Allogeneic Stem Cell Transplant Patients Research Articles

Comparison of intermittent intravenous tacrolimus to continuous tacrolimus in adult allogeneic stem cell transplant recipients.

Introduction: Initial continuous intravenous (CIV) tacrolimus (0.03 mg/kg/day based on ideal body weight [IBW]) has been favored for graft versus host disease (GVHD) prevention in allogeneic stem cell transplant patients due to the consistent, steady-state degree of immunosuppression; however, this method poses many logistical challenges. We implemented intermittent (IIV) tacrolimus at a starting dose of 0.015 mg/kg IBW twice daily over 4 h. To our knowledge this is the first retrospective comparison of CIV to IIV tacrolimus. Objectives: The primary objective was to evaluate the safety of IIV tacrolimus in comparison to CIV with respect to nephrotoxicity and neurotoxicity. The secondary objectives were to compare the incidence of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at day +180, outcomes including relapse and overall survival, cell engraftment, and reactivation of cytomegalovirus and Epstein-Barr virus. Methods: This retrospective, single-center review evaluated adults who received an allogeneic stem cell transplant patients between January 1, 2020, and December 31, 2022. Results: Fifty-one unique patients were eligible for evaluation - 28 in the IIV cohort and 23 in the CIV group. The number of patients who developed nephrotoxicity and neurotoxicity were comparable between groups with no significant differences noted. No severe neurotoxicity was identified in either population. Secondary objectives revealed no significant difference in GVHD incidence or survival outcomes. Conclusion: IIV tacrolimus is comparable to CIV in terms of safety while also maintaining similar outcomes at day +180. IIV is a safe and feasible alternative to CIV in adult allogeneic stem cell transplant recipients.

Persistent Impairment in Immune Reconstitution and Worse Survival Outcomes Among Allogeneic Stem Cell Transplant Patients with Early COVID-19 Infection

Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplant-related complications in the first year following transplantation, in part due to the profound immune dysregulation with T- and B-cell lymphopenia and functional impairment. Although several large studies have described higher mortality rates from the coronavirus disease 2019 (COVID-19) in HSCT recipients, no reports have focused on the impact of early COVID-19 infection on immune reconstitution post-transplant and correlation with transplant outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection with a median time to diagnosis of 100 days. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% CI, 1.26 to 13.05; P=.019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P=.001).This was mainly attributed to higher non-relapse mortality (NRM) among early COVID(+) patients (P=.042). Allogeneic HSCT patients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P=.021), CD3+CD4+ (95% CI, -105.35 to -11.59; P=.042), CD3+CD8+ (95% CI, -324.55 to -57.13; P=.038), and CD3-CD56+ (95% CI, -193.51 to -47.31; P=.014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impairment in immune reconstitution post-transplantation.

A retrospective study of intravenous pentamidine for Pneumocystis jirovecii pneumonia prophylaxis in adult patients with hematologic malignancies—its utility during respiratory virus pandemics

ObjectivesIn hematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematologic malignancies. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent; however, its use is not straightforward. Inhaled pentamidine is the recommended second-line agent; however, aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. We evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic hematopoietic stem cell transplantation recipients and patients with hematologic malignancies during COVID-19. ResultsA total of 202 unique patients who received 239 courses of IV pentamidine, with a median of three doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The most common reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients developed an infusion reaction or experienced adverse effects from IV pentamidine. ConclusionsPentamidine administered IV monthly is safe and effective.

[Clinical Study of Allogeneic Hematopoietic Stem Cell Transplantation Patients with Co-Reactivation of Cytomegalovirus and Epstein-Barr Virus].

To explore the clinical characteristics and risk factors of cytomegalovirus(CMV) and Epstein-Barr virus(EBV) co-reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its influence on prognosis. The clinical data of 222 patients who received allo-HSCT from January 2015 to December 2020 were collected, and the patients were divided into groups according to the occurrence of CMV and EBV infection. Kaplan-Meier method was used for survival analysis, and Cox proportional hazard regression model was used to analyze the risk factors of co-reactivation of CMV and EBV. After allo-HSCT, there were 30 patients with co-reactivation of CMV and EBV (CMV++EBV+ group), 101 patients with CMV viremia (CMV+ group), 149 patients with EBV viremia (EBV+ group), and 28 patients with CMV and EBV inactivation (CMV-+ EBV- group). Compared with the other groups, the incidence of acute graft-versus-host disease (aGVHD) and hemorrhagic cystitis (HC) was higher in CMV++ EBV+ groups (53.3% vs 42.6%, 36.9%, 17.9%, P < 0.001; 36.7% vs 32.7%, 22.8%, 10.7%, P =0.042). The incidence of post-transplant lymphoproliferative disease (PTLD) in CMV++ EBV+ group was similar to CMV+ group and EBV+ group (3.3% vs 3.0%, 3.4%, P =0.811). Univariate and multivariate analysis showed that the persistent time of CMV and EBV after transplantation were independent risk factors for co-reactivation of CMV and EBV. Compared with the other groups, the 2-year overall survival (OS) rate and 2-year disease-free survival (DFS) rate of patients in CMV++EBV+ group were lower (46.7% vs 74.9%, 83.4%, 71.4%, P < 0.001; 46.7% vs 70.9%, 79.5%, 69.9%, P =0.002), and 2-year non-recurrence mortality (NRM) was higher (48.2% vs 22%, 13.6%, 18.7%, P <0.001). The persistent time of CMV and EBV after transplantation are independent risk factors for patients with co-reactivation of CMV and EBV. Patients with co-reactivation of CMV and EBV had lower OS and DFS rate and higher NRM, suggesting that the clinical prognosis of the patients are worse.

