Mixed Donor Research Articles

Limitations of Bu/Flu-based preparative regimen in CTLA-4 haploinsufficiency to achieving disease phenotype correction

BackgroundCTLA-4 haploinsufficiency (CTLA4-HI) is a broad immune dysregulation disorder characterized by multisystem autoimmunity and immune deficiency. In this report, we highlight the limitations of Busulfan-Fludarabine (Bu-Flu)-based conditioning regimens for HSCT in CTLA4-HI patients. MethodsThree patients with CTLA4-HI underwent HSCT at three centers between 2018–2019. Nine patients with nonmalignant disorders, without T cell (TC) dysregulation, who underwent allo-HSCT with Bu-Flu-based regimens were utilized as comparison. Further, we performed TC subset chimerism studies in CD4 recent thymic emigrants (RTE), CD4 and CD8 naïve TC cells, T regulatory cells (Tregs), circulating T follicular helper cells (cTfh), and CD4 and CD8 effector memory (EM). ResultsTwo patients (P1, P2) underwent MSD and 1 patient, MUD BM HSCT (P3). Cumulative Busulfan AUC was 66–95 mg*h/L and Fludarabine was 160 mg/m2. Only P1 and P2 had Alemtuzumab 0.3–0.48 mg/kg. Neutrophil (Day +18) and platelet (Day +24) engraftment was achieved in all patients with 100% donor myeloid chimerism. None had aGVHD. Mean TC chimerism at engraftment, 3 and 6 months, 1 year, 2 years, and last follow-up in the CTLA4-HI group was 20%, 26%, 25%, 45%, 46%, and 49%, respectively; lower than the comparison cohort – 59%, 52%, 70%, 87%, 93%, and 97%, respectively. With low TC chimerisms, all three patients had relapse of autoimmune manifestations, necessitating immune-modulatory therapy. No advantage of donor T cells in Treg, cTfh, CD4, or CD8 EM compartments was noted. P1 died unexpectedly at 25 months post-HSCT while still on sirolimus. P2 continues on medications for cytopenias. P3 came off sirolimus 3 years post-HSCT without autoimmune manifestations. CD4 RTE remains mixed donor (69%) >3 years post-HSCT (P2), suggesting incomplete thymic niche clearance, and chimerisms were only 54% in Tregs and 52% in cTfh. Correspondingly, P2 immunophenotype showed CD4 and CD8 activation with expansion of cTfh and decreased Treg frequency, suggesting ongoing immune dysregulation. ConclusionsIn our CTLA4-HI cohort, Bu-Flu-based conditioning resulted in inadequate immune ablation, low TC chimerisms, and incomplete or delayed disease phenotype correction. Moreover, no donor Treg benefit was noted in CTLA4-HI. Thus, in addition to augmenting immunoablation, strategies to enhance graft vs. immune dysregulation must be explored.

Type-1 regulatory T cells are critical for curative immunotherapy outcomes

Abstract IL-10 producing CD4 +type-1 regulatory T cells (Tr1) mediate immune tolerance during chronic infection, autoimmunity, and transplantation. We previously demonstrated that eomesodermin (Eomes) promotes Tr1 cell (Eomes +IL-10 +) development after allogenic bone marrow transplantation (alloBMT). Here we define the differentiation trajectory of Tr1 cells and the functional states therein. Eomes −IL-10 −, Eomes +IL-10 −and Eomes +IL-10 +subsets (defined by mCherry and GFP expression respectively) were FACS sorted after alloBMT and transferred into secondary recipients. Eomes +IL-10 +T cells were stable in phenotype after transfer while the Eomes +IL-10 −T cell subset differentiated into Eomes +IL-10 +Tr1 cells. Tr1 differentiation was associated with progressive enrichment for cytotoxicity (Perforin, Nkg7, Granzyme K, Tnfrsf9), immune regulatory (IR) (Tim-3, Lag3, Tox, Nr4a2) and chemokine (Ccl3, Ccl4, Ccl5) RNA expression. Equivalent IR, cytotoxic and cytokine/chemokine expression was confirmed at a protein level. The conditional deletion of Eomes in CD4 T cells prevented Tr1 differentiation and resulted in impaired cytotoxicity in vivo, the accumulation of donor CD11c +dendritic cells, mixed donor chimerism and leukemia relapse, consistent with a critical role for this lineage in tolerance, engraftment and graft-versus-leukemia effects. The deletion of Eomes from CD19-targeted chimeric antigen receptor (CAR) T cells, reduced cytotoxic molecule expression (perforin, granzyme A/B) in CD4 CAR T cells and resulted in immune escape due to CD19 antigen loss in leukemia cells. In sum, Tr1 cells mediate critical Eomes-dependent cytotoxic and regulatory function that are critical for curative immunotherapy outcomes.

Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease. ObjectiveWe investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT. Study designThis retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90–120 post allo-HSCT. ResultsA total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients. ConclusionOur study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.

The acceptor-donor pair recombination of beryllium-treated sapphires

Recently, the concept of Fe3+-Ti4+ mixed acceptor states in the energy band gap of sapphire has been proposed as the cause of blue coloration. The blue color in sapphire is faded and turns yellow by beryllium heat treatment. It has been revealed as the color center in Be-treated yellow sapphires. In this work, the mechanism of such phenomena was explained and discussed. The experiment was set by preparing sapphire samples from Songea, Tanzania, into four color groups (purplish blue, light blue, light yellow with dark zone, and light green). One sample from each group, altogether four, has been heat-treated with beryllium. The colors of Be-treated samples show fading of blue coloration and adding the yellow component to the samples. The analyses and spectroscopic testing were conducted on both the untreated and treated samples, in each group which consisted of one natural and one Be-treated sample. The content of color-related trace elements such as Be, Mg, Ti, Fe, and Cr was measured by the LA-ICP-MS. The oxidation state of Fe [III] was confirmed by X-ray absorption spectroscopy. Each color group showed quite similar UV–Vis–NIR absorption spectra for the natural and the Be-treated ones, regardless of differences in their color and treatment. However, their UV–Vis–NIR polychromatic excitation spectra were different, leading to the possible detection of blue color suppression due to the recombination of Fe3+-Ti4+ mixed-acceptor states by the Fe3+-Be2+ mixed donor states for Be-treated samples. Hence, the acceptor-donor pair recombination has been proposed for the blue color fading in beryllium-treated sapphire samples.

Synthesis of P-stereogenic 1-phosphanorbornane-derived phosphine-phosphite ligands and application in asymmetric catalysis.

A convenient synthesis of enantiopure mixed donor phosphine-phosphite ligands has been developed incorporating P-stereogenic phosphanorbornane and axially chiral bisnaphthols into one ligand structure. The ligands were applied in Pd-catalyzed asymmetric allylic substitution of diphenylallyl acetate, Rh-catalyzed asymmetric hydroformylation of styrene and Rh-catalyzed asymmetric hydrogenation of an acetylated dehydroamino ester. Excellent branched selectivity was observed in the hydroformylation although low ee was found. Moderate ee's of up to 60% in allylic substitution and 50% in hydrogenation were obtained using bisnaphthol-derived ligands.

Long-Term Persistence of Mixed Full Donor Chimerism after Double Cord Blood Transplantation. Example of Tolerance in Allogeneic Hematopoietic Cell Transplantation Setting

