Allogeneic Transplantation Research Articles

Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.

After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.

A machine learning-based workflow for predicting transplant outcomes in patients with sickle cell disease.

Allogeneic haematopoietic cell transplantation (HCT) with HLA-matched sibling donor remains the most established curative therapeutic option for patients with sickle cell disease (SCD). However, it is not without risks, highlighting the need for a risk stratification system. Utilizing a machine learning (ML) approach that combines clinical and imaging variables, we identified red cell distribution width and renal organ damage as important risk factors for patients undergoing HCT. This ML-based algorithm, similar to an approach previously reported for predicting mortality in patients with SCD, should be applicable to risk factor discovery in similar studies.

Allogeneic stem cell Transplant in Hematological Disorders: A Decade of Experience

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a complex procedure with the potential to provide curative treatment for various hematological disorders. This study aims to evaluate the outcomes of allo-HCT in hematological diseases and identify significant complications in a single-center setting. Materials and Methods: We conducted a retrospective analysis of 180 patients with hematological diseases who underwent allo-HCT between January 2011 and December 2021. Key outcomes, including indications for transplantation, overall survival, engraftment time, relapse rates, graft-versus-host disease (GVHD), and transplant-related mortality (TRM) were assessed. Results: The most common indications for allo-HCT were benign hematological diseases, particularly aplastic anemia, and thalassemia major. Despite the majority of patients receiving fully matched transplants, Acute GVHD was observed in 30% of the cohort. Graft failure occurred in 13 patients, with primary and secondary graft failure rates of 1.6% and 5.5%, respectively. Sepsis emerged as the primary cause of non-relapsed mortality at day 100 and beyond. The overall survival rate in this study was 62%, with 79% of patients disease-free on their last visit. Conclusion: This study provides valuable insights into the treatment strategies and patient care of allo-HCT for hematological disorders by offering a comprehensive overview of multiple relevant outcomes. The findings underscore the significance of addressing complications and risk factors associated with allogeneic transplantation, including GVHD and infections. Future research should focus on further optimizing transplantation techniques to minimize complications and enhance patient survival.

Acquired Partial Lipodystrophy: Clinical Management in a Pregnant Patient.

Pregnancy represents an additional challenge to the complex clinical picture of lipodystrophy disorders, and the management of such conditions with related comorbidities has been underreported. This work aims to outline the risk associated with a pregnancy event for women dealing with acquired partial lipodystrophy and the need for diverse but specialized care. We report on the successful pregnancy outcome of a 28-year-old woman with an acquired partial form of lipodystrophy related to an allogenic bone marrow transplant that occurred at pediatric age. Although metabolic control was challenging, glucose levels progressively improved during the pregnancy, and triglycerides increased less than expected. The periodic monitoring of leptin levels showed a progressive increase with a peak in the third trimester (41.53 ng/mL), followed by a fast decline the day after giving birth, with a lower basal level than the prepregnancy period. However, preterm delivery occurred associated with cardiac complications in the mother. A total of 12 studies were retrieved concerning women aged 14 to 38 years with various lipodystrophy phenotypes. Diabetes and hypertriglyceridemia were the most common comorbidities. Most women had successful pregnancies despite gestational complications (including miscarriages), preterm and emergency deliveries, and newborns undergoing partum or postpartum transient or chronic complications. Lipodystrophy disorders expose both mothers and children to very high risk. Intensive monitoring and care of all potential clinical complications should be planned and carried out by a multidisciplinary team before, during, and after the pregnancy. Leptin secretion during pregnancy should be investigated more deeply in these patients.

Comparative outcomes of various transplantation platforms, highlighting haploidentical transplants with post-transplantation cyclophosphamide for adult T-cell leukaemia/lymphoma.

This study retrospectively compared outcomes of various allogeneic haematopoietic cell transplantation (allo-HCT) platforms in patients with adult T-cell leukaemia/lymphoma. Platforms included human leukocyte antigen (HLA)-haploidentical-related donors using post-transplant cyclophosphamide (PTCY), HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD) and cord blood transplantation (CBT). Patients who underwent their first allo-HCT between 2016 and 2021 were included. Outcomes analysed were overall survival (OS), relapse and non-relapse mortality (NRM). Seven hundred patients were included (PTCY, n = 121; MRD, n = 91; MUD, n = 160; CBT, n = 328). With a median follow-up of 794 days for survivors, 2-year OS was 48.1% (PTCY), 48.8% (MRD), 48.4% (MUD) and 34.6% (CBT); the respective 2-year cumulative incidence of relapse was 37.1%, 47.5%, 33.9% and 45.1% and that of NRM was 24.2%, 19.8%, 24.7% and 27.3%. PTCY was associated with delayed platelet engraftment relative to MRD and MUD. There was no increase in the incidence of severe acute or chronic graft-versus-host disease. In the PTCY group, poor performance status was a significant predictor of inferior OS, and infused CD34+ cell numbers of less than 5 × 106/kg were associated with delayed neutrophil and platelet engraftment. These results suggest that allo-HCT with PTCY is a safe and effective platform for patients with adult T-cell leukaemia/lymphoma.

