Allogeneic Transplantation Research Articles

Mini‐consolidations or intermediate‐dose cytarabine for the post‐remission therapy of AML patients over 60. A retrospective study from the DATAML and SAL registries

AbstractAccording to current recommendations, older AML patients in first complete remission (CR) after induction chemotherapy should receive consolidation with intermediate‐dose cytarabine (IDAC). However, no study has demonstrated the superiority of IDAC over other regimen. In this retrospective study, we compared the efficacy of mini‐consolidations (idarubicin 8 mg/m2 day 1, cytarabine 50 mg/m2/12 h, day 1–5) and IDAC. Inclusion criteria were newly diagnosed AML, age > 60 years, first CR after induction and at least 1 cycle of consolidation. Of the 796 included patients, 322 patients received mini‐consolidations and 474 patients received IDAC. Mini‐consolidation patients were older, and more often, they had de novo AML and unfavorable risk. The rate of allogeneic transplantation was higher in the IDAC group. The median number of cycles was higher in the mini‐consolidation group (4 vs. 2; p < .0001). Median relapse‐free survival was 18 months with mini‐consolidations and 12 months with IDAC (p = .0064). In multivariate analysis, the risk of relapse or death was significantly higher in the IDAC group (p = .004). Median OS was 36 versus 31 months with mini‐consolidations or IDAC, respectively (p = .46). In multivariate analysis, the consolidation regimen had no significant influence on OS (p = .43). In older AML patients, post‐remission therapy with mini‐consolidations represents an alternative to IDAC.

Successful colonization of the testicular germinal epithelium by bone marrow stem cells producing spermatozoa of donor genotype is rare

AbstractBackgroundIt is not known whether bone marrow stem cells when injected intravenously for a bone marrow transplant colonize the human testicular epithelium. No previous studies of sperm genotype after bone marrow transplantation are reported.ObjectivesTo differentiate host from donor genotype in spermatozoa of men who have undergone successful bone marrow transplants.Materials and methodsTriplet DNA samples (spermatozoa, blood, and hair) obtained from men who had recovered sperm production after bone marrow transplant were genotyped using 44 autosomal and three sex‐related single nucleotide polymorphisms to determine the tissue genotype in pairwise comparisons of DNA profiles.ResultsParticipants were 14 men at a median of 5.5 years after allogeneic bone marrow transplant who had a median sperm output of 77 million spermatozoa/ejaculate. In 14/14 the donor (leukocyte) DNA genotype differed significantly from the spermatozoa and hair genotypes whereas hair and sperm genotypes showed no variations.DiscussionThese data suggest that paternity after a successful bone marrow transplant is likely to be of the host and not the donor's genetic origins. The study's small sample size reflects the paucity of eligible man with recovered spermatogenesis after bone marrow transplant and represents preliminary evidence. A large‐scale epidemiological analysis to estimate the frequency of bone marrow donor stem cell colonization of the testicular germinal epithelium based on progeny sex ratio and frequency of female donors is proposed.ConclusionSuccessful colonization of the testicular germinal and hair follicle epithelia by allogeneic bone marrow transplant donor stem cells is rare or does not occur.