Background Double umbilical cord blood transplantation (UCBT) is recognized as an alternative source of hematopoietic donor cells for allogeneic haematopoietic cell transplantation (HCT), particularly in adult setting. Because of important infectious complications, UCBT are rarely utilized and more and more replaced by haplo-identical cell transplantation for adult patients. Nevertheless, some very good results were observed with a long-term follow-up. In most cases, after several weeks, one unit turns immuno-dominant and thus, the second one is no longer detected. Patients and Methods We reported three cases of long-term mixed full donor chimerism associated to documented complete remission of haematological malignancies after double UCBT. The indications of UCBT were acute myeloid leukaemia for 2 patients [1 AML MRC (female of 65 years) and 1 transformation of Fanconi disease (female of 20 years)] and acute lymphoid leukaemia for 1 patient (female of 22 years). AML received a reduced intensity and ALL a standard conditioning. The general characteristics of recipients and UCB are presented in Table 1. The chimerism follow-up were performed by STR and qPCR techniques with a sensitivity of 5 and 0.2% respectively. Early after transplantation, patient 1 developed a grade I graft-versus-host disease (GVHD), patient 3 a grade II GVHD treated by extracorporeal photopheresis, and patient 2 did not develop any GVHD. The follow-up of these patients were 14, 13 and 8 years respectively after UCBT without any episodes of relapse and at the last follow-up still a total donor mixed chimerism. Results Results of STR and qPCR after transplantation early revealed the presence of the two transplant units with a total donor chimerism (Table 1). Patient 1 presented a perfectly balanced chimerism with 54 % of the majority unit. The other two patients showed an imbalance in the proportions of their two UCB with 83% and 72% of their majority units respectively but a long-term persistence of 17% and 28% of their second UCB. The study of total blood chimerism during their follow-up revealed a stabilization of the proportions of the two units during the first year (Figure 1). A more in-depth study of circulating cell subsets (CD3+, CD15+ and CD19+) chimerism of patient 1 revealed a very strong initial imbalance of the two units, which ended up being balanced at two years after transplantation. In the other two patients, the respective study of CD3+ and CD33+ cells showed a stabilization of the two unit percentage around six months after transplantation. At five years after transplantation, patient 1 had an in-depth study of circulating cells sub-populations (CD4+ T lymphocytes, CD8+ T lymphocytes, B-lymphocytes, natural killer cells, regulatory T cells, monocytes, naive CD4+ and CD8+ T lymphocytes) by flow cytometry, after separation of the two units cells by specific monoclonal antibody directed against HLA mismatching antigen (HLA-A2). This analysis revealed an imbalance in the percentage of NK and monocytes. The immune-dominant unit had three times more NK cells than the other one and this imbalance ratio increased by twenty-two for monocytes. A co-culture study of the CD4+ lymphocytes demonstrated a lack of reactivity of both unit against the other one but a normal ability to react against an allogeneic third-part cell. Conclusions This expected tolerance, highlighted in co-culture experience, showed rare cases of naturally induced graft tolerance. A study of tolerance markers and underlying mechanisms in these special cases of persistent mixed full donor chimerism is necessary to acquire better knowledge and to define more investigations ways for the induction of tolerance in patients receiving hematopoietic cell transplantation or organ transplantations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes with Eltrombopag for Poor Graft Function Following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Background: Poor graft function (PGF) is a known life-threatening complication following the allogeneic stem cell transplantation (Allo-SCT) characterized by multilineage cytopenia in the absence of mixed donor chimerism (<95% donor), relapse, or graft-versus-host disease (GVHD). The incidence of PGF after Allo-SCT is 5-20%, with limited treatment options. We present a systematic review and meta-analysis to assess the efficacy of thrombopoietin-mimetic agent Eltrombopag (EPAG) for PGF in adult Allo-SCT recipients. Method: A literature search was performed on four databases (PubMed, Cochrane Register of Controlled Trials, Embase and Clinicaltrials.gov) using MeSH terms and keywords for "Leukemia, Plasma Cell" AND "Hematopoietic Stem Cell Transplantation" AND "Receptors, Thrombopoietin" OR "Eltrombopag" from the date of inception to March 09, 2022. We selected seven retrospectives studies after screening 1034 articles, reporting data on EPAG efficacy for PGF following Allo-SCT in adult patients. Data were extracted following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Quality evaluation was performed using the NIH quality assessment tool. The inter-study variance was calculated using Der Simonian-Laird Estimator. The pooled analysis was conducted using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). A random-effects model was used to estimate the proportions with 95% confidence intervals (CI). Results: A total of 141 patients from seven studies were included in this systematic review and meta-analysis. (Table 1) Six studies reported that the median age of patients was 48.5 (18-73) years, and 53.4% were males. The median daily dose of EPAG was 150 (50-150) mg, while the median duration of treatment was 114 (30-133) days. The median time to EPAG administration after Allo-SCT was 95 (70-114) days and the median time to response was 60 (48-93) days, as reported by five studies. The source of stem cells was peripheral blood stem cells and bone marrow in 57.42% (58/101) and 37.62% (38/101) patients, respectively, as reported by five studies. The donor type was haploidentical 59% (83/141), matched unrelated donor (MUD) 19% (27/141), mismatched unrelated donor (MMUD) 15.6% (22/141), matched related donor (MRD) 5.7% (8/141), and umbilical cord blood (UCB) 0.7% (1/12). The pooled overall response rate (ORR) was 66% (95% CI 0.45-0.84, p&lt;0.01, I 2 = 81%) while pooled complete response (CR) and pooled partial response (PR) was 58% (95 % CI 0.46-0.69, p= 0.33, I 2 =14%) and 19.5% (95% CI 0.11-0.29, p= 0.68, I 2 = 0%), respectively. At a median follow-up of 12 (2-30) months, the median pooled overall survival (OS) was 66% (95 % CI 0.47-0.82, p< 0.01, I 2 =75%). One study reported skin hyperpigmentation as a side effect of EPAG in 1/12 (8.3%) patients, and two studies reported transaminitis as a side effect in 4/20 (20%) patients. Conclusion: Eltrombopag could provide an effective treatment option for poor graft function after Allo-SCT with an acceptable toxicity profile. However, there is an unmet need for randomized trials to address the optimal dosing and duration of Eltrombopag treatment for PGF after Allo-SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Transplant Cyclophosphamide Associated with Increased Early Mixed Donor Chimerism in Myeloid Malignancies; A Single-Center Experience

