Donor genetic determinant of thymopoiesis, rs2204985, and stem cell transplantation outcome in a multipopulation cohort

\ua9 2024 The Author(s)Background: A genetic polymorphism, rs2204985, has been reported to be associated with the diversity of T-cell antigen receptor repertoire and TREC levels, reflecting the function of the thymus. As the thymus function can be assumed to be an important factor regulating the outcome of stem cell transplantation (SCT), it was of great interest that rs2204985 showed a genetic association to disease-free and overall survival in a German SCT donor cohort. Tools to predict the outcome of SCT more accurately would help in risk assessment and patient safety. Objective: To evaluate the general validity of the original genetic association found in the German cohort, we determined genetic associations between rs2204985 and the outcome of SCT in 1,473 SCT donors from four different populations. Study design: Genetic associations between rs2204985 genotype AA versus AG/GG and overall survival (OS) and disease-free survival (DFS) in 1,473 adult, allogeneic SCT from Finland, the United Kingdom, Spain, and Poland were performed using the Kaplan-Meier analysis and log-rank tests. We adjusted the survival models with covariates using Cox regression. Results: In unrelated SCT donors (N = 425), the OS of genotype AA versus AG/GG had a trend for a similar association (p = 0.049, log-rank test) as previously reported in the German cohort. The trend did not remain significant in the Cox regression analysis with covariates. No other associations were found. Conclusion: Weak support for the genetic association between rs2204985, previously also associated with thymus function, and the outcome of SCT could be found in a cohort from four populations

Long-term allogeneic hematopoietic cells transplantation survivors proinflammatory cytokine profile compared to their respective donors and immunophenotype differences depending on GvHD history and infection status

Background In the course of allogeneic hematopoietic cell transplantation (allo-HCT) the donor’s hematopoietic progenitor cells are exposed to immense proliferative stress to reconstitute in the recipient the functional hematopoiesis. Moreover, recipients who develop infections or chronic GvHD are subjected to further proliferative stress, especially in the lymphocyte subset. We hypothesized that allo-HCT may induce changes in proinflammatory cytokines profile and immunophenotype in the allo-HCT recipients, especially in patients with cGVHD history. We compared the cytokine profile (Il-6, Il-10, and TNF-) between long-term allo-HCT recipients and their respective donors and we analyzed cytokines profile and the immunophenotype of lymphocytes in long-term recipients grouped according to the infection and GvHD history. Results We have found no differences in the proinflammatory cytokines between allo-HCT recipients and their respective donors, as well as between recipients grouped according to infectious risk status. Immunophenotyping of recipients grouped according to GvHD status revealed an increased percentage of B-cell presenting PD-1 in recipients without a history of GvHD. Conclusions Lack of differences in proinflammatory cytokines concentrations between recipients and donors of allo-HCT would suggest that allo-HCT does not induce acceleration of the inflammageing-resembling phenomenon. No differences in the cytokine profile and immunophenotype between recipients grouped according to infectious risk status suggest that infectious risk is not reflected by the immunophenotype and cytokine profile. Furthermore, the lack of significant differences in immunophenotype of the recipients grouped according to the history of GvHD may suggest that in long-term survivors the immune system tends to stabilize with time

Real-world study of children and young adults with myeloproliferative neoplasms: identifying risks and unmet needs

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN

JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms.

Item does not contain fulltextWe report three novel mutations in JAK2 exons 12, 19 and 25 in V617F-negative patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Scanning of JAK2 exons 12-25 and MPL exon 10 revealed the presence of JAK2 alterations in six and MPL W515L/K mutations in five of 34 patients with myeloproliferative disorders. Our results confirm that routine JAK2 analysis should include exon 12 mutations in polycythemia vera patients. MPL gene mutations seem to be associated with thrombocytosis, regardless of the type of myeloproliferative neoplasm.1 maart 201