Hematopoietic Stem Cell Recipients Research Articles

Mutations in human cytymegalovirus (Orthoherpesviridae: Herpesvirales: Cytomegalovirus: Cytomegalovirus humanbeta 5) UL97 gene lead to increase in viremia duration and poor antiviral response in recipients of allogeneic hematopoietic stem cells

Introduction. Human cytomegalovirus (Orthoherpesviridae: Herpesvirales: Cytomegalovirus: Cytomegalovirus humanbeta 5) (HCMV) is one of the most commonly detected viruses in recipients of allogeneic hematopoietic stem cell (allo-HSCT) transplants. However, the emergence of resistance to antiviral drugs such as ganciclovir (GCV) poses a challenge in managing these patients. This study aims to investigate the prevalence and impact of mutations in the HCMV UL97 gene associated with resistance to GCV on the course of infection among allo-HSCT patients. Materials and methods. The study examined the association between UL97 mutations and the clinical course of HCMV infection in allo-HSCT patients. Genetic sequencing was performed to identify mutations, and their impact on viral replication and resistance to GCV was assessed. Results and discussion. Six mutations were identified (D490A, T502A, C592G, C592F, E596G, C603W). C592G, C592F, E596G, and C603W are associated with resistance to antiviral drugs, while D490A and T502A described for the first time. When comparing patients with wild-type and those carrying the mutant variant, several parameters of peripheral blood were significantly lower in the former group. The median time to peak viral load following allo-HSCT, duration of viremia, and rate of virological response to high-dose therapy also differed significantly between the two groups. Conclusion. It was shown that approximately one third (4 out of 14) of allogeneic stem cell transplant recipients had mutations associated with resistance to GCV. Patients carrying the mutant variant of HCMV had longer viremia and took longer to achieve a negative virological test result after starting high-dose therapy. Performing genotyping may help make more evidence-based therapeutic decisions.

Anti-CD45 PBD-based antibody-drug conjugates are effective targeted conditioning agents for gene therapy and stem cell transplant

Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) require conditioning to ablate the recipient's hematopoietic stem cells (HSCs) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities and resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers. Invitro, these ADCs internalized to lysosomes for drug release, resulting in potent and specific killing of human CD45+ cells. In humanized NSG mice, the ADCs completely ablated human HSCs without toxicity to non-hematopoietic tissues, enabling successful engraftment of gene-modified autologous and allogeneic human HSCs. The ADCs also delayed leukemia onset and improved survival in CD45+ tumor models. These data provide proof of concept that conditioning with anti-human CD45-PBD ADCs allows engraftment of donor/gene-corrected HSCs with minimal toxicity to non-hematopoietic tissues. Our anti-CD45-PBDs or similar agents could potentially shift the paradigm in transplantation medicine that intensive chemo/radiotherapy is required for HSC engraftment after gene therapy and allogeneic SCT. Targeted conditioning both improve the safety and minimize late effects of these procedures, which would greatly increase their applicability.

Impact of donor NKG2D and MICA gene polymorphism on clinical outcomes of adult and paediatric allogeneic cord blood transplantation for malignant diseases.

NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome. We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes. In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02). CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts.

Determinants of radiological patterns and severity in immunocompromised adults with Metapneumovirus infection

