48, 2023. Persistent symptoms and lung function abnormalities are common in COVID-19 survivors.
To determine the effect of altitude and other independent variables on respiratory function in COVID-19 survivors.
Analytical, observational, cross-sectional cohort study done at 13 medical centers in Latin America located at different altitudes above sea level. COVID-19 survivors were invited to perform pulmonary function tests at least 3 weeks after diagnosis.
1,368 participants (59% male) had mild (20%), moderate (59%), and severe (21%) disease. Restriction by spirometry was noted in 32%; diffusing capacity of the lung for carbon monoxide (DLCO) was low in 43.7%; and 22.2% walked less meters during the 6-minute walk test (6-MWT). In multiple linear regression models, higher altitude was associated with better spirometry, DLCO and 6-MWT, but lower oxygen saturation at rest and during exercise. Men were 3 times more likely to have restriction and 5.7 times more likely to have a low DLCO. Those who had required mechanical ventilation had lower DLCO and walked less during the 6-MWT.
Men were more likely to have lower lung function than women, even after correcting for disease severity and other factors. Patients living at a higher altitude were more likely to have better spirometric patterns and walked farther but had lower DLCO and oxygen saturation.
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