Abstract C020: Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors

Abstract While adoptive cellular therapies (ACT) such as CAR-T and NK therapy have shown clinical efficacy against hematologic malignancies, their use against solid tumors (such as ovarian or pancreatic cancer) has had limited success to date. In particular, CAR-T therapy for solid cancers has led to severe toxicities, including on-target, off-tumor killing of healthy cells and graft vs. host disease (GVHD) with allogeneic transplant. NK cell therapies, in contrast, have fewer associated toxicities due to specific and innate recognition/killing of cancer cells. This greater safety profile makes NK therapies an attractive treatment option for solid cancers. NK therapies are currently limited by insufficient in vivo tumor clearance, caused largely by their lower cytotoxicity and in vivo expansion compared to CAR-T cells. To address this, we have screened 300,000 small molecule compounds for their ability to enhance NK cytotoxicity against ovarian cancer (OVCAR) cells. Our primary screen identified 11 lead compounds which increase NK killing activity against OVCAR cells >= 10% over baseline (vehicle-treated control). Secondary in vitro assays have confirmed that at least 3 out of 11 lead compounds enhance NK cytotoxicity by at least 10% over baseline. As such, we hypothesize that our lead compounds will increase in vivo NK cytotoxicity and tumor clearance, through mechanisms which might include I) upregulation of NK activating receptors, II) downregulation of NK inhibitory receptors, and/or III) modulation of NK metabolism in the immunosuppressive tumor microenvironment. Immediate future studies include in vivo testing of our lead compounds’ ability to enhance NK cytotoxicity, using immunodeficient mouse models of subcutaneous OVCAR tumors. Moreover, we will utilize 2D and 3D in vitro culture techniques alongside flow cytometry and RNA sequencing to identify how lead compounds impact markers of NK activation and metabolism. This will include expression of activating/inhibitory receptors, exhaustion markers, and key metabolic factors. Finally, we will assess the effect of lead compounds on NK function within an immunosuppressive tumor environment. Our findings will contribute to effective future NK cell therapies for solid tumors. Citation Format: Indrani Das, Olubukola Abiona, Riufu Liu, Grace K. Lee, David N. Wald. Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C020.

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.

Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

B2M or CIITA knockdown decreased the alloimmune response of dental pulp stem cells: an in vitro study.

Dental pulp stem cells (DPSCs) have acquired noteworthy attention for their application in treating ischemic diseases and facilitating tissue regeneration. However, the host's immune response following allogenic DPSC transplantation often handicaps the long-term survival of transplanted cells, thereby limiting the application of DPSCs in cell therapy. This study aims to investigate whether genetic modification can alleviate the immunogenicity of DPSCs. Beta 2-microglobulin (B2M) and the class II histocompatibility complex transactivator (CIITA) were individually knocked down in DPSCs by lentiviral particles encoding short hairpin (sh) RNAs. The self-renewal capacity and pluripotency of DPSCs-shB2M (B2M silenced DPSCs) and DPSCs-shCIITA (CIITA silenced DPSCs) were evaluated by CCK8 and differentiation assays including osteogenesis, adipogenesis, and neurogenesis. The expression of HLA-I and HLA-II in DPSCs-shB2M and DPSCs-shCIITA after IFN-γ treatment were analyzed by western blotting, immunofluorescence, and flow cytometry. The function of genetically modified cells was assessed by leukocyte-mediated cytotoxicity and T-cell proliferation assays. Western blotting, immunofluorescence, and flow cytometry revealed that DPSCs-shB2M and DPSCs-shCIITA exhibited impaired IFN-γ inducible HLA-I and HLA-II expression. There were no significant differences in the self-renewal capacity and pluripotency among DPSCs-shB2M, DPSCs-shCIITA, and control groups (p > 0.05). Lower leukocyte-mediated cytotoxicity and higher cell survival rates were found in DPSCs-shB2M and DPSCs-shCIITA groups compared to the control (p < 0.05). T cell proliferation was significantly inhibited in both DPSCs-shB2M and DPSCs-shCIITA groups (p < 0.05). Genetic knockdown of B2M or CIITA in DPSCs substantially reduced their immunogenicity without compromising their stemness, thereby broadening the clinical application of DPSCs in cell therapy and tissue regeneration.

Pathophysiology and preclinical relevance of experimental graft-versus-host disease in humanized mice.