BackgroundHuman Metapneumovirus (HMPV) belongs to the Pneumoviridae family and is responsible for respiratory infections. Mild infections are well-recognized in children, while its precise impact in various categories of immunocompromised adults has not been well addressed. Research questionWe retrospectively studied HMPV infections in immunocompromised adults followed in two large French university medical centers. Study design and methodsWe identified immunocompromised adults with positive HMPV Polymerase Chain Reaction (PCR) for 36 months and reviewed their medical charts. For lung transplant recipients (LTR), FEV1 was collected at baseline, during and after infection. Imaging was centralized and chest involvement was categorized by dominant CT patterns. We compared severe patients (requiring oxygen or ventilation) and non hypoxemic patients. ResultsSeventy-two patients were included, 27 were LTR, 25 had a hematological malignancy or were hematopoietic stem cell recipients, 20 had another immunocompromised status. Twenty patients (28%) presented a hypoxemic infection, requiring hospitalization and intensive care units transfers in 50/72 (69.4%) and 9/72 (12.5%) respectively, with only one death. Hypoxemia was less pronounced in LTRs (p = 0.014). Finally, age and dyspnea remained independent factors associated with hypoxemia (p < 0.005). The most frequent radiological patterns were bronchopneumonia (34.2%) and bronchiolitis (39.5% and 64.3% in the overall population and in LTRs respectively, p = 0.045). FEV1 improved in LTRs at one month and 85% had recovered their baseline FEV1 within 6 months. InterpretationsIn immunocompromised adults, HMPV infections required frequent hospitalizations and ICU transfers, while mortality is low. In LTRs, bronchiolitis pattern was predominant with short and long-term favorable outcome.

Real-Life Data on the Efficacy and Safety of Letermovir for Primary Prophylaxis of Cytomegalovirus in Allogeneic Hematopoietic Stem Cell Recipients: A Single-Center Analysis

Cytomegalovirus (CMV) reactivation is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Introduction of letermovir (LMV) seems to improve post-transplant outcomes, but delayed-onset CMV reactivation still remains a challenge. In this study, we report on our first experience with LMV prophylaxis in 93 CMV-seropositive adult patients receiving HSCT in our center. We retrospectively analyzed the data of 93 adult CMV-seropositive recipients receiving LMV as CMV prophylaxis after HSCT for hematological malignancies between 2019 and 2023. The starting LMV dose was 480 mg daily, reduced to 240 mg daily for those receiving cyclosporin A co-administration. CMV DNA in the blood was measured by real-time polymerase chain reaction weekly for the first 2 months after transplantation, then every other week until the end of immunosuppressive treatment. LMV was continued to day +100 or to CMV reactivation. The median recipient age at the time of transplant was 51 (range: 20-71) years. All patients received grafts from peripheral blood, mostly for acute myeloid leukemia (60%). The median time from transplantation to LMV initiation was 3 (range: 0-24) days. While 55% of patients were transplanted from matched related donors, 32% had unrelated donors and 13% underwent haploidentical HSCT. Four patients (4%) had CMV “blips” while on LMV, but the drug was continued and repeated assays were negative. Only 2 patients (2%) experienced CMV reactivation while on LMV, on days 48 and 34 after HSCT, respectively. Seven patients (7%) developed late-onset CMV reactivation after a median of 124 days after HSCT (range: 118-152 days) and they were successfully treated with ganciclovir. CMV disease was not observed. Grade III-IV acute graft-versus-host disease occurred in 6 patients (6%) during LMV treatment. LMV treatment was free of side effects. LMV prophylaxis was effective in preventing CMV reactivation with a favorable safety profile. CMV reactivation occurred mostly after LMV discontinuation; thus, extending the duration of prophylaxis beyond 100 days could be beneficial.

Supportive Care of Hematopoietic Stem Cell Donors.

Supportive care needs for hematopoietic stem cell recipients have been studied. Less is known about the care needs of stem cell donors. Care challenges arise at donor selection, preparation for the donation, the donation procedure and the immediate and long-term after-care. Care needs were analyzed for 1,831 consecutive bone marrow and peripheral stem cell donors at MedStar Georgetown University Hospital between January 2018 and August 2023 in support of a review of the current literature. During the selection, related donors may experience psychological pressures affecting their motivation, while donation centers may be willing to accept co-morbidities in these donors which might preclude donation in unrelated peers. For bone marrow donations, it is important to select donors not only according to optimal genetic matching criteria but also according to suitable donor/recipient weight ratios, to facilitate sufficient stem cell yields. During the donation preparation phase, side effects and complications related to stem cell stimulation must be anticipated and managed for peripheral cell donors, while the pros and cons of autologous blood donation should be evaluated carefully for bone marrow donors. The stem cell donation procedure itself carries potential side effects and complications as well. Peripheral cell donors may require a central line and may encounter hypocalcemia, thrombocytopenia, and anemia. Bone marrow donors face risks associated with anesthesia, blood loss and pain. Post-procedure care focusses on pain management, blood cell recovery and the psychological support necessary to regain a high quality-of-life existence. Hematopoietic stem donors are giving part of themselves to save another's life. They deserve comprehensive supportive care to accompany them throughout the donation process.