Application of CMV-IVIg as prophylaxis against cytomegalovirus reactivation in allogeneic hematopoietic stem cell transplantation patients.

Cytomegalovirus (CMV) reactivation remains one of the major and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Yet, there is still a lack of safe and effective ways to prevent CMV reactivation in allo-HSCT patients. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our transplant center between 2018 and 2022 to evaluate the efficacy of prophylactic CMV-specific intravenous immunoglobulin (CMV-IVIg) against CMV reactivation. After Propensity Score Matching, the CMV reactivation rate was significantly decreased in the CMV-IVIg group (HR, 2.952; 95% CI,1.492-5.841; P=.002) compared with the control group. Additionally, the time duration of CMV reactivation (P=.001) and bacterial infection rate (P=.013) were significantly lower in the CMV-IVIg group. Moreover, prophylactic CMV-IVIg was more effective in CMV seropositive patients who received ATG as part of GVHD prevention (HR, 8.225; 95% CI,1.809-37.39; P=.006). In conclusion, CMV-IVIg is considered an effective and safe way to prevent CMV reactivation in HSCT recipients, which may be related to the acceleration of immune reconstitution in the early stage after transplantation.

Immunogenicity and Tolerance of BNT162b2 mRNA Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Allogeneic hematopoietic stem cell transplantation (ASCT) induces acquired immunodeficiency, potentially altering vaccine response. Herein, we aimed to explore the clinical tolerance and the humoral and cellular immune responses following anti-SARS-CoV-2 vaccination in ASCT recipients. A prospective, non-randomized, controlled study that involved 43 ASCT subjects and 31 healthy controls. Humoral response was investigated using the Elecsys® test anti-SARS-CoV-2. Cellular response was assessed using the QFN® SARS-CoV-2 test. The lymphocyte cytokine profile was tested using the LEGENDplex™ HU Th Cytokine Panel Kit (12-plex). Adverse effects (AE) were observed in 69% of patients, encompassing pain at the injection site, fever, asthenia, or headaches. Controls presented more side effects like pain in the injection site and asthenia with no difference in the overall AE frequency. Both groups exhibited robust humoral and cellular responses. Only the vaccine transplant delay impacted the humoral response alongside a previous SARS-CoV-2 infection. Noteworthily, controls displayed a Th1 cytokine profile, while patients showed a mixed Th1/Th2 profile. Pfizer-BioNTech® anti-SARS-CoV-2 vaccination is well tolerated in ASCT patients, inducing robust humoral and cellular responses. Further exploration is warranted to understand the impact of a mixed cytokine profile in ASCT patients.

Recombinant mannan-binding lectin magnetic beads increase pathogen detection in immunocompromised patients

The microbiological diagnosis of infection for hematological malignancy patients receiving chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients relies primarily on standard microbial culture, especially blood culture, which has many shortcomings, such as having low positive rates, being time-consuming and having a limited pathogenic spectrum. In this prospective observational self-controlled test accuracy study, blood, cerebrospinal fluid (CSF), and bronchoalveolar lavage fluid (BALF) samples were collected from chemotherapy or allo-HSCT patients with clinical symptoms of infections who were hospitalized at Peking University First Hospital. Possible pathogens were detected by the method based on recombinant mannan-binding lectin (MBL) magnetic bead enrichment (M1 method) and simultaneously by a standard method. The analytical sensitivity of M1 method was close to that of standard culture method. Besides, the turn-around time of M1-method was significantly shorter than that of standard culture method. Moreover, the M1 method also added diagnostic value through the detection of some clinically relevant microbes missed by the standard method. M1 method could significantly increase the detection efficiency of pathogens (including bacteria and fungi) in immunocompromised patients.Key points• The detection results of M1-method had a high coincidence rate with that of standard method• M1 method detected many pathogens which had not been found by standard clinic method

Impaired Immune Reconstitution and Worse Survival Outcomes Among Allogeneic Stem Cell Transplant Patients with Early COVID-19 Infection

Impaired Immune Reconstitution and Worse Survival Outcomes Among Allogeneic Stem Cell Transplant Patients with Early COVID-19 Infection

Cytomegalovirus Reactivation in Allogenic Haematopoietic Stem Cell Transplant Patients with Haploidentical Versus Fully Human Leukocyte Antigen Matched Donor