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantations (allo-HCT) used for the treatment of hematological malignancies and other blood-related disorders. Until recently, the discovery of actionable molecular targets to treat GVHD and their preclinical testing was almost exclusively based on modeling allo-HCT in mice by transplanting bone marrow and splenocytes from donor mice into MHC-mismatched recipient animals. However, due to fundamental differences between human and mouse immunology, the translation of these molecular targets into the clinic can be limited. Therefore, humanized mouse models of GVHD were developed to circumvent this limitation. In these models, following the transplantation of human peripheral blood mononuclear cells (PBMCs) into immunodeficient mice, T cells recognize and attack mouse organs, inducing GVHD. Thereby, humanized mice provide a platform for the evaluation of the effects of candidate therapies on GVHD mediated by human immune cells in vivo. Understanding the pathophysiology of this xenogeneic GVHD is therefore crucial for the design and interpretation of experiments performed with this model. In this article, we comprehensively review the cellular and molecular mechanisms governing GVHD in the most commonly used model of xenogeneic GVHD: PBMC-engrafted NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice. By re-analyzing public sequencing data, we also show that the clonal expansion and the transcriptional program of T cells in humanized mice closely reflect those in humans. Finally, we highlight the strengths and limitations of this model, as well as arguments in favor of its biological relevance for studying T-cell reactions against healthy tissues or cancer cells.

Allogeneic Hematopoietic Stem Cell Transplantation in Refractory Multiple Myeloma-A Retrospective Multicenter Analysis.

A growing list of therapies available for patients with multiple myeloma (MM) results in deep response rates, but eventually almost all patients relapse. Allogeneic hematopoietic cell transplantation (allo-SCT) is a familiar approach for MM, but responses are often short and side effects burdensome. Simultaneously, allo-SCT provides a unique platform on which novel immune therapies can be employed to improve clinical outcomes. Our work describes the characteristics and outcomes of 128 refractory myeloma patients who underwent allo-SCT at five German centers between 2010 and 2021. The median number of therapies before the transplant was 6. With a median follow-up of 6, 4 years, the median progression-free survival and overall survival were 7 and 19 months, respectively. NRM was 28% after 6 years. OS and PFS were 61% and 45% at 1 year, 49% and 34% at 2 years, and 38% and 25% at 6 years. Achieving a CR before transplant was the single most significant variable before transplant. Allo-SCT yet remains an option for fit patient's refractory to all other treatments available. It is potentially curative for a subset of patients. Finding the characteristics of patients with durable remissions is key to sparing unnecessary toxicity for those unlikely to benefit.

Influence of glycodelin on the formation of immune response at the level of T-helpers and T-regulatory cells in an &lt;i&gt;in vivo&lt;/i&gt; experiment

Objective. To study the influence of glycodelin on T-helpers and Tregs level in the process of forming an immune response to the introduction of allogeneic bone marrow (BM) cells in a dynamic experiment on Wistar rats. Materials and methods. The original experimental model "host versus transplant reaction" on male Wistar rats without preliminary conditioning in recipients was used in the study. Animals were administered recombinant glycodelin against the background of allogeneic intraperitoneal transplantation of BM cells in a dynamic experiment. The level of peripheral T-helpers (CD4+) and Tregs (CD4+CD25+FOXP3+), and the expression of FOXP3 in the spleen and mesenteric lymph nodes were assessed. The material was collected on the 3rd and 21st days of the experiment. Results. Glycodelin was shown to reduce the absolute number of T-helpers in the peripheral blood (on the 3rd and 21st days) and to increase the proportion of Tregs on the 21st day of the experiment against the background of the introduction of allogeneic BM cells. It was found out, that glycodelin reduced the level of Tregs in the white pulp of the spleen on the 3rd day of the experiment, while the number of these cells on the 21st day increased, reducing the number of T-helpers at the same time. At the level of the mesenteric lymph nodes, glycodelin reduced the level of T-helpers on the 21st day of the experiment, simultaneously increasing the number of Tregs. In general, a unidirectional and distributed effect of glycodelin on the immune response at the level of T-helpers was observed, that was a decrease of T-helpers, but an increase of Tregs on the 21st day of the experiment. Conclusion. Thus, glycodelin had an immunomodulatory effect on T-helpers and Tregs formation. The vector of the obtained effects was immunosuppressive in nature and contributed to the suppression of the immune response to allogeneic cells.

Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML.

Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD-positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD-positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.

Early mixed donor chimerism is a strong negative prognostic indicator in allogeneic stem cell transplant for AML and MDS.

Allogeneic bone marrow transplantation remains the most potent curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) due to the graft-versus-tumor effect provided by donor cells. Donor chimerism is utilized early after transplantation to evaluate engraftment and to monitor the persistence of donor hematopoiesis. Literature is conflicting regarding to the prognostic utility of early mixed donor chimerism, chimerism kinetic patterns as well as factors associated with it and we sought to clarify this uncertainty. In this single-centre retrospective analysis, 141 adults aged 18 years of age or older with AML (n=104) and MDS (n=37) who received their first transplant from HLA matched related, matched unrelated or mismatched related (haploidentical) donors between 2016 and 2022 and had at least day 30 chimerism measured were included. Approximately 30% received post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis and 67% of subjects received reduced-intensity conditioning. Chimerism was measured using STR-PCR from unfractionated peripheral blood mononuclear cells (whole blood; WB) and CD3+ (T cell; TC) compartment at each time point. Complete donor chimerism was defined as ≥95% whereas <95% defined as mixed. Competing risk analysis was used to estimate cumulative incidence of relapse with kinetic calculations completed using an increment factor. Kaplan-Meier was used for overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to explore prognostic factors for OS and RFS. Both day 30 mixed WB and TC donor chimerism were individually associated with an increased risk of relapse and worse overall and relapse-free survival at days 30, 60 and 90 post-transplant. Day 30 mixed WB was more specific for relapse (86%), while mixed TC was more sensitive (67%). Complete day 30 chimerism had a negative predictive value of 63% and 70% and positive predictive value of 57% and 67% for WB and TC, respectively. Day 30 WB and TC donor chimerism of <88.92% and 89.29% had specificities of 79.17% and 82.19% although sensitivities only approximated 50%. Evaluating the kinetics of chimerism over the first 90 days provided additional information for prognosticating relapse than absolute chimerism values at individual time points in both WB day 30 to 90 [HR, 1.75 (95% CI, 1.04-2.94); p<0.035] and TC day 60 to 90 [HR, 1.32 (95% CI, 1.03, 1.69); p<0.29]. Twice as many patients with complete chimerism developed acute GVHD compared to those with mixed chimerism. Factors that were found to be associated with day 30 mixed TC chimerism were donor source, ATG GVHD prophylaxis, myeloablative conditioning and female sex, while only donor source was associated with mixed WB. Both TC and WB day 30 mixed chimerism were associated with an increased risk of relapse. Early mixed WB and TC chimerism is strongly associated with a worse overall and relapse-free survival. The serial measurement of chimerism early post-transplant for monitoring chimerism kinetics provides additional prognostic information beyond the absolute donor chimerism value at a single time point. Haploidentical stem cell transplants were associated with a lower likelihood of mixed chimerism than other donor sources.

Allogeneic hematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for multiple myeloma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Therapy-related myeloid neoplasms (t-MN) are a complication of multiple myeloma (MM) treatment. Our retrospective, EBMT registry study included 157 such patients allografted (allo-HCT) between 2006 and 2018. Most patients (130) had a prior autologous HCT. Fifty-seven (36.4%) were transplanted for t-AML and 100 (63.6%) for t-MDS. Median times from MM and t-MN diagnoses to allo-HCT were 72.6 (interquartile range (IQR), 46.1-102.9) and 6.4 (IQR, 3.9-9.4) months. Fifty-eight (38.4%) t-MN patients were in complete remission (CR) at allo-HCT predominantly conditioned with reduced intensity (70.3%). With a median follow-up of 64.9 (95% CI: 39-76) months, relapse incidence (RI) from MM at 1 and 5 years was 4% (0-10%) and 12% (2-22%), respectively, with few deaths (n = 3) only due to MM disease progression, whereas t-MN RI and non-relapse mortality (NRM) at 1 and 5 years were 35% (95% CI 28-43%) and 45% (95% CI: 36-53%) and 20% (95% CI 13-26%) and 31% (95% CI: 23-39%). Overall survival (OS) and progression-free survival (PFS) estimates at 1 and 5 years were 55% (95% CI: 47-63%) and 27% (95% CI: 19-35%) and 45% (95% CI 36-53%) and 24% (95% CI 16-32%). Older (>65 years) t-MN patients with high-risk cytogenetics do not benefit from allo-HCT.