Molecular diagnosis of Cytomegalovirus infection: clinical performance of the Aptima transcription-mediated amplification assay toward conventional qPCR chemistry on whole blood samples.

In this paper, we describe the clinical performance of a novel transcription-mediated amplification (TMA) assay for the detection and quantification of human Cytomegalovirus (HCMV) DNA from whole blood samples. This is a pivotal analysis in immunocompromised patients [transplanted, HIV-positive, and Hematopoietic Stem Cell (HSC) recipients], and molecular tests with high sensitivity and specificity are necessary to evaluate the HCMV viral load in these patients. To our knowledge, this is the first in-depth evaluation of TMA chemistry for HCMV diagnosis on whole blood samples. Moreover, also technical aspects of this assay make it suitable for clinical diagnostics.

Assessing Post-Transplant Outcomes in Hematopoietic Stem Cell Recipients from Rural, Appalachian, and Medically Underserved Regions: Insights from a Single-Center Investigation

Assessing Post-Transplant Outcomes in Hematopoietic Stem Cell Recipients from Rural, Appalachian, and Medically Underserved Regions: Insights from a Single-Center Investigation

Fungal Infections, Treatment and Antifungal Resistance: The Sub-Saharan African Context

Fungal pathogens cause a wide range of infections in humans, from superficial to disfiguring, allergic syndromes, and life-threatening invasive infections, affecting over a billion individuals globally. With an estimated 1.5 million deaths annually attributable to them, fungal pathogens are a major cause of mortality in humans, especially people with underlying immunosuppression. The continuous increase in the population of individuals at risk of fungal infections in sub-Saharan Africa, such as HIV patients, tuberculosis patients, intensive care patients, patients with haematological malignancies, transplant (haematopoietic stem cell and organ) recipients and the growing global threat of multidrug-resistant fungal strains, raise the need for an appreciation of the region’s perspective on antifungal usage and resistance. In addition, the unavailability of recently introduced novel antifungal drugs in sub-Saharan Africa further calls for regular evaluation of resistance to antifungal agents in these settings. This is critical for ensuring appropriate and optimal use of the limited available arsenal to minimise antifungal resistance. This review, therefore, elaborates on the multifaceted nature of fungal resistance to the available antifungal drugs on the market and further provides insights into the prevalence of fungal infections and the use of antifungal agents in sub-Saharan Africa.

The Impact of Cryopreservation on Hematopoietic Stem Cell Engraftment and Post-transplant Outcome During the COVID-19 Pandemic.