A limbal stem cell deficiency murine model with residual limbal stem cells.

Bilateral limbal stem cell deficiency (LSCD) is a significant cause of corneal blindness and is more difficult to treat, as compared with unilateral LSCD because no source of autologous limbal stem cells (LSCs) remains in these patients. Thus, bilateral patients could be candidates for treatment with allogeneic LSC transplants that require long-term systemic immunosuppression therapy. Thus, if possible, for the correct candidates, using autologous LSCs could be a preferred treatment. Recent in vivo laser confocal microscopic examination of the ocular surface in situ , combined with impression cytology, has indicated that some patients diagnosed with a complete bilateral LSCD possess residual LSCs. However, it remains unknown whether these residual LSCs still have stem cell potential due to the lack of animal models that mimic this pathology. The goal of the current study is to make a complete LSCD model that possesses evidence of residual LSCs. We induced complete LSCD in mice using two methods: (1) removed the corneal epithelium and the epithelial basement membrane using a rotating burr, and (2) removed the corneal epithelium using 20% ethanol but retained an intact epithelial basement membrane. A complete LSCD was defined by a lack of CK12-positive corneal epithelial cells and the presence of infiltrating CK19-positive conjunctival epithelial cells. Corneas were examined for wound closure, corneal opacity, LSC exhaustion, and inflammation. We observed that complete LSCD mice without an intact epithelial basement membrane resulted in few residual LSCs. By contrast, complete LSCD mice that retained the epithelial basement membrane were accompanied by a reduced inflammatory response plus a significant number of residual LSCs. This model will allow future studies to determine the function of residual LSCs in complete LSCD.

Overcoming Graft Rejection in Induced Pluripotent Stem Cell-Derived Inhibitory Interneurons for Drug-Resistant Epilepsy.

Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson's disease (PD) and Huntington's disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Non-systematic literature review. While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity.

DEVELOPMENT OF SYSTEMIC MASTOCYTOSIS AFTER BONE MARROW TRANSPLANTATION FOR AN ACUTE MYELOID LEUKEMIA: DONOR DERIVEN DISEASE OR SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED MYELOID NEOPLASM

Abstract Introduction/Objective Systemic mastocytosis may have variable presentation ranging from an indolent disease to an aggressive form. Systemic mastocytosis with an associated myeloid neoplasm can occur simultaneously, or within an interval of a myeloid neoplasm and should meet the diagnostic criteria of both entities. Methods/Case Report Herein, we present a patient with history of acute myeloid leukemia with KMT2A(11q23) amplification who initially underwent an allogeneic hematopoietic stem cell transplantation from a matched sibling donor. One year later, the patient developed isolated central nervous system relapse, as well as evidence of molecular relapse in the bone marrow and underwent a second allogeneic transplantation, but this time, from a matched unrelated donor. The 100 days post second transplant bone marrow biopsy was negative for involvement by acute myeloid leukemia and the chimerism study revealed evidence of total engraftment with 100% donor cells. Additionally, Fluorescence in situ hybridization analysis detected no evidence of KMT2A amplification. However, morphologic examination of the bone marrow biopsy demonstrated involvement by systemic mastocytosis with multiple dense aggregates of CD117 and tryptase positive mast cells showing spindled cell morphology. Mast cells were positive for CD25 and demonstrated negative expression of CD2 and CD30. PCR analysis of the peripheral blood did not detect evidence of KIT mutation, but serum tryptase was elevated. Results (if a Case Study enter NA) NA Conclusion This case highlights a rare instance of systemic mastocytosis in the setting of remission from an acute myeloid leukemia in a post transplantation bone marrow and represents a diagnostic challenge. While development of systemic mastocytosis in a patient with prior history of an acute myeloid leukemia suggests the possibility of systemic mastocytosis with an associated myeloid neoplasm, some other features including the complete remission and total engraftment of the post transplantation bone marrow with 100% donor cells, raise the possibility of a donor driven disease.