A Thrilling Case of Anemia

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that presents with triad of peripheral blood cytopenias, hemolytic anemia and thrombosis. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is due to acquired somatic mutations in phosphatidylinositol glycan class A (PIGA) gene.Terminal complement inhibition with eculizumab and allogeneic bone marrow transplantation (BMT) are the only widely effective therapies for patients with classical PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3).

Comfort Care Needs of Allogeneic Stem Cell Transplant Survivors: Lived Experience

Introduction: Allogeneic Stem Cell Transplantation (ASCT) and, consequently, the chronicity associated with this life event have a growing prevalence and a significant impact on the life and daily life of each person who experiences it. It is necessary to reflect on the care needs of this group of vulnerable people. Comfort is a concern, and its improvement is a desired outcome of healthcare. To achieve this, it is necessary to know the needs of the people who are the focus of care. Aim: This paper aims to understand the needs of comfort care in the lived experience of comfort for survivors of ASCT. Methodology: Qualitative approach using van Manen’s phenomenology of practice. We uncovered the phenomenon through phenomenological interviews, which integrated narratives and illustrative episodes that reflected the lived experience of 20 survivors. Participants in the study were people who had undergone allogeneic hematopoietic progenitor cell transplantation, who were monitored on an outpatient basis and who met the following conditions: (i) were over 18 years old; (ii) had undergone SCT at least 3 months previously; (iii) had no evidence of disease relapse; (iv) were able to express themselves verbally, providing information relevant to the study, as well as expressing emotions and feelings. Descriptions of lived experiences were collected from participants between July 2020 and May 2021. In the phenomenological reflection on the lived descriptions, we followed the “stages” epoché, reduction, and vocative. Results: The following themes emerged from the ASCT survivor’s lived experience of comfort related to comfort care needs: continuous follow-up, reference nurse, information, assistance in adapting to the new self, mental health intervention, spiritual support, adaptation to changes in sexuality, physical rehabilitation, and job reintegration. Conclusion: This study reveals the importance of continuous follow-up for ASCT survivors. Survivors experience major changes in their lives in the long term and require a response from health professionals to find comfort in their daily lives.

10-Year Real-World Data on Acute Myeloid Leukemia:

Introduction: Despite advances in Acute Myeloid Leukemia (AML) diagnosis and treatment, the outcomes in low- and middle-income countries (LMIC) are far apart from those in high-income countries (HIC). Objective: To describe the clinical features and outcomes of AML patients in Brazil's public health system, we conducted a retrospective analysis of all cases of non-promyelocytic AML diagnosed within 10 years (2007- 2017) in northeastern Brazil, Bahia. Methodology: We analyzed the real-life outcomes of 62 patients diagnosed with non-promyelocytic AML between 2007 and 2017 at a university hospital in Northeast Brazil. We classified patients using the European LeukemiaNet 2022 guideline into favorable (n=8), intermediate (n=18), and adverse risk (n=7) groups. Twenty-nine were not otherwise classified because no cytogenetic and/or molecular tests were available at diagnosis. Results: Allogeneic bone marrow transplant (alloBMT) was performed in 16 patients (37%). Median overall survival (mOS) was seven months. Among patients receiving alloBMT, mOS was 49 months, while for the chemotherapy group, it was six months (P = 0.003). For 10-year real-life data, we found complete remission of 53%, 5-year OS of 27%, and a mortality rate during induction therapy of 27%, inferior to HIC. Conclusion: Inferior outcomes found in LMIC result from a multifactorial scenario and an unmet need in the worldwide panorama of AML.

Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia.

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n = 53, 36%) and negative pre-transplant (overall survival (OS): p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.

Scalable log-ratio lasso regression for enhanced microbial feature selection with FLORAL.

Identifying predictive biomarkers of patient outcomes from high-throughput microbiome data is of high interest, while existing computational methods do not satisfactorily account for complex survival endpoints, longitudinal samples, and taxa-specific sequencing biases. We present FLORAL, an open-source tool to perform scalable log-ratio lasso regression and microbial feature selection for continuous, binary, time-to-event, and competing risk outcomes, with compatibility for longitudinal microbiome data as time-dependent covariates. The proposed method adapts the augmented Lagrangian algorithm for a zero-sum constraint optimization problem while enabling a two-stage screening process for enhanced false-positive control. In extensive simulation and real-data analyses, FLORAL achieved consistently better false-positive control compared to other lasso-based approaches and better sensitivity over popular differential abundance testing methods for datasets with smaller sample sizes. In a survival analysis of allogeneic hematopoietic cell transplant recipients, FLORAL demonstrated considerable improvement in microbial feature selection by utilizing longitudinal microbiome data over solely using baseline microbiome data.

Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

Advancements in Autologous Stem Cell Transplantation for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease marked by comparatively focal dopaminergic neuron degeneration in the substantia nigra of the midbrain and dopamine loss in the striatum, which causes motor and non-motor symptoms. Currently, pharmacological therapy and deep brain stimulation (DBS) are the primary treatment modalities for PD in clinical practice. While these approaches offer temporary symptom control, they do not address the underlying neurodegenerative process, and complications often arise. Stem cell replacement therapy is anticipated to prevent further progression of the disease due to its regenerative capacity, and considering the cost of immunosuppression and the potential immune dysfunctions, autologous stem cell transplantation holds promise as a significant method against allogeneic one to treat Parkinson's disease. In this review, the safety concerns surrounding tumorigenicity and complications associated with transplantation are discussed, along with methods utilized to evaluate the efficacy of such procedures. Subsequently, we summarize the preclinical and clinical studies involving autologous stem cell transplantation for PD, and finally talk about the benefits of autologous stem cell transplantation against allogeneic transplants.

NK Cell-Based Cancer Immunotherapies: Current Progress, Challenges and Emerging Opportunities.

Natural killer (NK) cells are vital innate immune cells that play a crucial role in cancer therapy. They are targeted by therapies designed to modulate, retain, and enhance their antitumor function in vivo. In addition to whole-cell therapy, NK cell-derived exosomes (NDEs) offer high immune safety and are easily subject to chemical, biological, and immunological modifications. This makes them suitable for use in combination with various current cancer therapies to enhance efficacy, treatment outcomes, and reduce side effects in vivo. This review aims to outline summarizes the antitumor potential of NK cells, as well as the current challenges and opportunities in NK cell-based immunotherapies such as allogeneic and autologous NK cell transplantation, CAR NK cell therapy, and the use of cytokines and monoclonal antibodies. The review also explores the dual regulatory effects of tumor exosomes on NK cells, and highlights the potential of NDEs, either alone or in combination with other antitumor therapies, to reprogram the immunosuppressive tumor microenvironment and expedite the therapeutic effects of cancer immunotherapy in future clinical research.

Management of Post-transplant Infections in Collaborating Hospitals (MATCH) Programme: a prospective cohort of all transplant recipients at Copenhagen University Hospital—Rigshospitalet, Denmark

PurposeThe Management of Post-transplant Infections in Collaborating Hospitals (MATCH) programme, initiated in 2011 and still ongoing, was created to 1) optimise the implementation of existing preventive strategies against viral infections...