allo-SCT Recipients Research Articles

Low-Dose Acyclovir Reduces the Reactivation of Herpes Simplex and Varicella Zoster Viruses After Allogeneic Stem Cell Transplantation.

Reactivation of herpes simplex virus (HSV) and varicella zoster virus (VZV) is a potential complication following allogeneic stem cell transplantation (alloSCT). Sincedifferent doses and durations of acyclovir prophylaxis may be utilized across transplant centers, this study aimed to evaluate the effectiveness of a lower dose of acyclovirin preventing HSV and VZV reactivation in alloSCT recipients within our institution. A retrospective chart review was conducted for patients who underwent alloSCT between April 2016 and May 2023. Patients received acyclovir 400 mg orally twice daily as prophylaxis, startingbefore stem cell infusion and continuing for two years after alloSCT, with ongoing use while on immunosuppressive therapies. Outcomes measured include incidence of HSV and VZVreactivation,timing of viral reactivation, acyclovir-related adverse events, and hospitalizations due to viral reactivation. Pertinentdata collected were risk factors for viral reactivation in patients such asimmunosuppressive therapies and chemotherapy regimens. Descriptive statistics were used for data analysis. A total of 246 patients were included in this study. The majority of patients were male with a median age of 60 years (range 20-76) and a diagnosis of acute myeloid leukemia.HSV reactivation occurred in 10 out of the 246 patients (4%)and none had VZV reactivation. The median time to HSV reactivation was 100 days (range 10-1400). No patienthad acyclovir-related adverse events such asacute kidney injury, neurotoxicity, or rash. Hospitalization related to HSVreactivation occurred in four of the 10 affected patients (40%). Oral acyclovir 400 mg taken twice daily for prophylaxis in alloSCT recipients is both effective and well-tolerated. This lower-dose regimen effectively prevents HSV and VZV reactivation without compromising efficacy or patient safety.

Impact of Donor Age and Gender on Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplant (allo-SCT) is critical in managing hematologic disorders. Donor age and gender are essential factors for post-transplant outcomes, and younger male donors have been associated with improved outcomes. We aimed to investigate the impact of donor age and gender on outcomes in patients undergoing matched unrelated donor (MUD) and haploidentical (haplo) allo-SCT. Methods: For this retrospective single-center study, we included allo-SCT recipients who received a MUD (n=276) or haplo (n=176) SCT at the University of Kanas Medical Center from August 2016 to July 2021. Cox regression analysis compared overall survival (OS) and disease-free survival (DFS). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Logistic regression was performed to compare relapse, non-relapse mortality (NRM), acute and chronic graft versus host disease (GVHD), and GVHD-free Relapse-free survival (GRFS). Odds ratios (0R) with 95% CI were calculated. Linear regression was performed to compare platelet and neutrophil engraftment, and the correlation coefficient (R) was calculated. Multivariate analyses were performed for donor age as a continuous and categorical variable (<30 years vs 30 years and above). SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p<0.05. Results: We included 452 Allo-SCT recipients who received a MUD (n=276) or Haplo (n=176) SCT. The median recipient age was 57 (18-77) years and 277 (61%) were male. The median age of the donor was 28 (10-65) years, with 57% of donors being younger than 30 years. Seventy-one percent (n=331) of donors were male. Myeloablative and reduced-intensity conditioning were performed in 169 (37%) and 283 (63%) recipients. The graft source was bone marrow in 224 (49.6%), and 228 (50.4%) had peripheral blood stem cell grafts. The median graft cell dose was 4 million CD34 cells/kg. GVHD prophylaxis included tacrolimus/methotrexate (n=241, 53%) and post-transplant cyclophosphamide-based (n=211, 47%). Hematologic diagnoses included myeloid (n=322, 71%), lymphoid (n=101, 22%), and others (n=29, 7%). After adjusting for significant variables in the multivariate regression models, OS was not affected by the donor age (HR 1.005, 95% CI 0.991-1.021, p=0.476) and donor age <30 years (HR 0.923, 95% CI 0.681-1.252, p=0.608). Donor age had a marginal association with relapse (donor age: OR 0.974, 95% CI 0.950-0.997, p=0.032; donor age <30 years: OR 1.760, 95% CI 1.131-2.775, p=0.013) and NRM (donor age: OR 1.025, 95% CI 1.001-1.048, p=0.034; donor age <30 years: OR 0.656, 95% CI 0.417-1.031, p=0.067). The donor's age did not affect GRFS, DFS, acute and chronic GVHD, and engraftment. Allo-SCT with male donors had superior OS (HR 0.626, 95% CI 0.452-0.868, p=0.0049) compared to female donors. Faster platelet engraftment was observed using male donors (R -4.212, -7.90 to -0.517, p=0.0250). GRFS, Relapse, DFS, NRM, acute and chronic GVHD, and neutrophil engraftment were not affected by donor gender. Conclusion: The use of male donors was associated with superior overall survival and faster platelet engraftment, while donor age did not significantly impact post-transplant outcomes. Our findings suggest improved survival with the use of male donors regardless of donor age, and these findings should be validated in a larger contemporary cohort.

