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Summary: Routine ABO blood group typing of apparently healthy individuals sporadically uncovers unexplained mixed‐field reactions. Such blood group discrepancies can either result from a haematopoiesis‐confined or body‐wide dispersed chimerism or mosaicism. Taking the distinct clinical consequences of these four different possibilities into account, we explored the responsible cause in nine affected individuals. Genotype analyses revealed that more than three‐quarters were chimaeras (two same‐sex females, four same‐sex males, one sex‐mismatched male), while two were mosaics. Short tandem repeat analyses of buccal swab, hair root and nail DNA suggested a body‐wide involvement in all instances. Moreover, genome‐wide array analyses unveiled that in both mosaic cases the causative genetic defect was a unique copy‐neutral loss of heterozygosity encompassing the entire long arm of chromosome 9. The practical transfusion‐ or transplantation‐associated consequences of such incidental discoveries are well known and therefore easily manageable. Far less appreciated is the fact that such findings also call attention to potential problems that directly ensue from their specific genetic make‐up. In case of chimerism, these are the appearance of seemingly implausible family relationships and pitfalls in forensic testing. In case of mosaicism, they concern with the necessity to delineate innocuous pre‐existent or age‐related from disease‐predisposing and disease‐indicating cell clones. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 36-year-old man with Chediak-Higashi syndrome (CHS), a rare immunodeficiency disorder. The man underwent an allogeneic stem cell transplant (AlloSCT) 25 years ago, which resolved his haematological and immunological dysfunction but did not prevent neurological deterioration. The patient presented with symptoms of immune haemolysis, and laboratory investigations revealed a mixed chimerism state, where haematopoiesis originated from both the donor and recipient. The article highlights the importance of leucocyte inclusions in diagnosing CHS and discusses the potential benefits of mixed chimerism in improving haemopoietic function and immune competence. [Extracted from the article]

ABO blood group discrepancies in healthy individuals were caused by body-wide chimerism and mosaicism. They can be evaluated with new diagnostic options for disease-related cell clones that are typically associated with mosaicism. The observations raise the attention for sporadic mixed-field observations of any blood group antigen. Commentary on: Dauber et al. Body-wide chimerism and mosaicism are predominant causes of naturally occurring ABO discrepancies. Br J Haematol 2024; 205:1188-1196., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P

Keywords: graft versus leukaemia effect; haematopoietic stem cell transplantation; interferon alpha; juvenile myelomonocytic leukaemia; mixed chimerism EN graft versus leukaemia effect haematopoietic stem cell transplantation interferon alpha juvenile myelomonocytic leukaemia mixed chimerism e34 e36 3 11/24/22 20221201 NES 221201 Juvenile myelomonocytic leukaemia (JMML) is an aggressive disorder of childhood, characterized by clonal evolution of the myelomonocytic populations, driven by mutations in five genes ( I PTPN11, KRAS, NRAS, CBL, NF1 i ).1 For most patients, the only curative option is allogeneic haematopoietic stem cell transplantation (HSCT). IFN administration increased or stabilized donor chimerism in the CD3 compartment but not in the CD15/14 (Table S3); all patients relapsed and underwent a second HSCT. At a median follow up of 4 years from diagnosis, 20/27 (74%) patients are alive in CR, five patients died of disease progression and two of transplant-related mortality (TRM) following second HSCT. [Extracted from the article]

Summary: Allogeneic haematopoietic stem cell transplant (allo‐HSCT) offers potentially curative therapy for patients with relapsed/refractory lymphoid malignancies. Reduced‐intensity conditioning (RIC) with Alemtuzumab reduces transplant‐related mortality and graft‐versus‐host disease (GvHD), but may be associated with increased risk of relapse. With the aim of studying the effect of GVHD and donor lymphocyte infusions (DLI) on relapse, we performed a retrospective study of 288 patients (57% non‐Hodgkin lymphoma, 24% Hodgkin lymphoma and 19% chronic lymphocytic leukaemia; 58% were relapsed/refractory) who underwent RIC‐Alemtuzumab‐HSCT between 2000 and 2012. Median follow‐up time for survivors was 64 months. Five‐year overall survival, relapse incidence, GvHD/relapse‐free survival and non‐relapse mortality were 47%, 33%, 37% and 28% respectively. Cumulative incidence of grade II‐IV acute and extensive chronic GvHD was 22% and 21% at 100 days and 5 years respectively. On multivariate analysis, presence of GvHD (P = 0·03) and unrelated donor type (P = 0·03) were protective of relapse. 62/288 patients received DLI for either mixed donor chimerism (prophylactic DLI, n = 37) or clinical relapse (therapeutic DLI, n = 25). Prophylactic and therapeutic DLI successfully converted the patient to full or stable mixed donor chimerism in 78% and 56% of patients respectively. These data demonstrate good long‐term outcomes and support the concept of the graft‐vs‐lymphoma effect as a key protective factor against relapse following RIC‐Alemtuzumab allo‐HSCT for patients with mature lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Summary: Allogeneic haematopoietic stem‐cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high‐risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T‐cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft‐versus‐leukaemia effects. T‐replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single‐arm prospective Phase II clinical trial of sequential chemotherapy and T‐replete transplantation using reduced‐intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty‐seven patients with relapsed/refractory AML or high‐risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment‐related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late‐onset graft‐versus‐host disease protected against relapse. In conclusion, a T‐replete sequential transplantation using reduced‐intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft‐versus‐leukaemia effects without DLI. [ABSTRACT FROM AUTHOR]