The COVID-19 pandemic has had a significant impact on the current management of allotransplanted patients in whom fresh hematopoietic stem cells (HSCs) were replaced by cryopreserved ones. The aim of the study was to determine the efficacy and safety of cryopreserved HSCs when compared with the fresh ones. A retrospective analysis of 254 allogeneic stem cell transplantations (HSCT) procedures performed between 2020-2021 included the following donors: matched related (MRD; n=68), matched unrelated (MUD; n=148) and haploidentical (HID; n=38). 50% of patients (non-cryo group) received fresh grafts, whereas the remaining patients (cryo group) were transplanted with cryopreserved cells. No differences in terms of median days to neutrophil [MRD/MUD/HID cryo- and non-cryo groups: 17 vs. 16 (p=0.27), 19 vs. 18 (p=0.83), 22 vs. 22 (p=0.83) days, respectively] and platelet [MRD/MUD/HID cryo- and non-cryo groups: 14 vs. 14 (p=0.25), 17 vs. 17 (p=0.33), 21 vs. 19 (p=0.36) days, respectively] engraftments were demonstrated. Among MUD graft recipients, platelet engraftment rates were 81% in the cryo- and 96% in the non-cryo group (p=0.01). OS rates were comparable at 1 year after HSCT between MRD/MUD/HID cryo- and non-cryo groups: 53% vs. 60% (p=0.54), 60% vs. 66% (p=0.5), 50% vs. 41% (p=0.56), respectively. During the COVID-19 pandemic, cryopreserved HSCs did not have a negative impact on median engraftment time and OS when compared to fresh HSCs. In the MUD group, platelet engraftment rate was lower in cryopreserved HSC recipients.

The novel HLA-A*30:01:25 allele found in a Korean hematopoietic stem cell recipient.

The novel HLA-A*30:01:25 allele differs from HLA-A*30:01:01:01 by a single nucleotide substitution located within exon 2, codon 1.

Decline in Cardiolipin in Hematopoietic Stem Cell during Aging Alters Their Regenerative Potential

Hematopoietic Stem Cells (HSCs) are known for their regenerative potential. This property allowed the use of HSC in bone marrow transplantation to treat hematological disorders such as leukemia. However, aging influences these characteristics of HSCs. The major hallmarks of aging are limited self-renewal and reconstitution capacity resulting in HSC exhaustion in aged individuals. Mitochondrial metabolism and activity are active drivers of HSC fate decisions and data from our lab shows that mitochondria in aged HSCs have increased sphericity with a polarized mitochondrial network and a lower mitochondrial membrane potential. An important aspect of mitochondrial functions is the lipid composition of their membranes. A lipid trafficking assay showed an atypical pattern of lipid incorporation by mitochondria in aged HSCs suggesting that mitochondrial lipids become abnormal upon aging. The overall content of Cardiolipin (CL) which is a signature mitochondrial lipid, found exclusively in the inner mitochondrial membrane was also reduced during aging. This was done with flow cytometry using a CL marker NAO (Non-Acridine Orange). Tafazzin encoded by the gene TAZ is crucial for remodeling CL into its mature form which is required for maintaining mitochondrial functions. Mutations in the TAZ gene have been known to cause a reduction in the synthesis of mature CL which is often associated with HSCs functional defect. Western Blot analysis showed a considerable decrease in Taz protein expression in aged stem and progenitor cells (HSPC) compared to young HSPC. To understand the effect of reduced Taz expression on HSC functions, we used a doxycycline inducible, sh-RNA mediated TAZ knock-down (KD) mouse model. Bone marrow analysis indicates that the frequency of HSC and multipotent progenitors decreases significantly in 6-month-old TAZ KD mice compared to wild type (WT) mice. Our data shows that following 5FU induction TAZ KD mice have a significant reduction in the multipotent progenitor and HSC population on day 10 and day 21 post 5FU, indicating TAZ KD decrease the regenerative potential of HSCs under stress conditions. Further pointing towards the significance of cardiolipin in HSC regeneration. TAZ KD mice also have abnormal peripheral blood recovery post 5FU mainly affecting the platelets. We next examined the repopulation potential of HSCs isolated from TAZ KD mice using serial competitive transplantation assays. While primary transplanted mice of TAZ KD HSCs exhibited similar donor-cell chimerism compared to mice transplanted with WT HSCs, about 50-60%, secondary recipient of TAZ KD cells had significantly lower donor-cell chimerism than secondary recipients of WT cells. Further, donor-derived HSC frequency in the bone marrow of recipients of TAZ KD HSCs 24 weeks following engraftment was also significantly lower than recipients of WT HSCs. Hence, Taz-deficiency causes a defect in HSC self-renewal under regenerative conditions. We next evaluated whether restoring cardiolipin levels in mid-aged HSCs could rescue their functions. For this, mid-aged HSC were incubated for 3 days under conditions that maintain HSC functions in vitro with Alcar (Acetyl-L-Carnitine), which promotes CL production. In lipid incorporation assay, Alcar supplementation restored mitochondrial membrane potential, mitochondrial organization and lipid incorporation of mid-aged HSCs. In competitive transplant assay, while mid-aged WT HSC treated with vehicle gave rise to a myeloid-bias graft, Alcar supplemented mid-aged WT HSC gave rise to a more balanced graft with increased ratio lymphoid to myeloid cells in the peripheral blood 16 weeks following transplantation, albeit the rescue was partial. This study indicates that HSC mitochondrial membrane lipids become abnormal with aging which causes a decline in HSC function and highlights the critical role of mitochondrial cardiolipin in HSC functions. It implies that metabolite supplementation is a viable option for restoring age-related HSC functional defects.