Post-Transplant Cyclophosphamide Associated with Increased Early Mixed Donor Chimerism in Myeloid Malignancies; A Single-Center Experience

Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice

Despite advancement of neural progenitor cell transplantation to spinal cord injury clinical trials, there remains a lack of understanding of how biological sex of transplanted cells influences outcomes after transplantation. To address this, we transplanted GFP-expressing sex-matched, sex-mismatched, or mixed donor cells into sites of spinal cord injury in adult male and female mice. Biological sex of the donor cells does not influence graft neuron density, glial differentiation, formation of the reactive glial cell border, or graft axon outgrowth. However, male grafts in female hosts feature extensive hypervascularization accompanied by increased vascular diameter and perivascular cell density. We show greater T-cell infiltration within male-to-female grafts than other graft types. Together, these findings indicate a biological sex-specific immune response of female mice to male donor cells. Our work suggests that biological sex should be considered in the design of future clinical trials for cell transplantation in human injury.

Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation

Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.

Efficacy of a Second Allogeneic Hematopoietic Cell Transplant in Relapsed Acute Myeloid Leukemia: Results of a Systematic Review and Meta-Analysis

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that can offer the possibility of cure for acute myeloid leukemia (AML). Unfortunately, relapse and disease progression still occur in more than one third of cases even when patients are allografted in complete hematologic remission (CR). Treatment of AML relapsing after a first allo-HCT is particularly challenging. A second allo-HCT is offered to patients considered fit for the procedure, but reported outcomes have been conflicting. To perform a systematic review and meta-analysis to assess the totality of evidence on the role of a second allo-HCT in patients with AML, we performed a comprehensive literature search using PUBMED/MEDLINE and EMBASE on August 25, 2021, and extracted clinical outcome data relating to benefits (CR, overall survival [OS], and progression-free/disease-free survival [PFS/DFS]) and harms (acute and chronic graft-versus-host disease, non-relapse mortality [NRM], and relapse). The search identified 821 studies. Only 20 studies (n = 2772 patients) met our inclusion criteria. A second allo-HCT resulted in pooled CR, OS, PFS/DFS, NRM and relapse rates of 67%, 34%, 30%, 27%, and 51%, respectively. OS was 2-fold higher when the second allo-HCT was performed in CR (38% versus 17%) and 3-fold higher in patients who had a later relapse from the first allo-HCT (34% versus 10%). There was no apparent difference in pooled OS (hazard ratio = 1.01; 95% confidence interval, 0.78-1.31; P = .94) whether the same original donor or a different one was used. Notwithstanding several limitations apart from the high heterogeneity among included studies, this analysis shows that a second allo-HCT is a reasonable treatment option for relapsed AML. The procedure appears to be more effective when performed in CR and in patients who had a later relapse from the first allo-HCT. The high pooled relapse rates exceeding 50%, even when receiving the second allo-HCT in CR is worrisome and emphasizes the need to incorporate new therapies whether as post-transplantation maintenance or consolidation to mitigate relapse risk. This analysis was limited to patients receiving a second allo-HCT for the sole purpose of treating AML relapse. Accordingly, we caution against extrapolating these findings to other indications such as treatment of graft failure, poor graft function, or mixed donor chimerism.

Non-relapse cytopenias following allogeneic stem cell transplantation, a case based review.