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia ( ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease ( MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days −30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions ( DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10−3. Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival ( OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment ( P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. [ABSTRACT FROM AUTHOR]

Red blood cell ( RBC) antibodies can persist for decades or decrease quickly to undetectable levels. Antibody persistence has not been systematically studied. Women whose children are treated with intrauterine transfusions ( IUT) for haemolytic disease of the fetus ( HDFN) often produce additional antibodies, which can be evoked by the intrauterine transfusion or by fetomaternal haemorrhage during the procedure. Factors associated with persistence of both the antibodies responsible for HDFN and additional antibodies were studied in 260 women whose children were treated with IUT between 1988 and 2008. They possessed 499 (205 anti-D and 294 non-D) antibodies after the last IUT. After a median follow-up of 8·7 years, all 260 antibodies primarily responsible for HDFN had persisted. Additional antibodies directed against antigens of the children persisted in 70·6%, and in 32·3% if they were not child-specific ( P < 0·001). Antibodies induced by irradiated IUT persisted in only 7·1%. Multivariate analyses showed that non- HDFN antibody persistence was dependent on the antibody titre and specificity. In conclusion, persistence of antibodies mainly depends on antibody strength and specificity. Difference between fetal or non-fetal immunogens suggests maintenance of antigenic stimulation possibly by long-term fetomaternal chimerism. [ABSTRACT FROM AUTHOR]

Analysis of short tandem repeats ( STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease ( GVHD)/graft-versus-tumour ( GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping ( UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant ( SCT) Chimerism Monitoring Programme. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 44-year-old man with asymptomatic Binet stage A chronic lymphocytic leukaemia (CLL). It mentions administration of courses of fludarabine, cyclophosphamide, alemtuzumab and high-dose methylprednisolone because of insufficient response and immune thrombocytopenia. It also mentions ibrutinib have the ability to enhance the activity of donor T cells in the context of relapse after haematopoietic stem cell transplantation (HSCT).

The article discusses the retrospective study on CD3+ T-cell purities to determine purity variability degree of the fractionated product used for lineage-specific chimerism assessments and factors that influence these levels. Topics discussed include blood samples collected from patients who had undergone allogeneic haematopoietic stem cell transplantation (HSCT), and findings like highly variable post-fractionation purity testing quality, especially with low lymphocyte count.

This study aimed to describe kinetics of complete donor chimerism occurrence ( cDC, >99·9% donor) after unrelated cord blood transplantation ( UCBT), to identify its predictive factors and its impact on post-transplant outcome. Ninety-four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post-transplant dates, using a real-time polymerase chain reaction method with 0·1% sensitivity. Cumulative incidence of cDC at 1 year post-transplantation was 61·8%. Three predictive factors were identified in multivariate analysis: history of malignant disease ( P = 0·03), older age (above 2·16 years, the first quartile of age, P = 0·0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5-6/6, P < 0·001) increased the probability of post-transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99·9% donor chimerism on days 15-30 post-transplant) appeared useful to predict engraftment ( P = 0·003) as well as acute and chronic graft-versus-host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC ≤99·9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT. [ABSTRACT FROM AUTHOR]