Antiviral Approach to Cytomegalovirus Infection: An Overview of Conventional and Novel Strategies.

Human cytomegalovirus (HCMV) is a herpesvirus capable of establishing a lifelong persistence in the host through a chronic state of infection and remains an essential global concern due to its distinct life cycle, mutations, and latency. It represents a life-threatening pathogen for immunocompromised patients, such as solid organ transplanted patients, HIV-positive individuals, and hematopoietic stem cell recipients. Multiple antiviral approaches are currently available and administered in order to prevent or manage viral infections in the early stages. However, limitations due to side effects and the onset of antidrug resistance are a hurdle to their efficacy, especially for long-term therapies. Novel antiviral molecules, together with innovative approaches (e.g., genetic editing and RNA interference) are currently in study, with promising results performed in vitro and in vivo. Since HCMV is a virus able to establish latent infection, with a consequential risk of reactivation, infection management could benefit from preventive treatment for critical patients, such as immunocompromised individuals and seronegative pregnant women. This review will provide an overview of conventional antiviral clinical approaches and their mechanisms of action. Additionally, an overview of proposed and developing new molecules is provided, including nucleic-acid-based therapies and immune-mediated approaches.

BNT162b2 or CoronaVac as the Third Dose against Omicron: Neutralizing Antibody Responses among Transplant Recipients Who Had Received Two Doses of CoronaVac.

We evaluated neutralizing antibodies against the Omicron variant and Anti-Spike IgG response in solid organ (SOT) or hematopoietic stem cell (HSTC) recipients after a third dose of BNT162b2 (BNT) or CoronaVac (CV) following two doses of CV. In total, 95 participants underwent SOT (n = 62; 44 liver, 18 kidney) or HSCT (n = 27; 5 allogeneic, 22 autologous) were included from five centers in Turkey. The median time between third doses and serum sampling was 154 days (range between 15 to 381). The vaccine-induced antibody responses of both neutralizing antibodies and Anti-Spike IgGs were assessed by plaque neutralizing assay and immunoassay, respectively. Neutralizing antibody and Anti-Spike IgG levels were significantly higher in transplant patients receiving BNT compared to those receiving CV (Geometric mean (GMT):26.76 vs. 10.89; p = 0.03 and 2116 Au/mL vs. 172.1 Au/mL; p < 0.001). Solid organ transplantation recipients, particularly liver transplant recipients, showed lower antibody levels than HSCT recipients. Thus, among HSCT recipients, the GMT after BNT was 91.29 and it was 15.81 in the SOT group (p < 0.001). In SOT, antibody levels after BNT in kidney transplantation recipients were significantly higher than those in liver transplantation recipients (GMT: 48.32 vs. 11.72) (p < 0.001). Moreover, the neutralizing antibody levels after CV were very low (GMT: 10.81) in kidney transplantation recipients and below the detection limit (<10) in liver transplant recipients. This study highlights the superiority of BNT responses against Omicron as a third dose among transplant recipients after two doses of CV. The lack of neutralizing antibodies against Omicron after CV in liver transplant recipients should be taken into consideration, particularly in countries where inactivated vaccines are available in addition to mRNA vaccines.