Objective: To determine CMV reactivation in hematopoietic stem cell transplant patients with haploidentical versus fully HLA matched donors  Methodology: Retrospective Observational study was conducted at Armed Forces Bone Marrow Transplant Centre (AFBMTC) between March 2019 and October 2022. We enrolled a total of 60 consecutive patients.CMV DNA PCR analysis was carried out every week from day +14 to day +100 in order to monitor CMV reactivation during the 100-day post-transplantation period. The SaMag viral nucleic acid extraction kit (Sacace Biotechnologies, Como, Italy) was used to extract the DNA from two millilitres of blood collected in EDTA tubes. The kit's lower limit of detection for blood and serum was 5 copies/mL, while for other body fluids it was 500 copies/mL. An Applied Biosystems 7500 real-time PCR machine (Thermo Fisher Scientific, Waltham, MA) was used to conduct the PCR analysis. Result: The age range from 0.6 to 53 years ago was a median of 15±10.6. 39 patients had CMV reactivation (65%). With a range of 13 to 66 days, the median time to CMV DNAemia was 19.25 days.. Only two (3.3%) of the 39 patients received ganciclovir, while 26 (43.3%) received valganciclovir. Patients with aplastic anaemia had the highest rate of CMV infection (41%), followed by those with ALL (20.5%), AML (12.8%), and primary immunodeficiency (10.2%). A statistically significant connection between the underlying diagnosis and CMV infection. CMV infection was higher in haplo identical transplant recipients (66.6%) than in completely matched recipients (33.3%) and was statistically significantly. Sadly, 14 people passed away, yielding a mortality rate of 23.3%. Primary graft failure was the most frequent cause of mortality, resulting in neutropenic sepsis in 6 patients (42.85%), but 3 of these patients also had CMV reactivation. The rate of overall survival (OS) was found to be 76.7%. The rate of disease-free survival (DFS) was estimated at 71.7%. Notably, neither OS nor DFS in our analysis showed a statistically significant connection with CMV infection. Conclusion: The findings demonstrated a statistically significant association between haploidentical transplantation and CMV reactivation, with higher rates observed in the haploidentical group compared to fully matched recipients. Various factors, including underlying diagnosis, conditioning regimen, and GVHD prophylaxis, were also found to be correlated with CMV reactivation. However, while CMV reactivation was associated with specific factors, it did not impact overall survival or disease-free survival in the study population.

Venous Thromboembolism in Hematopoietic Stem Cell Transplantation

Background: Venous thromboembolism (VTE) is an underappreciated complication seen amongst allogeneic and autologous hematopoietic stem cell transplant (HSCT) patients and a major cause of morbidity and mortality. Despite these challenges, VTE in HSCT remains understudied, with a paucity of established guidelines on thrombosis surveillance, prevention, and treatment. Balancing risk of bleeding and thrombosis is particularly challenging as HSCT patients are concurrently pancytopenic and coagulopathic. We aimed to describe the incidence, predictors, and adverse events of VTE amongst patients at 90 days post-HSCT. Methods: We conducted a retrospective cohort study of adult patients, age &amp;gt;18-years-old, who underwent HSCT for a hematological malignancy between January 1, 2011 and December 31, 2021 at a tertiary care centre in Canada. Patients were followed from transplant until Day 90 post-transplant, or death. Baseline, transplant, laboratory, and cancer characteristics were analyzed. Results: Four Hundred and Seventy Six (476) HSCT patients were included (age range 18 - 74), 285 (59.9%) of our patients were male, and 191 (40.1%) were female. Three Hundred and Seventeen (317) (66.6%) patients underwent autologous transplant, and 159 (33.4%) patients underwent allogeneic transplant ( Table 1). Forty Seven (47) patients (9.8%) suffered from VTE within 90 days post-HSCT; 74.5% were catheter related. 9.43% of allogeneic, versus 10.09% autologous patients were diagnosed with VTE (p=0.820). 11.9% of allogeneic, versus 4.1% of autologous patients (p=0.001) suffered from bleed unrelated to anticoagulation. There was significant association of VTE post-HSCT with history of unprovoked DVT (p = 0.026), previous treatment with steroids (p = 0.032), infectious complications (including bacteremia (p = 0.025), and skin and soft tissue infection (p &amp;lt; 0.001)), use of peripherally-inserted central catheters (PICCs (p &amp;lt;0.001), left-sided CVC placement (p = 0.007), second central venous line insertion (due to complications from the first) (p &amp;lt; 0.001), and blocked or malfunctioning central venous catheter (p = 0.003). There was no significant association of VTE post-HSCT with transplant graft (autologous versus allogeneic), underlying hematological malignancy, age, BMI, or sex. Mortality rate at 90 days amongst VTE patients was 14.89%, versus 3.27% in non-VTE patients (p &amp;lt; 0.001) ( Figure 1). Conclusion: The majority of VTE post-HSCT were catheter-related and were more frequently associated with use of PICCs. VTE post-HSCT was associated with higher mortality. VTE prophylaxis or active surveillance could be considered in patients with the above-mentioned risk factors balancing the risk of bleeding, particularly in allogeneic stem cell transplant patients, and those who are concurrently thrombocytopenic.

