The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Risk Factors Associated with Survival Following Ganciclovir Prophylaxis through Day +100 in Cytomegalovirus At-Risk Pediatric Allogeneic Stem Cell Transplantation Recipients: Development of Cytomegalovirus Viremia Associated with Significantly Decreased 1-Year Survival.

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and nonrelapse mortality (NRM) in pediatric allogeneic stem cell transplantation (alloSCT) recipients. Approximately 80% of CMV seropositive alloHCT recipients will experience CMV reactivation without prophylaxis. The impacts of ganciclovir prophylaxis and subsequent CMV viremia on 1-year survival and 1-year NRM are unknown. The primary objective of this study was to determine the effect of CMV viremia on the probability of 1-year survival and 1-year NRM in pediatric alloSCT recipients receiving 100 days of ganciclovir prophylaxis. The secondary objective was to determine the effect of other risk factors on 1-year survival and 1-year NRM. All patients age 0 to 26 years who underwent alloSCT between June 2011 and May 2020 and received ganciclovir prophylaxis for 100 days at Westchester Medical Center, an academic medical center, were analyzed. Ganciclovir was administered to at-risk alloSCT recipients (donor and or recipient CMV+ serostatus) as 5 mg/kg every 12 hours from the first day of conditioning through day -1 (recipient CMV+ only) followed by 6 mg/kg every 24 hours on Monday through Friday beginning on the day of an absolute neutrophil count >750/mm3 and continuing through day +100. National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria were used to grade toxicity. NRM was analyzed using competing survival analysis with relapse death as a competing event. The log-rank and Gray tests were performed to compare the 1-year survival probabilities and NRM cumulative incidence between patients who experienced CMV viremia post-alloSCT and those who did not. Univariate Cox regression analysis was performed for the following risk factors: CMV viremia, donor source, sex, malignant disease, disease risk index, conditioning intensity, receipt of rabbit antithymocyte globulin (rATG)/alemtuzumab, graft-versus-host disease (GVHD) prophylaxis, CMV donor/recipient serostatus, grade II-IV acute GVHD, and grade 3/4 neutropenia necessitating discontinuation of ganciclovir, treating the last 3 factors as time-dependent covariates. Those with P values < .2 were included in the multivariate Cox regression analysis. Eighty-four alloSCT recipients (41 males, 43 females; median age, 10.8 years [range, .4 to 24.4 years]) were analyzed. Multivariate analysis showed significantly lower 1-year survival and significantly higher 1-year NRM in patients who developed CMV viremia compared to those who did not (P = .0036). No other risk factors were significantly associated with 1-year survival or 1-year NRM. One-year survival was significantly decreased and 1-year NRM was significantly increased in pediatric alloSCT recipients who developed CMV viremia following ganciclovir prophylaxis. No other risk factors were found to be associated with 1-year survival or 1-year NRM. Alternative CMV prophylaxis regimens that reduce CMV viremia should be investigated in pediatric alloSCT recipients at risk for CMV infection.

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

Manufacture and Characterization of Good Manufacturing Practice-Compliant SARS-COV-2 Cytotoxic T Lymphocytes.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2-vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS). METHODS: Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of interferonγ (IFN-γ)+ CD4 and CD8 T cells using flow cytometry. Clinical-grade SARS-CoV-2-vCTLs were manufactured using the CliniMACS CCS. The enriched SARS-CoV-2-vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis. RESULTS: Of the convalescent donor blood samples, 93% passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that were 79% (standard error of the mean 21%) IFN-γ+ T cells. SARS-CoV-2-vCTLs displayed a highly diverse T-cell receptor repertoire with enhancement of both memory CD8 and CD4 T cells, especially in CD8 TEM, CD4 TCM, and CD4 TEMRA cell subsets. SARS-CoV-2-vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways. CONCLUSIONS: Highly functional SARS-CoV-2-vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors. CLINICAL TRIALS REGISTRATION: NCT04896606.

Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD): The First Reported Use in Pediatric Patients.

Allogeneic hematopoietic stem cell transplant (alloHSCT) can be a life-saving treatment for patients with hematological disorders but far too often carries the feared complication of graft-versus-host disease (GVHD). The first-line treatment of GVHD is typically corticosteroids, but steroid-refractory chronic GVHD (cGVHD) has led to the Food and Drug Administration (FDA) approval of ruxolitinib (Jakafi), ibrutinib (Imbruvica), and belumosudil (Rezurock). Patient 1 was a four-year-old female diagnosed with natural killer (NK) cell dysfunction who underwent alloHSCT with cells from a 9/10 National Marrow Donor Program (NMDP) donor and subsequently developed chronic GVHD (cGVHD) of the skin and gut. This cGVHD was refractory to steroids and ibrutinib but improved with the administration of concomitant ibrutinib and ruxolitinib. Patient 2 was a one-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother but developed bronchiolitis obliterans organizing pneumonia (BOOP) and pathology-confirmed GVHD. This cGVHD was steroid-refractory and resolved with the administration of concomitant ibrutinib and ruxolitinib. To our knowledge, this is the first reported use of concomitant ruxolitinib and ibrutinib in pediatric patients. The combination was well tolerated with no significant adverse events. Neither patient had to discontinue these drugs. We propose a further investigation into this dual therapy in cGVHD either compared to steroids or as a second-line option.

Significant improvement of child physical and emotional functioning after familial haploidentical stem cell transplant.

Allogeneic stem cell transplantation (AlloSCT) represents the only curative therapy for sickle cell disease (SCD). However, limited availability of matched related donors and suboptimal outcomes following AlloSCT with unrelated donors has led to investigation of alternative donors. Among children with high-risk SCD, we evaluated health-related quality of life (HRQoL) impact in the two years following familial haploidentical SCT. HRQoL was collected from parent and child raters, using the Child Health Ratings Inventories Generic measure and haploidentical SCT-specific module. Repeated measures models were fit to assess HRQoL changes over time and by rater. Nineteen children (mean age 12.9 yrs [standard deviation, 5.3]; 63% male) and their parents were included. There were no differences in the 2-yr trajectories of child physical or emotional functioning (EF) by rater. Child physical functioning and EF scores were significantly lower at day +45 than baseline, but scores recovered by day +180. There was significant improvement in EF (p = 0.03) at 2 yrs vs baseline. A similar pattern of scores over time was seen for parent ratings of child's global HRQoL. Despite treatment intensity in the initial months following AlloSCT, patient scores recovered or exceeded baseline scores at two years. This trial is registered at clinicaltrials.gov (NCT01461837).

Modelling group movement with behaviour switching in continuous time.

This article presents a new method for modelling collective movement in continuous time with behavioural switching, motivated by simultaneous tracking of wild or semi-domesticated animals. Each individual in the group is at times attracted to a unobserved leading point. However, the behavioural state of each individual can switch between 'following' and 'independent'. The 'following' movement is modelled through a linear stochastic differential equation, while the 'independent' movement is modelled as Brownian motion. The movement of the leading point is modelled either as an Ornstein-Uhlenbeck (OU) process or as Brownian motion (BM), which makes the whole system a higher-dimensional Ornstein-Uhlenbeck process, possibly an intrinsic non-stationary version. An inhomogeneous Kalman filter Markov chain Monte Carlo algorithm is developed to estimate the diffusion and switching parameters and the behaviour states of each individual at a given time point. The method successfully recovers the true behavioural states in simulated data sets , and is also applied to model a group of simultaneously tracked reindeer (Rangifer tarandus).

Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.