Calcineurin inhibitor blocks tolerance by suppressing donor T cell terminal exhaustion after allogeneic hematopoietic cell transplantation.

Calcineurin inhibitor blocks tolerance by suppressing donor T cell terminal exhaustion after allogeneic hematopoietic cell transplantation.

Navigating 'grey areas' and challenges during evaluation of transplant eligibility in specific myelofibrosis populations: a perspective on behalf of the Chronic Malignancies Working Party of the EBMT.

Significant efforts have been made to effectively select myelofibrosis (MF) patients who can benefit from allogeneic hematopoietic cell transplantation (allo-HCT), the only current cure for MF. The recent EBMT/ELN 2024 recommendations offer valuable guidance for hematologists and transplant physicians. However, several grey areas remain in day-to-day clinical practice regarding the feasibility and optimal preparation for transplantation in patients with this disease. Effective spleen size reduction, often achieved with JAK inhibitors, appears crucial for transplant success. For resistant cases, switching JAK inhibitors, splenectomy, or spleen irradiation may be considered, taking into account patient profiles, treatment availability and center preferences. Managing splanchnic vein thromboses, portal, and pulmonary hypertension is critical as these conditions may affect transplant outcomes. Cytopenias, particularly transfusion-dependent anemia and thrombocytopenia, complicate treatment and impact on outcomes, though new drugs show promise. Comorbidities play a significant role and tools like the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and frailty assessments are useful for evaluating transplant risks while allowing the implementation of corrective measures. Especially in low- and medium-income countries where access to novel therapies may be challenging, allo-HCT still represents an attractive therapeutic option for MF. Future directions include integrating new therapeutics into the transplant algorithm and leveraging artificial intelligence for more informed risk assessment, highlighting the need for tailored approaches to improve allo-HCT outcomes in such a setting.

Can you spare 100days? The allogeneic hematopoietic cell transplant caregiver requirement from the perspective of social workers.

A caregiver is generally required for a patient to proceed with allogeneic hematopoietic cell transplantation (alloHCT). If continuous caregiver support is not available, alloHCT will likely not be a treatment option. A qualitative study design was used to explore caregiver requirements from the perspectives of social workers (SWs). Secondary objectives included learning about requirement flexibility, barriers, and ideas to support patients and caregivers. Semi-structured web-based focus groups were conducted with alloHCT SWs who worked with adults at the United States (U.S.) transplant centers (TCs) from May to July 2022. Focus groups explored TC caregiver requirements, including flexibility and exceptions, origins, and barriers. Twenty-two SWs from TCs across the U.S. participated. All noted their TC required a caregiver to proceed to alloHCT, though there was variation in the length of time a caregiver was required and the distance needed to stay near the TC post-alloHCT. Most participants described differences within the transplant team in allowing exceptions to caregiver requirements. SWs described barriers including finances and patients needing to relocate closer to the TC. SWs reported variation in caregiver requirements across TCs. Though variation may allow for some flexibility, it may contribute to access barriers. Additional research is needed to identify essential requirements for safe post-transplant care and monitoring and to develop patient-centered models to help patients access life-saving treatment.

Evaluation of CMV T-cell Mediated Immunity in Children with CMV DNAemia After Allogeneic Hematopoietic Cell Transplantation