Statin Use and Its Effects on Survival Outcomes and Rates of Gvhd in Allogeneic Stem Cell Transplant Patients: Results from Real-World Cohorts

Introduction: The effect of statin use in allogeneic stem cell transplant remains unclear. There have been conflicting results in studies examining the impact of statins on engraftment, graft-versus-host-disease, survival, and long-term outcomes in stem cell transplant recipients. Methods: Retrospective data was extracted using the TriNetX database. The primary endpoint was overall survival at 5 years, risk of death, and graft-versus-host-disease in the two cohorts. Results: 5045 patients were identified in cohort-1 (statin cohort) and 10,181 patients were identified in cohort-2 (non-statin cohort). Table-1 shows patient characteristics at baseline. Propensity-score-matching was used to balance the two cohorts. Patient count in each group after matching was 3702 (Table-2). Overall survival was 59.32% in cohort-1 versus 48.55 % in cohort-2, with HR of 0.685 (95% CI 0.634, 0.740) in favor of cohort 1 (Figure-1). Median OS for cohort-1 was not reached versus 1593 days for cohort-2. Risk of death in cohort-1 and 2 was 0.311 and 0.4 respectively (Figure-2), with a risk difference for the death of -0.089 (95% CI, -0.110, -0.067, p-value &amp;lt;0.001), in favor of cohort-1. Risk of graft-versus-host-disease was 0.648 and 0.674 in cohort-1 and 2 respectively (Figure-3), with a risk difference of -0.026 (95% CI -0.054, 0.002, p-value 0.065), and risk ratio of 0.961 (95% CI 0.921, 1.003). Survival-probability was higher at 5 years in cohort-1 regardless of presence or absence of GVHD. Conclusions: Our retrospective analysis of a large patient cohort showed improved OS and decreased risk of death with statin use in allogeneic stem cell transplant patients, regardless of presence or absence of GVHD, even though the average total and LDL cholesterol levels were higher in statin-group. The difference in graft-versus-host-disease was not statistically significant in both cohorts, however, there was a trend towards decrease GVHD in statin-cohort. To the best of our knowledge, this is the first large database based study evaluating the effect of statin use on outcomes in patients undergoing allogeneic stem cell transplant. Phase 3 clinical trials are needed to further answer this question.

Bleeding Risk Factors in Thrombocytopenic Patients with Hematologic Malignancies

Introduction Despite prophylactic platelet transfusions, World Health Organization (WHO) grade ≥ 2 bleeding occurs in 50 to 70% of patients with hematologic malignancies and hypoproliferative thrombocytopenia secondary to therapy and/or underlying disease (Gernsheimer et al, Blood 2022). Anemia (hematocrit, HCT ≤ 25%), coagulopathy (activated partial thromboplastin time ≥ 30s, international normalized ratio ≥ 1.2), and platelet count ≤ 5000/µl were independently associated with increased risk of bleeding in the PLADO (platelet dose) trial of 1272 patients with hypoproliferative thrombocytopenia treated between 2004 to 2007 (Uhl et al, Blood 2017). Updated data on bleeding outcomes and risk of bleeding is lacking. Methods We performed a post-hoc analysis of bleeding outcomes and bleeding risk factors in 330 patients with hematologic malignancy and hypoproliferative thrombocytopenia from therapy and/or underlying disease randomized at 3 institutions to receive either tranexamic acid (TXA) or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) (Gernsheimer et al, Blood 2022). Patients received prophylactic platelet transfusions for a platelet count of ≤ 10,000/µl and WHO grade bleeding was assessed daily for 30 days after a platelet count ≤ 30,000/µl and study drug was started. Study drug was discontinued when platelet count was ≥ 30,000/ul for 46 hours without platelet transfusion support or until a maximum of 30 days after treatment activation, whichever came first. Red blood cell (RBC) transfusion was given according to local standard of care. Cox proportional hazards regression with time-varying covariates was used to assess the association of patient characteristics with the risk of a first major (grade 2+) bleeding event. HCT, platelet count, inpatient vs. outpatient status, steroid treatment, and fever were recorded daily. Patients were censored at the first of time of withdrawal, death, or day 30. Results WHO grade ≥ 2 bleeding occurred in 46% of patients overall with no difference between the TXA and placebo groups (TXA 44% versus placebo 47%, p=0.66). Bleeding rates were highest in allogeneic stem cell transplant patients, followed by chemotherapy, followed by autologous stem cell transplant. Overall bleeding rates by organ system showed oral and nasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%) bleeding (Table 1). WHO grade ≥ 2 vaginal bleeding occurred in 28% of patients of childbearing potential despite widespread use of hormonal suppression. In a proportional hazards regression model of time to first bleeding event, undergoing allogeneic stem cell transplant was associated with a non-significant increased hazard of bleeding vs chemotherapy (HR 1.32, 95% CI 0.92-1.89), whereas autologous transplant had significantly lower hazard of bleeding vs chemotherapy (HR 0.39, 95% CI 0.20-0.76) (Table 2). HCT &amp;lt; 21% was associated with increased bleeding risk even after adjusting for severe thrombocytopenia (HR 2.71, 29% CI 1.37, 5.36). Platelet count &amp;lt; 5000/µl was also associated with increased risk (HR 3.33, 95% CI 1.67-6.61). Inpatient status, presence of fever, and age did not significantly impact risk of first bleed. Conclusions The overall rate of WHO grade &amp;gt;2 bleeding was similar to historical literature with lower rates of gastrointestinal bleeding than previously reported (31% in PLADO). Vaginal bleeding was common despite standard use of hormonal suppression in patients of childbearing potential. Platelet count &amp;lt; 5000/µl remains a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT &amp;lt; 21% suggesting a red blood cell transfusion threshold higher than 21% is unlikely to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this patient population.