The development of non-relapse cytopenias (NRC) is a relatively common occurrence post allogeneic stem cell transplant (alloSCT). Whilst there have been attempts to classify post alloSCT cytopenias by transplantation groups, ambiguity of definitions in prior publications compounded by a lack of availability of high-quality evidence, provide challenges to clinicians attempting to manage these complex patients. In this review we describe 3 cases of NRC, (1) Graft Failure with graft rejection representing cytopenias with minimal donor chimerism (2) Poor Graft Function representing cytopenias with complete donor chimerism and (3) Cytopenias with mixed donor chimerism. This case-based review will evaluate the currently available evidence regarding the pathophysiology of each entity as well as the evidence for current therapies with the aim of providing guidance to clinicians managing these complex patients.

P1365: DONOR LYMPHOCYTE INFUSION IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: RESULTS FROM A RETROSPECTIVE STUDY

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a therapeutic option with curative intent in hematological malignancies. Despite improvements in alloHSCT, relapse of the underlying disease is still one of the main causes of mortality. Donor lymphocyte infusion (DLI) is an immunotherapy that can be used after alloHSCT in patients with high-risk disease (prophylaxis), mixed donor chimerism or minimal residual disease (preemptive) and relapse (therapeutic). Donor derived graft versus tumor effects induce a durable remission after DLI. Aims: To characterize the use of DLI as prophylaxis, preemptive or therapeutic strategy in alloHSCT and evaluate overall survival (OS). Methods: A retrospective unicenter study was conducted to evaluate the use of DLIs in a cohort of 50 patients (91 DLIs), treated in a Bone Marrow Transplantation Unit, between January 2005 and December 2021. The chi-square test (categorical variables) and t-test or Wilcoxon-Mann-Whitney test (continuous variables) were used. OS was estimated according to Kaplan-Meier and compared by the log-rank test. Statistical analysis was made using SPSS28®. Results: Our cohort showed male predominance (n= 29, 58%) and a median age of 40 years (4-65), with 4 pediatric patients. Patients were affected by acute myeloid leukemia (n=20), acute lymphoblastic leukemia (n=12), chronic myeloproliferative leukemia (n=6), Hodgkin lymphoma (n=2), myelodysplastic/myeloproliferative syndrome (n=4), non-Hodgkin lymphoma (n=3), chronic lymphocytic leukemia (n=1), mixed phenotype leukemia, (n=1), multiple myeloma (n=1). Conditioning regimen was myeloablative in 19 (38%) patients and reduced-intensity in 31 (62%). All 50 donors were HLA-matched, and 8 (16%) were HLA-matched unrelated (MUR). DLIs use was prophylactic in 2 (4%) patients, preemptive in 7 (14%) and therapeutic in 41 (82%) patients. The median number of DLI/patient was 1 (1-8) and the median dose of total CD3+ cells infused was 1,0x107/Kg (0,1-13,48). The median time between alloHSCT and the first DLI was 17 months (1-133). Complete Response (CR) was defined by completed donor chimerism or no MRD detected. CR was maintained in 1/2 (50%) patients undergoing prophylactic DLIs. Patients who received preemptive and therapeutic DLIs achieved CR in 2/7 (29%) and 9/41 (22%) cases, respectively. Overall, 11 patients (22%) developed GVHD after DLIs. Presence of GVHD was associated with higher number of DLIs (2,45 vs 1,64) and with CR (p=0,041) No significant differences were observed in age (p=0,154), number of CD3+ infused (p=0,414), DLIs strategy (p=0,433), time between alloHSCT to first DLI (p=0,668) and CR. Death occurred in 30 (60%) patients. OS survival was defined as time from date of first DLI to date of last follow-up (FU) or date of death. With a median FU of 141 months, the OS was superior in patients who achieved CR compared to relapsed patients (34 months), Log-rank p=0.109. OS was significantly superior in preemptive and prophylaxis DLIs compared with therapeutic DLIs (Log-rank p<0,01). Overall, 8/19 (42%) patients are currently alive in CR. Summary/Conclusion: DLI has been widely applied to the therapeutic intervention, with promising results in prevention and preemptive strategy. Although with the limits of a relatively small and heterogeneous cohort, we describe our experience in the use of DLI and demonstrate that it is an effective prophylactic and preemptive treatment option in alloHSCT patients. Prospective studies on homogeneous patient cohorts are needed improve the effectiveness of DLI.

