Introduction: Given limited prior data, we aimed to analyze all high-grade toxicities and associated risk factors after myeloablative conditioned (MAC) allo-HCT with ex-vivoCD34+ selection as GVHD prophylaxis. Methods: We retrospectively collected all grade ≥3 toxicities by CTCAE v4.0 of 131 adults who underwent ex-vivo CD34+ selected (CliniMACS¨ CD34 Reagent System) MAC allo-HCT between 2006-2012 and who were alive without relapse/progression at 1-year (yr) post-allo-HCT. Individual toxicities after 1-yr were modeled using time-dependent covariates in Cox proportional hazards regression. Results: We included 97 patients (pts) with AML/ALL/MDS (74%), 15 with myeloma (11%), and 19 with other hematologic malignancies (15%). Median age was 54 (19-72) and median HCT-CI was 2 (0-10). Donor allografts were HLA matched related in 51 pts (39%), mismatched (MM) related in 1 pt, matched unrelated in 53 (40%), or MM unrelated in 26 (20%). The incidence of grade 2-4 acute GVHD (aGVHD) and grade 3-4 aGVHD at day 100 was 10% and 3%, respectively. Grade 2-4 late aGVHD was seen in 14%. At 4 yrs, OS and PFS for the cohort were 77% and 70%, respectively (Figure 1), with 9 (7%) dying of relapsed disease and 20 (15%) of NRM. In a univariate analysis, having a HCT-CI ≥3 [HR 2.9 (.9-6.6), P = .04] prior to HCT or grade 2-4 GVHD in the first yr post-HCT [HR 3.5 (1.7-7.3), P = .001] was associated with poorer OS. Higher NRM was associated with HCT-CI ≥ 3 [HR 5.3 (1.2-23), P = .004] and grade 2-4 GVHD in the first yr [HR 5.9 (2.4-14.3), P < .001]. The median number of toxicities per pt in the first yr was 7. Pts with >7 toxicities had a 4-yr OS of 67% versus 86% [HR 3.2 (1.4-7.2), P = .006] (Figure 2) and higher NRM [HR 4.8 (1.6-14.4), P = .005]. Poorer OS and higher NRM were associated with incurring cardiovascular (CV), hematologic, hepatic, infectious, metabolic, neurologic or pulmonary toxicities after the first yr. Due to univariate associations and overall sample size, two different multivariate (MV) models were investigated: the first analyzed the association between individual toxicities and the risk of death and NRM while adjusting for HCT-CI; the second analyzed similar associations but adjusted for grade 2-4 GVHD in the first yr. In the MV model adjusting for HCT-CI, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities after 1-yr all increased the risk of OS and NRM (Figure 3). All toxicities remained significant for both outcomes in the second model adjusting for GVHD (not shown).Figure 3Significant associations of toxicities and HCT-CI with outcome.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: One-yr survivors of ex-vivo CD34+ selected allo-HCT have excellent OS, low rates of GVHD, and a toxicity burden comparable to unmanipulated MAC allo-HCT based on historical BMT CTN data. Pts with poor HCT-CI or those who develop GVHD are at risk for late toxicities, poorer OS and higher NRM. Identification of these pts for targeted survivorship care may further improve long-term outcomes.
Abstract To determine the extent intrinsic erythrocyte defects and/or extrinsic factors were involved in anemia of rats bearing Shay chloroleukemia (SCL), survival of 3 H‐DFP labeled erythrocytes was studied in leukemic and non‐leukemic hosts. Red blood cells labeled before induction of leukemia, were rapidly lost from the peripheral circulation of SCL rats in terminal stages of disease. However, labeled erythrocytes from terminal SCL animals displayed normal lifespans when transfused into nonleukemic controls. Thus the anemia of this leukemia probably resulted from extrinsic factors associated with the leukemic process. Hemorrhage appeared to be primarily responsible for the anemia of this disease.