Role of Nutrition Support in Improving Outcomes in Allogeneic Stem Cell Transplant Patients

Introduction: Allogeneic hematopoietic stem cell transplant (Allo-SCT) can be associated with several complications related to the cytotoxic conditioning regimen, infections associated with immune suppression, and GVHD. Malnutrition amongst Allo-SCT patients has been reported to be an independent negative prognostic factor. It may be evident on presentation or develop as a sequela of decreased appetite, mucositis, and digestive GVHD. Whether supportive nutrition (enteral feeding or total parenteral nutrition (TPN)) contributes to favorable transplant outcomes is yet to be determined. Methods: We conducted a retrospective single-center study that evaluated patients who underwent Allo-SCT from Jan 2018 through Sept 2021. A chart review was conducted, and relevant data was collected. Primary outcomes were the impact of nutrition support (enteral feeding, TPN or both) among malnourished patients during the first 100 days post-transplant (T+100) on mortality and the composite outcome of acute GVHD incidence, infection rate, and days to engraftment. A higher composite score indicated worse outcomes. GVHD grading was based on the CIBMTR grading system (I-IV). The data was analyzed using Chi-Square and two-sample t-test. Results: A total of 70 Allo-SCT patients were identified. Of them, 42 (60%) were diagnosed with malnutrition, of which 23 (55%) received nutrition support. The mortality rate in patients who required nutrition support was significantly higher compared to those who did not receive nutrition support (83% (19/23) vs 11% (2/19)) with an odds ratio of 40 for this association (CI 6.5-248.9, p-value &amp;lt; 0.0001). The composite outcome was statistically higher amongst patients requiring nutrition support (mean 2.0, median score 1.8, SD 0.6) compared to those who did not need nutritional support (mean 1.6, median score 1.5, SD 0.4). These differences were found to be statistically significant using the Satterthwaite method (p-value 0.0218). Conclusion: Based on this data, we found that a reactive approach of nutrition support in the setting of malnutrition had no benefit on mortality and our pre-defined composite outcome during the first 100 days of allogeneic stem cell transplantation. This is fuel for conducting a prospective study using a preemptive enteral feeding approach to prevent the development of malnutrition and related complications.

Bacterial and Bacteriophage Consortia Are Associated with Protective Intestinal Immuno-Modulatory Metabolites in Allogeneic Stem Cell Transplantation Patients

The human microbiome is a predictor of clinical outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungi and viruses as well as intestinal microbiota-derived metabolites are involved. However, it is still unclear how dynamic shifts in these three kingdoms contribute to the production of intestinal metabolites, how metabolites are impacted by graft-versus-host disease (GvHD) or antibiotics and whether they are associated with clinical outcome. We report the two-year follow-up of a prospective, observational, longitudinal cohort of allo-SCT patients (n=78) at two German transplantation centers that combined three-kingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics ( Figure 1). Using Multi-omics factor analysis (MOFA), we uncovered a functional microbiome signature of bacteria from the Lachnospiraceae and Oscillospiraceae families and their associated bacteriophages, which correlated with the production of immuno-modulatory metabolites (IMMs) including short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFA), metabolites associated with induction of type-I IFN signaling (IIMs) and immuno-modulatory secondary bile acids ( Figure 2). We established an Immuno-modulatory Metabolite Risk Index (IMM-RI) consisting of five index IMMs, which was associated with improved survival, less transplant-related mortality and reduced relapse rate. Onset of gastrointestinal GvHD and exposure to antibiotics significantly impacted intestinal levels of protective IMMs. Using whole shotgun metagenomic sequencing, we observed that in IMM-RI low-risk patients, sustained production of protective IMMs was associated with a high abundance of microbial SCFA biosynthesis pathways, specifically butyric acid via butyryl-CoA:acetate CoA-transferase (BCoAT). Through genome assembly from viral metagenomic sequencing data, we detected two distinct bacteriophages which encoded BCoAT as an auxiliary metabolic gene. They were more abundant in IMM-RI low-risk patients and positively correlated with intestinal butyric acid levels, suggesting that these bacteriophages may modulate bacterial metabolite biosynthesis. Our study identifies a specific microbiome signature associated with protective IMMs that could improve fecal microbiota transplantation (FMT) donor selection and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies for cancer patients.

Impact of Concurrent and Previous Multidrug Resistant Bacteria Colonization in Adult Allogenic Hematopoietic Stem Cell Transplant Patients with Acute Leukemia: A Single Center Retrospective Study