Implementing a standardized workflow for early detection of steroid-induced hyperglycemia in allogeneic stem cell transplant recipients: A quality improvement project

BackgroundSteroid-induced hyperglycemia (SIH) worsens overall outcomes in the allo-SCT population. Currently, there is no standardized workflow for monitoring SIH. To address this need, a quality improvement (QI) initiative was implemented, as part of a Doctor of Nursing Practice project for the University of Kansas School of Nursing, to standardize glucose monitoring after the initiation of glucocorticoids (CGs) for the treatment of acute or chronic graft-versus-host-disease (GVHD). ObjectiveThis QI initiative aimed to decrease the median time to identification of SIH and the initiation of treatment in allo-SCT recipients on GCs for GVHD. Study DesignThe study took place at a large Midwestern blood and marrow transplant program. Patients diagnosed with acute or chronic GVHD and prescribed ≥0.5 mg kg-1/day prednisone equivalent (PE) steroids were requested to monitor postprandial blood glucose values for 14 days. A control group (retrospective chart review) was used for comparison. Time to the identification of SIH was compared between the two groups, as well as the time to treatment of hyperglycemia. ResultsOver 9 weeks, 19 patients enrolled in the QI initiative. The control group consisted of 21 patients. The median PE steroid dose was 1 mg kg-1/day in both groups (p = 0.8100). Eighteen of the 19 patients (95 %) had at least 1 blood glucose (BG) > 180 mg/dL and only 6 of 21 patients (29 %) had at least 1 BG > 180 mg/dL (p < 0.0001). The median time to a BG > 180 mg/dL was 1.5 days in the QI group and 7 days in the control group (p = 0.0232). The median time to insulin was 2 days in the QI group and 10 days in the control group (p = 0.0355). ConclusionThis project demonstrated that daily postprandial blood glucose monitoring is superior for the earlier identification and treatment of SIH when compared to monitoring at routine clinic visits alone.

Coordinating expensive, difficult-to-obtain prophylactic medications before discharge: A quality improvement project in an academic stem cell transplant unit.

337 Background: Infections are a significant source of morbidity/mortality in allogeneic stem cell transplant (alloSCT) patients and antimicrobial prophylaxis has reduced deaths. Between July 2022 and July 2023, 21% of new alloSCT recipients were discharged from UVA Medical Center without posaconazole or isavuconazonium +/- letermovir in-hand at the time of hospital discharge necessitating daily oral drug administration at the infusion center until medication could be obtained. This led to excess cost for UVA, burden on clinic staff, missed doses, and patient frustration. We sought to decrease the number of new alloSCT recipients discharged without appropriate prophylaxis in-hand from 21% to 10% by November 2024. Methods: Per the 2023 ASCO Quality Training Program associated with this project, a Model for Improvement and Plan Do Study Act (PDSA) methodology was utilized. The population included alloSCT patients with new prescriptions (Rxs) for posaconazole or isavuconazonium +/- letermovir. The outcome measure was percentage of newly discharged alloSCT patients requiring oral prophylaxis at the infusion center. The process measure was Time to Affordable Medication (TAM) defined as days from Rx prior-authorization (PA) request to paid claim with an affordable copay (defined as a copay the patient was able/willing to pay, including free drug approvals or assistance programs). The counter measure consisted of initiating the Rx PA process 10 days prior to planned admission via a discharge test Rx order set instead of waiting until admission. This standardized process allowed for clearer communication and more time for pharmacy technicians to process the Rx for PA, copays, free drug applications, and pharmacy logistics. Upon admission, the official Rx was released to the discharge pharmacy. If Rx shipment was required, this was set up the week prior to discharge. An I-chart (3-sigma) statistical process control (SPC) chart was used to assess the intervention. Results: The baseline TAM was assessed retrospectively in 22 Rxs over 3 months prior to intervention for a mean of 7.5 days. PDSA cycle 1 was implemented Nov. 2023. TAM for the first 35 Rxs was 4.3 days and the SPC upper control limit decreased from 26.3 days to 13.3 days demonstrating overall markedly decreased variation despite data from early 2024 having greater variability due to new insurance deductibles. Rxs requiring 10 or more days were due to free drug application processes. Importantly, no newly discharged alloSCT patients have required drug administration at the infusion center. Conclusions: PDSA #1 resulted in a decrease in TAM of 3.2 days, decreased variation in the process, and no patients discharged without drug in hand. Since we have already surpassed our aim, next steps include demonstrating sustainability of the process and a survey requesting feedback to identify balance measures.