The effects of alcohol on bone marrow are not well understood. We measured the influence of ethanol and its metabolite, acetaldehyde, on the in vitro proliferation of hematopoietic progenitor cells from mice and human beings. Colony formation by both early and late erythroid progenitor cells was suppressed by concentrations of ethanol (0.05 to 0.2 per cent) that are easily achieved in vivo. The corresponding suppressing concentration of acetaldehyde was 0.001 per cent. In contrast, suppression of granulocyte/macrophage progenitor cells required 3.0 per cent ethanol or 0.03 per cent acetaldehyde. Spleen colony formation by pluripotent stem cells was resistant to concentrations of ethanol and acetaldehyde that suppressed in vitro colony formation of committed myeloid and erythroid progenitor cells by 50 per cent. The suppression of both myeloid and erythroid colony formation was partially reversed by supplementing the cultures with folinic acid or pyridoxine. These data provide an explanation for the preferential suppression of erythropoiesis observed clinically in ethanol abuse. They also suggest that acetaldehyde has a role in ethanol-mediated bone-marrow suppression. (N Engl J Med. 1982; 307:845–9.)
The decline in students' interest in science and technology is a major concern in the western world. One approach to reversing this decline is to introduce modern physics concepts much earlier in the school curriculum. We have used the context of the recent discoveries of gravitational waves to test the benefits of one-day interventions, in which students are introduced to the ongoing nature of scientific discovery, as well as the fundamental concepts of quantum physics and gravitation, which underpin these discoveries. Our innovative approach combines role-playing, model demonstrations, single photon interference and gravitational wave detection, plus simple experiments designed to emphasize the quantum interpretation of interference. We compare understanding and attitudes through pre and post testing on four age groups (school years 7, 8, 9 and 10), and compare results with those of longer interventions with Year 9. Results indicate that neither prior knowledge nor age are significant factors in student understanding of the core concepts of Einsteinian physics. However we find that the short interventions are insufficient to enable students to comprehend more derived concepts.
Criteria for selecting cord blood (CB) units with high engraftment potential are not established. We investigated the donor variables associated with neutrophil engraftment in recipients of myeloablative double-unit CB transplantation at our transplant center (TC) and then evaluated whether these unit characteristics could be reliably determined at the time of unit selection in 402 CB units thawed at our TC from 10/2005-06/2013. The cumulative incidence of neutrophil engraftment in 130 recipients was 95% (95%CI: 90-98). In multivariate analysis, only the dominant unit infused viable CD34+ cell dose/kg independently influenced engraftment [HR 1.95, p = 0.001] (Figure). We then analyzed the components of infused viable CD34+ cell dose (i.e. post-thaw CD34+ cell count and percent viability) in 402 units (302 domestic and 100 international) from 43 Banks thawed at our TC. Bank CD34+ cell count correlated with post-thaw measurements (r2 = 0.6, p < 0.001). The median CD34+ cell recovery was 101% but ranged 12-1480%. Recovery < 65% occurred less frequently in units from FACT-accredited Banks. Moreover, while the median post-thaw CD34+ cell viability was 92%, 33 (8%) units had < 75% viable CD34+ cells post-thaw. Bank FACT accreditation and CB unit cryovolume were significantly associated with post-thaw viability (Table). Bank location (all domestic vs. all international), shipping distance (local vs. distant international) and duration of cryopreservation were not associated with viability. Infused viable CD34+ cell dose was the critical determinant of engraftment, and CD34+ cell count recovery and viability were linked to differences in banking practices. These findings have significant implications for banking and CB unit selection. At our TC, we now prioritize standard 25ml units from FACT-accredited banks and strongly consider the CD34+ cell dose. However, with such a practice, TC must be able to react to lower than expected post-thaw CD34+ cell counts and/or low CD34+ cell viability. This requires measurement of the infused viable CD34+ cell dose (or another rapidly available measure of potency) on transplant day and a back-up strategy in case of a compromised unit. This is even more critical in single-unit CBT in which engraftment is solely dependent on a single unit.Tabled 1N UnitsN (%) with <75% CD34+ Cell ViabilityUnivariate p value∗Multivariate p value∗∗FACT accreditation at time of unit collectionYes2598 (3%)Ref.<0.001No14325 (18%)<0.001Year of cryopreservation1997 - 20026111 (18%)0.009NS2003 - 201234122 (7%)Ref.Cryopreserved volume (ml)< 24.5145 (36%)<0.0010.02824.5 - 25.52748 (3%)Ref.25.6 - 30595 (9%)0.06>305515 (27%)<0.001Method of processingManual17822 (12%)0.003NSSemi-automated302 (7%)0.62Automated1837 (4%)Ref.Not RBC depleted61 (17%)0.23Unknown51 (20%)0.20∗ Fisher's exact test ∗∗ Linear Regression Open table in a new tab