Background Multidrug resistant bacteria (MDRB) pose a major challenge in allogenic hematopoietic stem cell transplant (allo-HSCT) since patient colonization with Gram - or Gram + MDRB has been identified as a risk factor for infections, acute graft versus host disease (aGVHD) and reduced overall survival (OS). Nevertheless, data on the prognostic value of MDRB colonization are still scarce, and whether it should represent a limit to allo-HSCT eligibility is controversial. Few data are also available on the impact of previously detected colonization that are absent at transplant time. Methods This is a retrospective single center study on 60 patients with acute myeloid or lymphoblastic leukemia who underwent allo-HSCT from January 2014 to March 2023 according to JACIE standards.All patients were treated at our department starting from induction. In each hospital stay MDRB colonization was assessed by rectal swabs performed at admission, and thereafter weekly. In case of fever 3 sets of blood culture from peripheral vein and central venous catheters, urine culture and chest X-ray were performed, and empiric antibiotic therapy initiated. In MDRB colonized patients, targeted antibiotic therapy was administered if clinically indicated. All patients received fluroquinolones as antimicrobial prophylaxis. Data were retrieved from hospital records. Aim of the study To assess the epidemiology of MDRB colonization and the related impact on allo-HSCT outcome in terms of MDRB-related infections, aGVHD within day 100, OS and non-relapse mortality (NRM). Results MDRB colonization was detected in 26/60 (43.4%) patients, in 13 (21.7%) at hospital admission and in additional 13 (21.7%) after allo-HSCT. Overall, 33 MDRB strains were isolated (Table 1). Among patients colonized at hospital admission, Gram - MDRB accounted for 10/16 (62.5%) strains, mostly Escherichia Coli producing extended-spectrum beta-lactamases (ESBL) and Klebsiella Pneumoniae ESBL, while Gram + MDRB were 6 (37.5%), mostly represented by vancomycin-resistant Enterococcus faecium (VRE). In 14/16 (87.5%) cases the colonization has been previously detected, in 78.5% since the first two hospital stays. Among patients with positive rectal swabs after allo-HSCT, Gram - MDRB accounted for 16/17 (94.1%) strains, mostly Escherichia Coli ESBL and Klebsiella Pneumoniae ESBL (1 producing carbapenemases). In these patients the rectal swab turned out positive after a median time of 10 (2-24) days after allo-HSCT, mostly during neutropenia. Albeit absent at hospital admission, 13/17 (76.5%) MDRB strains had been previously isolated in the same patients, being firstly identified during the first two hospital stays in 76.9% cases. No significant differences in patient baseline characteristics, leukemia classification, type of donor and conditioning or hospitalization length were observed between MDRB carriers (26, 43.4%) and non-carriers (34, 56.8%) (Table 2). During the whole hospital stay, 18/26 (69%) carriers and 32/34 (94%) non-carriers reported at least one febrile event (p=0.01). Only carriers experienced MDRB (Gram -) infections based on blood (4, 22%) and urine (7, 38%) culture, while the rate of positive chest X-ray (4, 22,2% vs 5, 15.6%, p=0.5) did not differ. Targeted antibiotics were administered to 14/18 (77.8%) febrile carriers, in 10 (71%) at fever onset and in 4 (29%) at fever persistence. Four (22.2%) did not receive treatment because not clinically indicated. Intensive care unit was never required in both cohorts. The incidence of aGVHD was similar between carriers and non-carriers (10, 38.5% vs 17, 50%, p=ns), but the proportion of grade 2-4 tended to be higher in the first group (70% vs 35.5%, p=0.08). Overall, 73% patients are alive with a median follow-up of 18 (0.8-49) months. Median OS was not reached in both groups (p=0.09). There was no difference in NRM between carriers and non-carriers (5, 19% vs 2, 6%, p=0.11). Conclusion In our series 43.3% of allo-HSCT patients were colonized by MDRB that, in line with recent literature, were mostly Gram -. The absence of life-threatening infections and the non-significantly inferior OS and NRM in colonized patients suggest that a careful investigation of concurrent and previous colonization and a prompt use of targeted antibiotics may temper the negative impact of MDRB-related infections in adult acute leukemia patients undergoing allo-HSCT. Larger prospective studies are awaited.

Development of a Combined Risk Assessment Model for Venous Thromboembolism and Bleeding in Hematopoietic Stem Cell Transplantation Patients