The lived experience of long-term follow-up clinical care for haematopoietic stem cell recipients in England: a qualitative exploration

PurposeDespite a haematopoietic stem cell transplant (HSCT) being a potentially curative treatment option for malignant and non-malignant disorders, patients may develop complex physical and psychological post-transplant complications. Consequently, transplant centres remain responsible for patients’ life-long monitoring and screening practices. We sought to describe how HSCT survivors experience long-term follow-up (LTFU) monitoring clinics in England.MethodA qualitative approach was adopted with data collected from written accounts. Seventeen transplant recipients were recruited from across England, and the data was analysed using thematic analysis.ResultsData analysis elicited four themes: Transfer to LTFU care: ‘will there be a change in my care, or will appointments just become less frequent?’; Care Coordination: ‘it is good to know I am still in the system’; Relationship continuity: ‘a good knowledge of me, my health and what is important to me’; and Late-effects Screening: ‘there was not much information about what to expect or be aware of’.ConclusionsHSCT survivors in England experience uncertainty and lack of information regarding the transfer from acute to long-term care and clinic screening practices. However, patients gain reassurance from remaining on a healthcare pathway and maintaining relationships with healthcare professionals.Implications for cancer survivorsHSCT recipients entering LTFU monitoring clinics are a growing population of cancer survivors. Understanding and acknowledging this cohort of patients’ needs may inform the development of tailored support to help patients navigate the complicated healthcare pathway.

Acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Acute graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation determining the prognosis of hematopoietic stem cell recipients because of the impairment of multiple organs and systems and subsequent secondary immunodeficiency caused by combination immunosuppressive therapy. Current strategies are focused on the prevention of this life-threatening complication and on the timely start of treatment with appropriate selection of medications based on the knowledge of acute GVHD pathogenesis and grading as well as of risk factors for its development / progression in different patients. Here we provide a brief overview of acute GVHD and the existing approaches to its prevention and treatment.

One-year mortality of hematopoietic stem cell recipients admitted to an intensive care unit in a dedicated Brazilian cancer center: a retrospective cohort study.

Hematopoietic stem cell transplantation (HSCT) recipients requiring intensive care unit (ICU) admission early after transplantation have a poor prognosis. However, many studies have only focused on allogeneic HSCT recipients. To describe the characteristics of HSCT recipients admitted to the ICU shortly after transplantation and assess differences in 1-year mortality between autologous and allogeneic HSCT recipients. A single-center retrospective cohort study in a cancer center in Brazil. We included all consecutive patients who underwent HSCT less than a year before ICU admission between 2009 and 2018. We collected clinical and demographic data and assessed the 1-year mortality of all patients. The effect of allogeneic HSCT compared with autologous HSCT on 1-year mortality risk was evaluated in an unadjusted model and an adjusted Cox proportional hazard model for age and Sequential Organ Failure Assessment (SOFA) at admission. Of the 942 patients who underwent HSCT during the study period, 83 (8.8%) were included in the study (autologous HSCT = 57 [68.7%], allogeneic HSCT = 26 [31.3%]). At 1 year after ICU admission, 21 (36.8%) and 18 (69.2%) patients who underwent autologous and allogeneic HSCT, respectively, had died. Allogeneic HSCT was associated with increased 1-year mortality (unadjusted hazard ratio, HR = 2.79 [confidence interval, CI, 95%, 1.48-5.26]; adjusted HR = 2.62 [CI 95%, 1.29-5.31]). Allogeneic HSCT recipients admitted to the ICU had higher short- and long-term mortality rates than autologous HSCT recipients, even after adjusting for age and severity at ICU admission.