Abstract Background Cytomegalovirus (CMV) is among the most common infectious complications following allogeneic hematopoietic cell transplantation (allo-HCT). A commercially available CMV T-cell immune panel (CMV-TCIP, Viracor®), reported as percentages of CMV-specific interferon gamma releasing CD4 and CD8 cells (%CMV-CD4 or %CMV-CD8 IFN-γ), may be used to assess CMV cell-mediated immunity (CMV-CMI). However, the utility of this assay among pediatric allo-HCT recipients remains unknown. Methods A retrospective analysis among pediatric allo-HCT recipients (age ≤18 years) from 1/2020 to 11/2023 who developed CMV DNAemia and had CMV-TCIP testing was performed. Per institutional protocol, weekly quantitative plasma CMV PCR was performed until day +100. Clinically significant CMV infection (csCMVi) was defined as CMV viral load (VL) ≥500IU/ml and pre-emptive therapy (PET) was provided for csCMVi. The most frequent indications for CMV-TCIP testing were to evaluate CMV-CMI to inform the need of CMV virus-specific T-cell therapy (CMV-VST) in the setting of resistant/refractory CMV, to monitor CMV-CMI as a proxy of VST expansion post CMV-VST, or to evaluate the need of ongoing secondary antiviral prophylaxis. A %CMV-CD4 or %CMV-CD8 IFN-γ ≤0.2% was categorized as a poor response, whereas a result >0.2% was classified as an adequate response. Specimens with insufficient quality, high background, or discrepant results from %CMV-CD4 or %CMV-CD8 were classified as a discordant response. Demographics, underlying condition, HCT type, conditioning regimen, antiviral agents and use of VST, VL, and CMV-TCIP results were recorded. Descriptive and nonparametric statistics (median, interquartile range [IQR]) were used for analysis. Results Twenty-seven CMV-TCIP results from 10 unique allo-HCT recipients were analyzed. The median age at transplant was 8.5 years (IQR 2.75-14.3), predominantly for hematologic malignancy (70%). CMV donor/recipient (D/R) serostatus were D+/R+ (60%), D-/R+ (30%) and D+/R- (10%). CMV DNAemia developed post-HCT in 80% (8/10) with median onset of 4 days post-HCT (IQR 3-40) and 2 subjects had known DNAemia prior to HCT. Nine (90%) subjects were started on PET for csCMVi, whereas 1 (10%) received antiviral therapy when VL was <500IU/ml. The first CMV-TCIP was obtained at median of 112 days (IQR 42-130) post-HCT. Despite appropriate antiviral therapy, patients with a peak VL ≥500 IU/mL (obtained within 1 week before and after CMV-TCIP testing) demonstrated significantly lower absolute CD4 (median 12 vs. 198 cells/uL, p=0.02) and CD8 (median 79 vs. 443 cells/uL, p=0.04) counts and %CMV-CD4 IFN-γ (0.04% vs. 0.36%, p=0.02) compared to those with a peak VL <500 IU/mL. Conclusion Our results suggest that CMV-CMI, particularly %CMV-CD4 IFN-γ >0.2%, was observed concurrently with downward trending VL, and may serve as a proxy of VST expansion in patients receiving CMV-VSTs. Figure 1A. The distribution of peak VLs over time based on %CMV-CD4 and %CMV-CD8 IFN-γ are demonstrated in Figure 1B. CMV peak VLs were lower with TCIP testing results reported as adequate combined responses compared to those with poor combined responses. In five subjects (50%) who received CMV-VSTs as part of CMV therapy, increased %CMV-CD4 and %CMV-CD8 IFN-γ were observed post-infusion with an observed downward trend in VL.

Antibody responses to re-immunization in recipients of allogeneic hematopoietic cell transplantation

Abstract Background Immunologic memory against vaccine-preventable diseases is often lost after an allogeneic hematopoietic cell transplant (allo-HCT), therefore recipients are required to be re-immunized after allo-HCT to regain immunity against these infections. But the response to vaccination after an allo-HCT can be highly variable and is not well understood. We performed a single center retrospective study to examine immunization practices and determine the rate of vaccine protection and seroconversion following vaccination after allo-HCT. Methods Electronic medical records (EMR) from patients ≤18 years of age who underwent allo-HCT at St. Jude Childrens’ Research Hospital between 2005 - 2021 were reviewed. Clinical information and serology results before and after completion of the immunizations series were extracted from the EMR. The vaccines included in this analysis were diphtheria, measles, mumps, rubella (MMR), varicella, and polio. Protection was evaluated only for infections with established immune correlates. Seroconversion was defined as 4-fold increase in titers for vaccines with quantitative antibody assays, or as a change from negative to positive IgG for vaccines with qualitative antibody tests. Results 760 patients were included in this cohort. Demographic and clinical data are summarized in Table 1. The mean age at allo-HCT was 10.4 years, most were male (56.8%) and white (74.6%). Acute leukemia accounted for 66.4% of allo-HCT recipients. Conditioning was myeloablative for 53.45%, and reduced intensity for 37.9%. Most received transplants from mismatched-related donors, (44.9%), followed by matched unrelated donors (35.4%) and matched related donors (19.5%). The number of patients who received the full vaccination series at our institution differed by vaccine and ranged from 41-150, and the respective subsets with available pre-vaccination and post-vaccination titers ranged from 24-93. The median time from transplant to initiation of immunizations was 12 months (range: 6-58) for non-live vaccines, 25 months (range: 23, 63) for MMR vaccine, and 28 months (range: 16, 117)) for varicella vaccine. Protection post immunization varied, with less patients demonstrating protections for mumps (79%) and measles (82%) (Figure 1). Seroconversion also varied among the different vaccine components and types of vaccines. Conclusion Current strategies to re-immunize patients after allo-HCT do not provide protection to all patients. Understanding the factors associated with suboptimal immune responses is critical for advancing our knowledge in this area. Whether time-based approaches combined with immune reconstitution data are required to further optimize protection remains unclear. Additionally, different vaccine schedules (i.e., higher doses) may be required in these patients. Figure 1. Protection and seroconversion rate by vaccine target.