Chemistry of tellurium containing macrocycles

Abstract The chemistry of Tellurium containing macrocycles has received great attraction and developed rapidly. Recently inorganic chemists are fascinated by ligands containing macrocycles having tellurium as soft donor and N and O as hard donor atoms. The tellurium atom is more electropositive than carbon due to its large size that resulted in polarisation of Te–C bond. So, tellurium containing macrocycles are explored due to their high reactivity and toxicity. Well-designed macrocycles containing different metals is an interesting field of chemistry as macrocycle with mixed donor atoms can bind two different metal atoms with different nature within the same cavity and thereby ion selectivity increases. Chemistry of macrocycles with tellurium as soft donor atoms also gives rise to very interesting coordination behaviour as addition of Tellurium in macrocycle adds an additional probe (125Te NMR help to monitor their structures in solutions). The chemistry of hard and soft donors in macrocyclic framework makes interesting coordination chemistry and need to be explore. The discussion includes different types of tellurium macrocycles and their chemistry.

RETRACTED: The impact of second-donor lymphocyte infusion on secondary graft failure after allogeneic hematopoietic stem cell transplantation through activation of Foxp3 and regulatory T cells

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Editor of Cytotherapy has retracted this article. The article duplicates significant parts of a paper that had already appeared in Transplantation and Cellular Therapy, Volume 28, Issue 3, 2022, Pages 152.e1-152.e7, https://doi.org/10.1016/j.jtct.2021.12.017 In accordance with Committee on Publication Ethics (COPE) and Elsevier's policies, the authors have been contacted. After considering the author's response, the decision has been made to retract the paper. Redundant publications overweigh the relative importance of published findings and distort the academic record of the authors. One of the conditions of submission of a paper for publication is therefore that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.

Unravelling the semiconductor properties of mixed stack donor acceptor cocrystals of pyrene derivatives and TCNQ: effect of crystal packing versus super-exchange mechanism

The role of crystal packing and super-exchange mechanism to dictate the semiconductor properties of two mixed DDADDA stack charge transfer cocrystals is elucidated via theoretical study.

