Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.

The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%) developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P < .01) and sirolimus concentration (HR, .94; 95% CI, .87 to .99; P < .01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.

T Cell and Cytokine Dynamics in the Blood of Patients after Hematopoietic Stem Cell Transplantation and Multipotent Mesenchymal Stromal Cell Administration.

Multipotent mesenchymal stromal cells (MSCs) are currently under intensive investigation for the treatment and prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), owing to their substantial immunomodulatory properties. The responses of recipients to MSC infusion following allo-HSCT are not yet well understood. T cells are central to the adaptive immune system, protecting the organism from infection and malignant cells. Memory T cells with different phenotypes, gene expression profiles, and functional properties are critical for immune processes regulation. The aim of this study was to study the dynamics of memory T cell subpopulations and cytokines in the blood of allo-HSCT recipients after MSC administration. In clinical trial NCT01941394, patients after allo-HSCT were randomized into 2 groups, one receiving standard GVHD prophylaxis and the other also receiving MSC infusion on the day of leukocyte recovery to 1000 cells/µL (engraftment, day E0). Blood samples of patients from both groups were analyzed on days E0, E+3, and E+30. T cell subpopulations were studied by flow cytometry, and cytokine concentrations were evaluated by the Bio-Plex Pro Human Cytokine Panel. Administration of MSCs to patients on day E0 did not affect the overall dynamics of restoration of absolute numbers and proportions of T and B lymphocytes after 3 and 30 days. At 3 days after MSC injection, only the numbers of CD8+ effector cells (CD8+TE, CD8+TM, and CD8+EM) were found to increase significantly. A significant increase in the number of CD4+ cells after 30 days compared to day E0 was observed only in patients who received MSCs, indicating faster recovery of the CD4+ cell population following MSC injection. An increase in CD8+ cell number by day E+30 was significant regardless of MSC administration. To characterize the immune status of patients following allo-HSCT in more detail, changes in the cytokine concentration in the peripheral blood of patients on days E0, E+3, and E+30 after MSC administration were investigated. On day E+30, significant increases in the numbers of CD4+CM and activated CD4+CD25+ cells were observed. The concentrations of proinflammatory and anti-inflammatory cytokines IL-6, IL-8, IL-17, TNF-α, and IFN-γ were increased significantly in patients injected with MSCs. Analysis of growth factor levels showed that in the group of patients who received MSCs, the concentrations of G-CSF, GM-CSF, PDGFbb, FGFb, and IL-5 increased by day E+30. Among the cytokines involved in regulation of the immune response, concentrations of IL-9, eotaxin, IP-10, MCP-1, and MIP-1a were increased after 30 days irrespective of MSC administration. The administration of MSCs exerts a positive effect on the restoration of T cell subpopulations and immune system recovery in patients after allo-HSCT.

T helper 17 and regulatory T-cell profile and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in pediatric patients with beta-thalassemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hereditary hemoglobin disorders, such as beta-thalassemia; However, this procedure is not without constraints, mainly engendering complications such as acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and susceptibility to infections. The clinical outcomes of allo-HSCT are highly dependant on the quality and quantity of T-cell subsets reconstitution. Following the allo-HSCT of six pediatric patients afflicted with beta-thalassemia, their mononuclear cells were isolated, and then cultured with a combination of phorbol myristate acetate (PMA)/ionomycin and Brefeldin A. The content of CD4 T-cell subsets, including T helper 17 (Th17) cells and regulatory T cells (Tregs), were determined by specific conjugated-monoclonal antibodies three and six months post-HSCT. An increased frequency of total CD4 T-cells, Tregs and Th17 cells was observed at day 90 and 180 after allo-HSCT, albeit the numbers were still lower than that of our healthy controls. In patients who developed cGvHD, a lower Th17/Treg ratio was observed, owing it to a decreased proportion of Th17 cells. In conclusion, creating balance between Th17 and Treg subsets may prevent acute and chronic GvHD in patients after allo-HSCT.

[Method and impact of allografts cryopreservation during the Covid-19 pandemic: guidelines from the SFGM-TC]. / Modalités et impact de la cryopréservation des greffons allogéniques en contexte pandémique : recommandations de la SFGM-TC.

