Generating derivative structures: Algorithm and applications

We present an algorithm for generating all derivative superstructures--for arbitrary parent structures and for any number of atom types. This algorithm enumerates superlattices and atomic configurations in a geometry-independent way. The key concept is to use the quotient group associated with each superlattice to determine all unique atomic configurations. The run time of the algorithm scales linearly with the number of unique structures found. We show several applications demonstrating how the algorithm can be used in materials design problems. We predict an altogether new crystal structure in Cd-Pt and Pd-Pt, and several new ground states in Pd-rich and Pt-rich binary systems

Embedding Four-directional Paths on Convex Point Sets

A directed path whose edges are assigned labels "up", "down", "right", or "left" is called \emph{four-directional}, and \emph{three-directional} if at most three out of the four labels are used. A \emph{direction-consistent embedding} of an \mbox{$n$-vertex} four-directional path $P$ on a set $S$ of $n$ points in the plane is a straight-line drawing of $P$ where each vertex of $P$ is mapped to a distinct point of $S$ and every edge points to the direction specified by its label. We study planar direction-consistent embeddings of three- and four-directional paths and provide a complete picture of the problem for convex point sets.Comment: 11 pages, full conference version including all proof

Haploidentical transplantation in primary refractory/relapsed secondary vs de novo AML: from the ALWP/EBMT

We compared the outcomes of haploidentical stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) in 719 patients with primary refractory (PR) or first relapse (Rel) secondary acute myeloid leukemia (sAML; n = 129) vs those with de novo AML (n = 590), who received HSCT between 2010 and 2022. A higher percentage of patients with sAML vs de novo AML had PR disease (73.6% vs 58.6%; P = .002). In 81.4% of patients with sAML, the antecedent hematological disorder was myelodysplastic syndrome. Engraftment was 83.5% vs 88.4% in sAML and de novo AML, respectively (P = .13). In multivariate analysis, haplo-HSCT outcomes did not differ significantly between the groups: nonrelapse mortality hazard ratio (HR), 1.38 (95% confidence interval [CI], 0.96-1.98; P = .083), relapse incidence HR, 0.68 (95% CI, 0.4.7.-1.00; P = .051). The HRs for leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)–free, and GVHD and relapse–free survival were 0.99 (95% CI, 0.76-1.28; P = .94), 0.99 (95% CI, 0.77-1.29; P = .97), and 0.99 (95% CI, 0.77-1.27; P = .94), respectively. We conclude that outcomes of haplo-HSCT with PTCy are not different for PR/Rel sAML in comparison with PR/Rel de novo AML, a finding of major clinical importance

Impact of debulking therapy on the clinical outcomes of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T -cell therapy, was approved for relapsed/refractory (R/R) large B -cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received >= 3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/RGDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for >= 8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade >= 3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade >= 3. Cytopenias were the most frequent grade >= 3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade >= 3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade >= 3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment -emergent AEs than those who received radiotherapy only. At the 24 -month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression -free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real -world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here

Haploidentical stem cell donor choice for patients with acute myeloid leukemia: a study from the ALWP of the EBMT

There is a paucity of information to guide the selection of the most suitable donor in haploidentical (Haplo) hematopoietic stem cell transplantation (HSCT). For this reason, from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we conducted a retrospective analysis to evaluate the impact of Haplo donor characteristics on outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease prophylaxis with posttransplant cyclophosphamide (PTCy). The primary end point was graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS). Overall, 2200 patients were included. The median age of donors was 37 years (range, 8-71); 820 (37%) were females, including 458 (21%) who were used for male recipients. In addition, 1631 donors (74%) donated peripheral blood (PB). Multivariable analysis identified certain donor-related risk factors with a detrimental impact on transplant outcomes. The use of PB, older donors’ ages (>37 years), and female donors to male recipients negatively affected GRFS. Donor’s age and female donor-to-male recipient combination also affected nonrelapse mortality, leukemia-free survival, and overall survival. In conclusion, donor-related variables significantly influence outcomes in patients with AML after Haplo-HSCT with PTCy. When possible, younger donors and male donors for male recipients should be prioritized. The use of bone marrow can additionally prevent GVHD

Significance of Degree of HLA Disparity Using T-cell Replete Peripheral Blood Stem Cells from Haploidentical Donors with Posttransplantation Cyclophosphamide in AML in First Complete Hematologic Remission: A Study of the Acute Leukemia Working Party of the EBMT

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2-3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2-3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2-3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2-4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2-3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS

Long-term outcomes of patients with large B-cell lymphoma treated with axicabtagene ciloleucel and prophylactic corticosteroids

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel–related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.</p

Donor KIR genotype based outcome prediction after allogeneic stem cell transplantation:no land in sight

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor’s Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.</p

Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Non peer reviewe