Background: Venous thromboembolism (VTE) and bleeding are common complications amongst allogeneic and autologous hematopoietic stem cell transplant (HSCT) patients. Balancing risk of bleeding and thrombosis in this population is particularly challenging as HSCT patients are concurrently pancytopenic and coagulopathic. However, risk factors for bleeding and thrombosis in HSCT patients are understudied. We aimed to derive a combined bleeding and VTE risk assessment tool to be used in the immediate post-transplant period (90 days). Methods: We conducted a retrospective cohort study of adult patients who underwent allogeneic or autologous HSCT between January 1, 2011 and December 31, 2021 at a tertiary care centre in Canada. The risk models patients were followed from transplant until occurrence of the event of interest with last follow up at Day 90 post-transplant, or death. Primary outcome for VTE was the occurrence of a confirmed thrombosis including proximal upper and lower extremity deep vein thrombosis, pulmonary embolism, or thrombosis of unusual sites, including cerebral and splanchnic. Primary outcome for bleeding was the occurrence of a major or clinically significant non-major bleeding event, not related to anticoagulation, as per the definition of the International Society of Thrombosis and Hemostasis. Group characteristics were compared using chi-square, Fisher's exact, or Student's T-tests as appropriate. Potential predictors for VTE and bleed amongst our patients were evaluated using single variable logistic regression and confirmed with multiple variable logistic regression with forward selection. For continuous variables, optimal cut-off points were estimated using ROC curves. Final VTE and bleed risk scores were derived based on weighted variables and compared using Cox regression with non-parametric bootstrapping used for internal validation. Results: A total of 476 patients (317 autologous, 159 allogeneic) were included. 47 patients (9.8%) suffered from VTE, and 32 patients (6.7%) suffered from bleed unrelated to anticoagulation within 90 days post-HSCT. A VTE risk assessment tool was derived, and internally validated, and it included: second central venous catheter insertion (due to complications from first central line) (2 points), and previous cancer treatment with steroids (1 point). The overall cumulative incidence of VTE was 31.8% in the high-risk group (&amp;gt;2 points) versus 7.6% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (15.9% versus 3.2%, p &amp;lt;0.001; Figure 1). A bleeding risk assessment tool was also derived, and internally validated, and it included: baseline (day 0 of transplant) platelet count of &amp;lt;90 (1 point), and baseline hemoglobin of &amp;lt;96 (1 point). The overall cumulative incidence of bleed was 17.2% in the high-risk group (2 points), versus 4.3% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (12.6% versus 2.6%, p&amp;lt;0.001). Amongst the low-risk bleed group, overall cumulative incidence of VTE was 10.03%, with 31.03% in the high-risk VTE group versus 8.33% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (10.26% versus 1.72%, p=0.001; Figure 2). Amongst the high-risk bleed group, overall cumulative incidence of VTE was 9.19%, with 33.33% in the high-risk VTE group, versus 4.17% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (37.5% versus 10.13%, p=0.026). Conclusion: We derived a predictive score, VTE and Bleeding in Marrow Transplant (VBMT) - risk score, for both VTE and bleeding in the immediate post-transplant period (90 days), to be used in conjunction with other criteria for bleeding and thrombosis. Amongst the low-risk bleed patients, we recommend strong consideration of chemical VTE prophylaxis, especially amongst the high-risk VTE group. These risk assessment models will help stratify patients based on bleed and thrombosis risk, and ultimately help guide VTE prophylaxis and surveillance strategies amongst HSCT patients.

RUNX1 Mutation Does Not Significantly Impact the Outcome of Newly Diagnosedadult AML: A Retrospective Study of Chinese AML Patients

Background RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML) with a frequency of 6%~15%. Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML- RUNX1mut) was eliminated from the 2022 WHO classification system. With the update of AML diagnosis and treatment protocol, different outcomes of AML- RUNX1muthave been reported. However, an in-depth study about the prognostic value of RUNX1 mutations, epecifically the classification change related to AML- RUNX1mut in a large well-annotated cohort is lacking. Methods The clinical data of 1065 AML (excluding acute promyelocytic leukemia and RUNX1 germline mutations) patients according to WHO 2016 and treated from January 2017 to December 2021 at Jiangsu Institute of Hematology were retrospectively collected and analyzed after informed consent. All AML diagnosis samples were analyzed by targeted Next Generation Sequencing (NGS) panel covering 172 frequently mutated genes in hematological malignancies. Demographic and clinical data, disease characteristics at diagnosis, first-line treatment and clinical outcome data were available for all patients. The survival time of allogeneic hematopoietic stem cell transplantation patients was censored at the time of stem cell transfusion. Cytogenetic and molecular characteristics were used to classify patients into ELN2017 and ELN2022 risk groups (excluding the effect of RUNX1 mutation). Results RUNX1 mutations were detected in 112 (10.5%) patients, namely, 66 (58.9%) male and 46 (41.1%) female. A total of 132 RUNX1 alterations were detected with a medianvariant allelic frequency of 40% (3%~93%). RUNX1 mutations were associated with older age (48.5 vs. 46.0 years old, P=0.087) and antecedent myeloid disorders (6.3% vs. 1.0%, P&amp;lt;0.001). One or more comutations were detected in 106 (94.7%) AML- RUNX1mut patients. The most frequent co-gene abnormalities were FLT3-ITD and DNMT3A mutations which represented the 23.2% and 18.7%. Mutations of CEBPA bZIP, NPM1 and translocations of t(8;21), t(16;16)/inv(16) were uncommon in AML- RUNX1mut with a frequency of 6.3%, 1.8%, 2.7%, 0%, respectively (Table 1). Compared with AML with wild-type RUNX1 (AML- RUNX1wt), AML- RUNX1mut patients had a lower complete remission rate (19.6% vs. 29.7%, P=0.034), lower overall response rate (ORR) (73.5% vs. 84.3%, P=0.006) and higher no response rate (26.5% vs. 15.5%, P=0.021) in the first induction chemotherapy. When comparing groups based on the ELN2017 risk stratification criteria, no significant difference in ORR was observed between RUNX1mut and RUNX1wt patients in the favorable (91.2% vs. 94.0%, P=0.572), intermediate (75.0% vs. 78.4%, P=0.570) and adverse (63.3% vs. 71.4%, P=0.370 ) subgroups (Table 2). The median duration of follow-up of the entire cohort was 8.7 months ( RUNX1wt: 8.4 months; RUNX1mut: 10.0 months). Comparing the two groups, patients with RUNX1 mutations had a lower 5-year overall survival (OS) rate (35.4% vs. 42.3%; HR=1.563; 95% CI: 1.091~2.237, P=0.026), but no significant difference was observed in the 5-year event-free survival (EFS) rate (40.8% vs. 35.4%; HR=1.084; 95% CI: 0.750~1.570, P=0.098) (Table 2). However, when patients were stratified according to the ELN2017 guidelines (excluding the effect of RUNX1 mutation), outcomes did not differ between patients withor without RUNX1 mutation in the favorable (OS: P=0.629, EFS: P=0.137), intermediate (OS: P=0.629, EFS: P=0.114) and adverse (OS: P=0.544; EFS: P=0.714) subgroups. Similar results were obtained according to the ELN2022 guidelines. In multivariate analysis, RUNX1 was not an independent prognostic factor for OS (HR=1.353, 95% CI: 0.922~1.985, P=0.122) and EFS (HR=1.422, 95% CI: 0.975~2.075, P=0.068), while significantly worse OS and EFS were observed in patients with mutated FLT3-ITD, TP53, and DNMT3A ( P-values were all less than 0.05). Conclusion RUNX1 mutations were rarely isolated genetic abnormities that conferred inferior outcomes. However, on the basis of ELN prognosis risk stratification, RUNX1mutation had no impact on the clinical outcomes of AML patients in stratified subgroups. RUNX1 was not an independent prognostic factor for survival. Overall, our findings agree with the updated WHO classification system for AML that AML- RUNX1mut should not be recognized as a distinct AML entity.

Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound

A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n=20) or acute leukemia patients prior to IT (n=20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.

Drug monitoring during ciprofloxacin prophylaxis of allogeneic stem cell transplant patients: associations with bacterial infections through a monocentric observational prospective study

Bacterial infection ranks amongst the most common causes of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT). Although ciprofloxacin (CIP) prophylaxis is recommended, information on serum levels and clinical course is lacking. To investigate relationships between CIP level and failure of prophylaxis, particularly in terms of whether different pharmacokinetic (PK) indices [area under the concentration-time curve (AUC0-24h) vs single time samples] correlate differently with the outcome. This prospective observational monocentric study was conducted at a 1500-bed teaching hospital (March 2018-March 2019), including 63 adult patients with alloHSCT receiving CIP prophylaxis. Blood samples were drawn at three sampling times (1, 6 and 12h post-administration), twice per week, and measured via high performance liquid chromatography. The onset of febrile episodes (FEBs) indicated suspected failure of CIP prophylaxis. Positive blood cultures [bloodstream infection (BSI)] indicated confirmed failure of prophylaxis. Seven of 63 patients died without significant differences in their average CIP levels compared with survivors, with patients experiencing FEBs (54/63) displaying a 13% [95% confidence interval (CI) 4-22%] lower probability of survival. In total, 225 sets of three values (triplets) were obtained from 58 primary CIP episodes. Triplets preceding BSI with Gram-negative bacteria (GNB-BSI) showed lower AUC0-24h on average, but similar single time sample indices. An AUC0-24h of ≤21.61mgh/L resulted in four-fold higher odds of GNB-BSI (adjusted odds ratio 3.96, 95% CI 1.21-13.00). These results were independent of the administration route, patient demographics or sampling protocol deviations, indicating reduced CIP exposure upon GNB-BSI events. Monitoring CIP levels, using multiple sampling times, may be useful to reduce alloHSCT-associated bacterial infections. Further analysis is needed to investigate causality.

Loading dose vitamin D3 improves vitamin D insufficiency in adults undergoing hematopoietic stem cell transplantation: A randomized controlled trial.

Allogeneic hematopoietic stem cell transplant (aHSCT) patients are well known to be at high risk of vitamin D (vit D) deficiency. This study assessed whether a loading dose (100,000 IU) of vitamin D3 pre-aHSCT could effectively achieve and maintain sufficient post-transplant vit D levels (serum total 25 hydroxy vitamin D (25(OH)D) ≥ 75nmol/L). Dual-energy X-ray absorptiometry (DXA) was also conducted for bone health evaluation. 74 patients were enrolled and randomly assigned, in a 1:1 ratio, either to the high vit D group (single loading dose (100,000 IU) plus 2,000 IU vit D3 daily) or the control group (2,000 IU vit D3 daily). Vit D levels were measured at three time points (baseline, day 30 and day 100 post-aHSCT). At baseline, fewer than 50% patients had a sufficient 25(OH)D (control: 42.9%; high vit D: 43.6%). The proportion of patients with sufficient 25(OH)D (nmol/L) was increased at day 30 and day 100, with a trend of higher proportion in the high vit D group at day 30 (high vit D vs. control: 89.7% vs. 74.3%, p = 0.08). The increased 25(OH)D was significantly higher in the high vit D group at day 30 (high vit D vs. control: 29±25.2 vs. 14 ±21.9, p = 0.01). Insufficient vit D level before transplant (baseline) was an independent risk factor for vit D insufficiency (serum 25(OH)D < 75nmol/L) post-aHSCT (OR = 4.16, p = 0.03). DXA suggested significant bone loss for total hip in both groups, and in the femoral neck for the control group only. In conclusion, single loading dose vitamin D3 significantly increased total 25(OH)D levels at day 30 post-transplant, and the intervention was especially beneficial for patients with baseline vit D insufficiency. We acknowledge that the primary outcome at day 100 post-aHSCT indicating superiority of loading dose versus daily dose supplementation was not met.