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy

BackgroundCerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.MethodsIn a phase 2–3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score.ResultsA total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up.ConclusionsAt a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.)

Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy

BackgroundGene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear.MethodsWe performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2–3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104.ResultsHematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM–EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT.ConclusionsHematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.)

Novel machine learning technique further clarifies unrelated donor selection to optimize transplantation outcomes

AbstractWe investigated the impact of donor characteristics on outcomes in allogeneic hematopoietic cell transplantation (HCT) recipients using a novel machine learning approach, the Nonparametric Failure Time Bayesian Additive Regression Trees (NFT BART). NFT BART models were trained on data from 10 016 patients who underwent a first HLA-A, B, C, and DRB1 matched unrelated donor HCT between 2016 and 2019, reported to the Center for International Blood and Marrow Transplant Research, then validated on an independent cohort of 1802 patients. The NFT BART models were adjusted based on recipient, disease, and transplant variables. We defined a clinically meaningful impact on overall survival (OS) or event-free survival (EFS; survival without relapse, graft failure, or moderate to severe chronic graft-versus-host disease) as >1% difference in predicted outcome at 3 years. Characteristics with <1% impact (within a zone of indifference) were not considered to be clinically relevant. Donor cytomegalovirus, parity, HLA-DQB1, and HLA-DPB1 T-cell epitope matching fell within the zone of indifference. The only significant donor factor that associated with OS was age, in which, compared with 18-year-old donors, donors aged ≥31 years old were associated with lower OS. Both donor age (≤32 years) and use of a male donor, regardless of recipient sex, improved EFS. We, therefore, recommend selecting the earliest available donor within the 18 to 30 years age range for HCT to optimize OS. If several donors in the 18 to 30 years age range are available, a male donor may be chosen to optimize EFS.

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT

AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML

AbstractMeasurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.

Universal protection of allogeneic T-cell therapies from natural killer cells via CD300a agonism

AbstractImmunogenicity limits the persistence of off-the-shelf allogeneic cell therapies and transplants. Although ablation of HLA removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered trans-antigen signaling receptors (TASRs) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. A model allogeneic T-cell therapy coexpressing an anti-CD19 chimeric antigen receptor and CD300a TASR, produced using multiplexed nonviral integration, exhibited enhanced B-cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies.

Toxoplasma qPCR kinetics to guide pre-emptive treatment of toxoplasmosis after allogeneic hematopoietic stem cell transplantation.

Recent ECIL-guidelines recommend a quantitative PCR (qPCR) guided pre-emptive treatment approach to toxoplasmosis in seropositive recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While qPCR might serve as a sensitive tool for early Toxoplasma detection, its role in treatment follow-up remains unknown. We analyzed the qPCR kinetics of allo-HCT recipients experiencing either Toxoplasma infection (TI, n=71) or disease (TD, n=14) in relation to different parameters. We included 85 patients with available qPCR values expressed as quantitative cycle (Cq) from four large hematological centers from 2009 to 2023, and kinetic analysis was performed in a selection of 74 patients screened at least weekly with blood qPCR. Day 0 (D0) was the day of anti-Toxoplasma treatment start or (when untreated) day of diagnosis. Time to qPCR negativity was inversely proportional to the Cq value at D0 (p=0.0063). Not reaching negativity at D10 was associated with a significantly higher mortality at D30 (p=0.023). Patients with a high D0-parasitic load and patients with TD showed slower clearance (p<0.001, p=0.032). Time to negativity was not significantly different for patients started on prophylactic vs curative doses as first-line treatment regimen (p=0.16). This study underscores the predictive value of qPCR kinetics monitoring in allo-HCT patients with toxoplasmosis. With the aforementioned risk factors, clinicians can identify patients at high-risk for worse outcome. Our results support to consider a therapeutic change or reinforcement if the parasitic load does not decrease after 10 days, supplementing existing clinical guidelines.