Chimerism in the realm of hematopoietic stem cell transplantation for non-malignant disorders-A perspective

Hematopoietic stem cell transplantation (HCT) is a curative intervention in non-malignant disorders (NMD) that benefit from donor-derived hematopoiesis, immunity, and establishment of vital cells or enzyme systems. Stability or reversal of disease symptoms depends on adequacy and long-term stability of donor cell engraftment in the compartment of interest. Unlike hematologic malignancies where complete replacement with donor derived hematopoiesis is desirable for a cure, NMD manifestations can often be controlled in the presence of mixed chimerism. This allows for exploration of reduced intensity conditioning regimens that can limit organ toxicity, late effects, and increase tolerability especially in young recipients or those with a large burden of disease related morbidity. However, the levels of donor chimerism conducive to disease control vary between NMD, need to focus on the hematopoietic lineage necessary to correct individual disorders, and need to be assessed for stability over time, i.e., a whole lifespan. An enhanced ability to reject grafts due to recipient immune competence, alloimmunization, and autoimmunity add to the complexity of this balance making NMD a highly diverse group of unrelated disorders. The addition of donor factors such as stem cell source and Human-Leukocyte-Antigen match extend the complexity such that \u27one size does not fit all\u27. In this perspective, we will discuss current knowledge of the role of chimerism and goals, approach to HCT, and emerging methods of boosting engraftment and graft function, and monitoring recommendations. We draw attention to knowledge gaps and areas of necessity for further research and research support

Sickle Cell Transplantation Evaluation of Long-term and Late Effects Registry (STELLAR) to compare long-term outcomes after hematopoietic cell transplantation to those in siblings without sickle cell disease and in nontransplanted individuals with sickle cell disease: Design and feasibility study

BACKGROUND: There are sparse data on the long-term and late effects of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). OBJECTIVE: This study aims to establish an international registry of long-term outcomes post-HCT for SCD and demonstrate the feasibility of recruitment at a single site in the United States. METHODS: The Sickle Cell Transplantation Evaluation of Long-Term and Late Effects Registry (STELLAR) was designed to enroll patients with SCD ≥1 year post-HCT, their siblings without SCD, and nontransplanted controls with SCD to collect web-based participant self-reports of health status and practices by using the Bone Marrow Transplant Survivor Study (BMTSS) surveys, health-related quality of life (HRQOL) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25 or Pediatric Profile-29 survey, chronic graft-versus-host disease (cGVHD) using the symptom scale survey, daily pain using an electronic pain diary, the economic impact of HCT using the financial hardship survey, sexual function using the PROMIS Sexual Function SexFSv2.0 survey, and economic productivity using the American Time Use Survey (ATUS). We also piloted retrieval of clinical data previously submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR); recorded demographics, height, weight, blood pressure, waist and hip circumferences, timed up and go (TUG) test, and handgrip test; and obtained blood for metabolic screening, gonadal function, fertility potential, and biorepository of plasma, serum, RNA, and DNA. RESULTS: Of 100 eligible post-HCT patients, we enrolled 72 (72%) participants aged 9-38 (median 17) years. We also enrolled 19 siblings aged 5-32 (median 10) years and 28 nontransplanted controls with SCD aged 4-46 (median 22) years. Of the total 119 participants, 73 (61%) completed 85 sets of surveys and 41 (35%) contributed samples to the biorepository. We completed ATUS interviews of 28 (24%) participants. We successfully piloted retrieval of data submitted to the CIBMTR and expanded recruitment to multiple sites in the United States, Canada, the United Kingdom, and Nigeria. CONCLUSIONS: It is feasible to recruit subjects and conduct study procedures for STELLAR in order to determine the long-term and late effects of HCT for SCD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36780

Aberrant T-cell exhaustion in severe combined immunodeficiency survivors with poor T-cell reconstitution after transplantation

BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4 METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4 CONCLUSIONS: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism \u3c5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels \u3e0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels \u3e0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level \u3e2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633

XPERT MYCOBACTERIUM TUBERCULOSIS/RIFAMPICIN ASSAY: A BOON IN TUBERCULOSIS DIAGNOSTICS

Objectives: Mycobacterium tuberculosis (MTB) remains one of the most significant causes of mortality and morbidity in developing countriesespecially India. India has the highest burden of TB, with an estimated incidence figure of 2.1 million cases out of the 9 million cases of TB globally.Diagnosis of TB relies on conventional microscopy and culture with drawbacks related to sensitivity, specificity, turn around time (TAT). The aim ofthis study was to evaluate the performance of Xpert MTB/rifampicin (RIF) assay (GX) for MTB detection in pulmonary and extrapulmonary clinicalsamples.Methods: A total of 209 clinical specimens (182: pulmonary and 27: extrapulmonary) were processed using auramine smear, culture by mycobacteria growth indicator tube and GenXpert.Results: The sensitivity of GenXpert was 62.63% for pulmonary and 55% for extrapulmonary samples. The sensitivity and specificity of GX were100% for the smear positive cases. The sensitivity, specificity, positive predictive value, and negative predictive value of the GX for smear negativecases were 67.8%, 97.5%, 90.4%, and 89.6%, respectively. RIF resistance was detected in 3.8% the samples.Conclusion: GenXpert, with short TAT, high sensitivity, specificity and less technical expertise required is a promising tool in TB diagnostics for thefuture.Keywords: GenXpert, Tuberculosis diagnosis, Molecular method, Rifampicin resistance

Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease

INTRODUCTION: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients. METHODS: CD34 cells were enriched using the CliniMACS RESULTS: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline. DISCUSSION: These results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution

The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue functio