Allogeneic haematopoietic stem cell transplantation ( HSCT) is the only curative option for patients with Diamond Blackfan anaemia ( DBA). We report the transplantation outcome of 30 Italian DBA patients referred to the Italian Association of Paediatric Haematology and Oncology Registry between 1990 and 2012. This is one of the largest national registry cohorts of transplanted DBA patients. Most patients (83%) were allografted after 2000. A matched sibling donor was employed in 16 patients (53%), the remaining 14 patients (47%) were transplanted from matched unrelated donors. Twenty-eight of the 30 patients engrafted. One patient died at day +6 due to veno-occlusive disease without achieving neutrophil recovery and another patient remained transfusion-dependent despite the presence of a full donor chimerism. The 5-year overall survival and transplant-related mortality was 74·4% and 25·6%, respectively. Patients younger than 10 years as well as those transplanted after 2000 showed a significantly higher overall survival and a significantly lower risk of transplant-related mortality. No difference between donor type was observed. Our data suggest that allogeneic HSCT from a related or unrelated donor was a reasonable alternative to transfusion therapy in young and well chelated DBA patients. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplants (HSCTs) are carried out across the world to treat haematological and immunological diseases which would otherwise prove fatal. Certain diseases are predominantly encountered in paediatric patients, such severe primary immunodeficiencies (PID) and diseases of inborn errors of metabolism (IEM). Chimaerism testing for these disorders has different considerations compared to adult diseases. This review focuses on the importance of cell-lineage-specific chimaerism testing and examines the appropriate cell populations to be assessed in individual paediatric patient groups. By analysing disease-associated subpopulations, abnormalities are identified significantly earlier than in whole samples and targeted clinical decisions can be made. Chimaerism methods have evolved over time and lead to an ever-increasing level of sensitivity and biomarker arrays to distinguish between recipient and donor cells. Short tandem repeat (STR) is still the gold standard for routine chimaerism assessment, and hypersensitive methods such as quantitative and digital polymerase chain reaction (PCR) are leading the forefront of microchimaerism testing. The rise of molecular methods operating with minute DNA amounts has been hugely beneficial to chimaerism testing of paediatric samples. As HSCTs are becoming increasingly personalised and risk-adjusted towards a child's individual needs, chimaerism testing needs to adapt alongside these medical advances ensuring the best possible care., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

A number of advances in clinical practice that are considered routine in modern allogeneic transplant programmes lack definitive supporting evidence, partly because they may offer modest incremental benefits that are difficult to demonstrate in a statistically robust manner given the relatively small cohorts of patients who undergo such procedures. Nevertheless, these marginal gains probably contribute therapeutically meaningful overall benefit, particularly when aggregated. We review the evidence for a number of these practices in terms of impact on transplant outcomes, with particular reference to the setting of T cell depletion as widely practiced in the United Kingdom, including high resolution tissue typing, surveillance for and therapy of infectious complications, chimerism-directed immune modulation and more sensitive monitoring for residual or progressive disease. [ABSTRACT FROM AUTHOR]

Following reduced intensity-conditioned allogeneic stem cell transplantation ( RIC allo- SCT) for chronic lymphocytic leukaemia ( CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease ( GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo- SCT and pre-emptive donor lymphocyte infusions ( DLI) for mixed chimerism or minimal residual disease ( MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p−). Of patients who were not in complete remission ( CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4·3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p−). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6·4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD. [ABSTRACT FROM AUTHOR]

Ninety-one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR-PCR) was used to stratify patients into five groups: (A) complete donor chimeras ( n = 39), (B) transient mixed chimeras ( n = 15) (C) stable mixed chimeras ( n = 18), (D) progressive mixed chimeras ( n = 14) (E) recipient chimeras with early graft rejection ( n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection ( n = 10, P < 0·0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR-PCR indicated an inverse correlation between detection of recipient cells post-SCT and occurrence of acute GvHD ( P = 0·008). PMC was a bad prognostic indicator of survival ( P = 0·003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA. [ABSTRACT FROM AUTHOR]

The article offers information on the association of T-cell chimerism switch and memory T-cell expansion with cord blood transplantation. It states that cord blood contains immature immune cells and is sources of stem cells. It further highlights cases of immune-mediated complications such as pre-engraftment immune reaction (PIR) and haemophagocyticsyndrome (HPS) are reported after early after cord blood transplantation(CBT).

The article discusses a study which investigated the effect of natural killer (NK) cells in promoting engraftment after haematopoietic stem cell transplantation (HSCT) for non-malignant disease. The study analyzed variations in the numbers of peripheral NK cells between people with full donor chimaerism (FDC) and those with mixed donor chimaerism (MDC). It notes that NK cells have a potential role in HSCT for non-malignant diseases.

A total of 57 patients with Wiskott-Aldrich syndrome (WAS) were studied after undergoing stem cell transplantation (SCT) in Japan between January 1985 and December 2004. Eleven patients received transplants from human leucocyte antigen (HLA)-matched related donors, 10 from HLA-mismatched related donors, 21 from unrelated bone marrow donors, and 15 from unrelated cord blood donors. Nine of the 57 patients rejected the initial graft. The overall 5-year survival rate was 73.7% and the 5-year failure-free survival rate was 65.7% (failure was defined as rejection or death). The overall 5-year survival rates for patients receiving bone marrow and cord blood from unrelated donors were both 80.0%. Based on univariate analysis, the factors associated with poor survival were: transplantation from an HLA-mismatched related donor, patient age of more than 5 years at the time of transplantation, and a conditioning regimen other than busulfan and cyclophosphamide (BU-CY) or busulfan, cyclophosphamide and antithymocyte globulin (BU-CY-ATG). In a multivariate analysis, a conditioning regimen other than BU-CY and BU-CY-ATG was the only independent factor associated with transplantation failure. Given the improved outcome for WAS patients following transplantation from an unrelated donor, we conclude that patients with WAS should receive SCT as soon as possible after diagnosis.