Poor graft function - causes and potential solutions

Introduction. Poor graft function is one of the most severe complications after allogeneic hematopoietic stem cell transplantation, which manifests as pancytopenia/cytopenia in the blood count, with the presence of complete or incomplete donor chimerism. There are three entities of graft weakness: 1. poor graft function: pancytopenia with complete donor chimerism, 2. graft failure: pancytopenia with incomplete, i.e., mixed donor chimerism and 3. graft rejection: progressive decline of donor chimerism. Definition. Poor graft function is diagnosed as pancytopenia (hemoglobin &lt; 70 g/L, absolute neutrophil count &lt; 0.5 x 109/L, platelets &lt; 20 x 109/L) for 3 consecutive days from D+28, excluding the presence of severe graft versus host disease and relapse, with complete donor chimerism in poor graft function, and incomplete in graft failure. Risk factors and therapeutic principles. The most common risk factors for poor graft function are a small dose of CD34+ hematopoietic stem cells in the transplant, graft versus host disease, cytomegalovirus infection, the presence of donor-specific antibodies, high serum ferritin, i.e., iron overload, as well as splenomegaly. Pathogenetic mechanisms in the development of poor graft function are still not fully elucidated. The role of the microenvironment of the patient?s bone marrow is also important, as well as disorders of the immune system Therapeutic options for overcoming this complication include using selected ?stem cell boost?, mesenchymal stem cells, and newer medical agents (N-acetyl cysteine, atorvastatin, thrombopoietin receptor agonists). Conclusion. The type of poor function of the graft is defined in relation to the percentage of donor chimerism, and is necessary for planning further treatment strategy.

Room temperature chemoselective hydrogenation of C[double bond, length as m-dash]C, C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds by using a well-defined mixed donor Mn(i) pincer catalyst.

Chemoselective hydrogenation of C[double bond, length as m-dash]C, C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds in α,β-unsaturated ketones, aldehydes and imines is accomplished at room temperature (27 °C) using a well-defined Mn(i) catalyst and 5.0 bar H2. Amongst the three mixed-donor Mn(i) complexes developed, κ3-(R2PN3NPyz)Mn(CO)2Br (R = Ph, iPr, t Bu); the t Bu-substituted complex ( tBu2PN3NPyz)Mn(CO)2Br shows exceptional chemoselective catalytic reduction of unsaturated bonds. This hydrogenation protocol tolerates a range of highly susceptible functionalities, such as halides (-F, -Cl, -Br, and -I), alkoxy and hydroxy, including hydrogen-sensitive moieties like acetyl, nitrile, nitro, epoxide, and unconjugated alkenyl and alkynyl groups. Additionally, the disclosed method applies to indole, pyrrole, furan, thiophene, and pyridine-containing unsaturated ketones leading to the corresponding saturated ketones. The C[double bond, length as m-dash]C bond is chemoselectively hydrogenated in α,β-unsaturated ketones, while the aldehyde's C[double bond, length as m-dash]O bond and imine's C[double bond, length as m-dash]N bond are preferentially reduced over the C[double bond, length as m-dash]C bond. A detailed mechanistic study highlighted the non-innocent behavior of the ligand in the ( tBu2PN3NPyz)Mn(i) complex and indicated a metal-ligand cooperative catalytic pathway. The molecular hydrogen (H2) acts as a hydride source, whereas MeOH provides a proton for hydrogenation. DFT energy calculations supported the facile progress of most catalytic steps, involving a crucial turnover-limiting H2 activation.

Scattering techniques for mixed donor-acceptor characterization in organic photovoltaics.

Precise control of the complex morphology of organic photovoltaic bulk heterojunction (BHJ) active layers remains an important yet challenging approach for improving power conversion efficiency. Of particular interest are the interfacial regions between electron donor and acceptor molecules where charge separation and charge recombination occur. Often, these interfaces feature a molecularly mixed donor-acceptor phase. This mixed phase has been extensively studied in polymer:fullerene systems but is poorly understood in state-of-the-art polymer:non-fullerene acceptor blends. Accurate, quantitative characterization of this mixed phase is critical to unraveling its importance for charge separation and recombination processes within the BHJ. Here, we detail X-ray and neutron scattering characterization techniques and analysis methods to quantify the mixed phase within BHJ active layers. We then review the existing literature where these techniques have been successfully used on several different material systems and correlated to device performance. Finally, future challenges for characterizing non-fullerene acceptor systems are addressed, and emerging strategies are discussed.