More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Background

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients, but indication to transplant remains controversial. We performed a retrospective multicentre study on 712 patients with CGD undergoing allo-HCT transplanted in EBMT centres between 1993 and 2018. We studied 635 children (aged < 18 years) and 77 adults. Median follow-up was 45 months. Median age at transplant was 7 years (range: 0.1-48.6). Kaplan-Meier estimates of OS and EFS at 3 years were 85.7% (95% CI, 82.8-88.5) and 75.8% (95% CI, 72.3-79.3), respectively. On MVA, older age was associated with reduced survival (HR= 1.69, p= 0.0001) and increased chronic GVHD (HR 1.35, p=0.01). Nevertheless OS and EFS at 3 years for patients ≥ 18 years was 76% (95%CI, 66-86) and 69% (95%CI, 57-80), respectively. Use of one antigen-mismatched donors was associated with reduced OS (HR= 2.29, p= 0.01) and EFS (HR 2.37, p=0.001). No significant difference was found in OS, but a significantly reduced EFS (HR 3.69 p=0.001), in the small group who received a transplant from a donor with more than one antigen-mismatch. Choice of conditioning regimen did not influence OS or EFS. In conclusion we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of one antigen-mismatched grafts have a less favourable outcome. Transplant should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

The monitoring of chimerism by PCR has become a routine diagnostic approach in patients after allogeneic bone marrow or peripheral blood stem cell transplantation. Nevertheless, a temporal correlation between molecular and hematologic assessment of engraftment has not been clearly established. To address this issue, and to determine the potential clinical implications of early kinetics of mixed chimerism, we have investigated 66 allogeneic stem cell transplantations (SCTs) in 58 pediatric patients suffering from different types of leukemia (n = 44) or non-malignant hematologic disorders (n = 14) by close molecular monitoring during the first days and weeks after transplantation. Patient-and donor-derived hematopoiesis were assessed at 1-to 3-day intervals in peripheral blood samples by PCR analysis of highly polymorphic microsatellite loci (STR-PCR). Detection of an increasing, and ultimately dominant donor-specific allelic pattern, which we defined as molecular engraftment, preceded hematologic engraftment by a median of 7 days (range 1-17 days) in all patients investigated. PCR analyses during the first days after transplantation facilitated detection of molecular engraftment according to the above definition by day +14 (range day +2 to day +14), thus permitting prediction of successful engraftment (upper limit of the two-sided confidence interval p o = 6%) while the peripheral leukocyte counts were mostly below 200/l. In three cases, however, the criteria for molecular engraftment were not fulfilled by day +14. These patients also failed to show hematologic engraftment, and required a second transplantation. Close monitoring by STR-PCR showed that graft rejection and autologous recovery can occur early and with very rapid dynamics. Molecular analysis of specific leukocyte subsets isolated by flow-sorting enabled sensitive assessment of changes in the pattern of chimerism which had escaped detection in assays using whole white blood cell (WBC) samples. This approach facilitated the identification of expanding or decreasing recipient cells, and permitted early detection of impending rejection or relapse. Moreover, monitoring of the dynamics of chimerism allowed rapid assessment of the response to therapy. Our observations provide support for the concept of initiating genotype analyses early after SCT and monitoring at rather short intervals to permit timely evaluation of clinically relevant processes, and to provide a basis for early implementation of treatment.

Adenoviral infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. Adoptive transfer of donor-derived human adenovirus (HAdV)-specific T-cells represents a promising treatment option. However, the difficulty in identifying and selecting rare HAdV-specific T-cells, and the short time span between patients at high risk for invasive infection and viremia are major limitations. We therefore developed an IL-15-driven 6 to 12 day short-term protocol for in vitro detection of HAdV-specific T cells, as revealed by known MHC class I multimers and a newly identified adenoviral CD8 T-cell epitope derived from the E1A protein for the frequent HLA-type A*02∶01 and IFN-γ. Using this novel and improved diagnostic approach we observed a correlation between adenoviral load and reconstitution of CD8+ and CD4+ HAdV-specific T-cells including central memory cells in HSCT-patients. Adaption of the 12-day protocol to good manufacturing practice conditions resulted in a 2.6-log (mean) expansion of HAdV-specific T-cells displaying high cytolytic activity (4-fold) compared to controls and low or absent alloreactivity. Similar protocols successfully identified and rapidly expanded CMV-, EBV-, and BKV-specific T-cells. Our approach provides a powerful clinical-grade convertible tool for rapid and cost-effective detection and enrichment of multiple virus-specific T-cells that may facilitate broad clinical application.

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE:To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS:We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS:We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor Tcell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS:HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.Aydin et al.

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