Antibody, cell-mediated response and infection susceptibility in allogeneic hematopoietic stem cell recipients after COVID-19 mRNA vaccination.

Patients undergoing allogeneic stem-cell transplantation (allo-SCT) have reduced responses to vaccines due to immunosuppressive status linked to GvHD prophylaxis and treatment. In our study, we compared humoral responses to anti-SARS-CoV-2 mRNA vaccine, and infection onset, according to patients and transplant features; we also evaluated cellular response in patients without seroconversion. We tested antibodies titer after second and third vaccine doses. Antibodies were detected through an immune-enzymatic assay. In a patients' subgroup without seroconversion, we tested cell-mediated responses evaluating interferon-gamma release by T-lymphocytes exposed to virus spike protein. Seroconversion rate increased from 66% at 30 days to 81% at 90 days after the second dose; it was 97% at 150 days after the third dose. We found a significant association between seroconversion after the second dose and two variables: shorter interval between allo-SCT and vaccination; ongoing immunosuppression. Twelve of 19 patients (63%) without antibodies after the second dose did not show cellular responses. Nineteen percent of patients developed SARS-CoV-2 infection after the third dose, with favorable outcome in all cases. Patients within 12 months after allo-SCT showed a significantly higher infection risk. Our study suggests that an interval shorter than 12 months between allo-SCT and first vaccine dose and/or ongoing immunosuppression were associated with humoral and cellular response deficiency after two doses. Third dose induced an increased and sustained humoral response in the majority of patients. However, patients within 1 year after allo-SCT remained at higher infection risk and may be candidate for prophylaxis with anti-SARS-CoV-2 monoclonal antibodies.

Graft failure in allogeneic hematopoietic stem cell recipients: diagnosis and treatment

Graft failure is a group of complications after allogeneic hematopoietic stem cell transplantation, which occurs according to different data up to 30%. The group of complications includes primary and secondary graft failure, primary, secondary and transient poor graft function and graft rejection. Diagnostic difficulties consist in the lack of unified diagnostic criteria accepted in the transplantation community and in the dual interpretation of these complications according to the foreign literature. The purpose of this literature review was to identify the most common criteria of different types of graft failure and determine the tactics of diagnosis and treatment. In this review we analyzed data from various literature sources, gave definitions of graft failure and poor graft function. We analyzed the literature data on the methods used to treat these conditions.

Impact of chronic graft-versus-host-disease on intensive care outcome in allogeneic hematopoietic stem cell recipients

Chronic graft-vs-host-disease (cGvHD) is the most relevant long-term complication after allogeneic stem cell transplantation (HSCT) with major impact on non-relapse mortality, but data on intensive care unit (ICU) outcome are missing. In this retrospective, multicenter study we analyzed 174 adult HSCT recipients with cGvHD requiring intensive care treatment. Skin, pulmonary, liver, and intestinal involvement were present in 76.7%, 47.1%, 38.1% and 24.1%, respectively, and a total of 63.2% had severe cGvHD. Main reasons for ICU admission were respiratory failure (69.7%) and sepsis (34.3%). Hospital- and 3-year OS rates were 51.7% and 28.6%, respectively. Global severity of cGvHD did not impact short- and long-term survival. However, patients with severe liver cGvHD or the overlap subtype had a reduced hospital survival, while severe pulmonary cGvHD was associated with worse long-term survival. In multivariate analysis need for invasive ventilation (HR 1.08 (95% CI 1.02–1.14)) or hemodialysis (HR 1.73 (95% CI 1.14–2.62)) and <1 year since HSCT (HR 1.56 (95% CI 1.03–2.39)) were independently associated with a poorer survival. While the global severity of cGvHD does not per se affect patients’ survival after intensive care treatment, pre-existing severe hepatic, intestinal or pulmonary cGvHD is associated with worse outcomes.