The COVID-19 pandemic disorganized the allogeneic stem cell transplantation activities all over the world, with the necessity to cryopreserve allografts to secure the procedure for both the recipient and the donor. Cryopreservation, usually anecdotal, has been used by all the French speaking centers; data collected from 24 centers were assessed in order to determine the impact of cryopreservation on the quality of allografts. Our analysis clearly demonstrates that increasing transit time (more than 48hours) is deleterious for CD34+ recovery, legitimates the slight increase of the requested CD34+ cell dose with respect to the average recovery rate as well as the importance of the quality control on the infused product.

Karnofsky performance status and visual analogue scale scores are simple indicators for quality of life in long-term AYA survivors who received allogeneic hematopoietic stem cells transplantation in childhood.

The purpose of this study was to investigate Karnofsky performance status (KPS) scores and visual analogue scale (VAS) scores to explain which domains in the standardized self-reported quality of life (QOL) are instrumental for long-term hematopoietic stem cell transplantation (HSCT) survivors. We conducted a nationwide cross-sectional questionnaire study on 221 survivors with allogeneic-HSCT in 28 pediatric centers. Patient-reported QOL was assessed at a single time point using the 36-item Short-Form Survey (SF-36), the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and VAS scores. KPS scores were significantly correlated with both physical and role component summary scores of the SF-36, while the VAS provided by the patient (VASpt) was significantly correlated with the mental component summary score of the SF-36 and many subscales of the FACT-BMT. The VAS provided by the participants' attending physician (VASdoc) was correlated well with KPS scores. A VASpt score more than 40% lower than KPS scores suggested mental health problems. In conclusion, KPS scores might be considered as an indicator for physical and role/social components and VASpt score as an indicator for mental components and HSCT-specific QOL.

"This Graft-vs.-Host Disease Determines My Life. That's It."-A Qualitative Analysis of the Experiences and Needs of Allogenic Hematopoietic Stem Cells Transplantation Survivors in Germany.

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment modality for many patients affected by hematologic malignancies. However, it can cause debilitating long-term effects. Understanding the impact of alloHSCT on all aspects of the patients' life is required for optimal survivorship management. Aim: To explore in-depth HSCT-survivors' experiences and needs post-transplant. Partners were included to provide further information on survivors' needs and how care could be improved in this area. Methods: We conducted semi-structured face-to-face and phone interviews with alloHSCT-survivors and their partners referred to a survivorship clinic in Germany. Theoretical sampling was used to recruit participants. Data were analyzed using framework analysis. Results: Thirty-two survivors (consent rate: 100%, response rate: 100%) and eighteen partners (consent rate: 84%, response rate: 72%) participated. Survivors were aged between 25 and 68 years (Median: 48, IQR: 25.3) and partners were aged between 26 and 64 years (Median: 54, IQR: 16, SD: 12.8). The themes emerging from the data involved survivors' needs included (i) the diversity of long-term treatment side-effects; and (ii) time post discharge as a dynamic process with individual peaks of burden. Survivors and their partners also suggested strategies for mitigating these unmet needs, i.e., (iii) transparent communication and patient empowerment; and (iv) improvement in continuity of care system and help with claiming social benefits as cornerstones of optimal survivorship care. Conclusion: To our knowledge, this is one of the first qualitative studies focused on the views of German alloHSCT-survivors on the long-term effects of alloHSCT and the first study integrating the view of their partners. Healthcare providers could better support survivors with managing their symptoms and adhering to their prescribed care by ensuring comprehensive, transparent communication that helps increase survivors' understanding and involvement in their care. Further efforts should be made to provide patient-centered, continuous survivorship care that involves additional support with navigating the healthcare and social service system. Intervention studies are required to test the effectiveness of the suggested strategies.

Early and Late Complications in Patients with Allogeneic Transplantation of Hematopoietic Stem Cell - Case Report.

BACKGROUND: Allogeneic hematopoietic stem cells transplantation (HSCT) is a curative intervention in patients with haematological malignant and non-malignant diseases, immunodeficiency, autoimmune, and other genetic diseases. Early complications are complications that are occurring in the first 100 days, while complications arising after the 100th day of transplantation belong to late complications. CASE REPORT: Forty-nine years old patient with AML treated with allogeneic HSCT from HLA-identical (sister) donor. Ascertained and display of early (acute Graft versus host disease (GvHD) and late complications (chronic GVHD, infections, cataract, secondary malignancy with MS deposits) are made, that emerged after the patient transplantation. CONCLUSION: Rapidly growing population of patients that undergo allogeneic HSCT creates an obligation to educate patients and physicians about observed late complications that occur after this therapy.