Targeting exercise and sedentary behavior for the prevention of allogeneic stem cell transplant-related cardiovascular dysfunction: The ALLO-Active trial.

12018 Targeting Exercise and Sedentary Behavior to Prevent Allogeneic Stem Cell Transplant-Related Cardiovascular Dysfunction: The ALLO-Active Trial Background: Allogeneic stem cell transplantation (allo-SCT) is a potentially life-saving therapy for hematological malignancy, however, quality of life and longevity post allo-SCT are hampered by exercise intolerance, cardiac dysfunction, and cardiovascular mortality. This randomized controlled trial evaluated the efficacy of a novel multi-component activity program on cardiorespiratory fitness (peak oxygen uptake [VO2peak]) and cardiac function in adults undergoing allo-SCT. Methods: Sixty-two hematological malignancy patients scheduled for allo-SCT were randomized to a 4-month multi-component Activity program (n = 30) designed to increase aerobic and resistance exercise (3-day.week-1) and reduce sedentary time (≥30-min.day-1), or to usual care ( UC, n = 32). The Activity program was delivered over two distinct phases: ‘Inpatient’, which commenced upon admission for allo-SCT and continued until discharge (~4 weeks), and ‘Outpatient’,which commenced at discharge and continued for 12-weeks. Physiological assessments were conducted pre-admission, and 12-weeks post-discharge (4-months from baseline) and included: (1) cardiopulmonary exercise testing to quantify VO2peak, (2) exercise cardiac magnetic resonance imaging to determine peak cardiac output and stroke volume index (COIpeak and SVIpeak), (3) standard of care resting echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and (4) cardiac biochemistry (troponin, B-type natriuretic peptide). Results: Fifty-two patients (84%) completed follow-up (25 Activity; 27 UC), and median (IQR) intervention adherence was 73% (50-81). Activity preserved VO2peak (-0.9ml.kg-1.min-1 [95%CI -2.5, 0.8]) which showed a marked decline with UC (-3.4ml.kg-1.min-1 [95%CI -4.9, -1.8]; interaction, p= 0.029). Activity also showed significant benefits on exercise cardiac function, as shown by a preservation of COIpeak (0.30L.min-1.m2, [95%CI -0.34, 0.41]) and SVIpeak (0.6ml.m2 [95%CI -1.3, 2.5]), both of which declined with UC (COIpeak: -0.68L.min-1.m2, [95%CI -1.3, -0.32]; interaction, p= 0.008; SVIpeak: -2.7ml.m2 [95%CI -4.6, -0.9], interaction, p =0.014). There were no treatment effects of Activity on cardiac injury biomarkers or global longitudinal strain and no changes in left ventricular ejection fraction in either group. Conclusions: Intervening early in the allo-SCT process with an exercise and sedentary behavior intervention can have significant benefits for the preservation of patient’s cardiovascular reserve capacity. Our results may have important long-term implications for cardiovascular disease incidence and mortality in allo-SCT recipients. Clinical trial information: ANZCTR12619000741189.

Outcome of 3q26.2/MECOM rearrangements in chronic myeloid leukemia.

To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89months, median survival was 14months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

Are any specific respiratory viruses more severe than others in recipients of allogeneic stem cell transplantation? A focus on lower respiratory tract disease.

In the general population, influenza virus, respiratory syncytial virus, and SARS-CoV-2 are considered the most severe community-acquired respiratory viruses (CARVs). However, allogeneic stem cell transplant (allo-SCT) recipients may also face severe courses from other CARVs. This retrospective study compared outcomes of various CARV lower respiratory tract diseases (LRTD) in 235 adult allo-SCT recipients, excluding co-infection episodes. We included 235 adults allo-SCT recipients experiencing 353 CARV LRTD consecutive episodes (130 rhinovirus, 63 respiratory syncytial virus, 43 influenza, 43 human parainfluenza virus, 23 human metapneumovirus, 19 Omicron SARS-CoV-2, 17 common coronavirus, 10 adenovirus and 5 human bocavirus) between December 2013 and June 2023. Day 100 overall survival ranged from 78% to 90% without significant differences among CARV types. Multivariable analysis of day 100 all-cause mortality identified corticosteroid use of >1 to <30 mg/d [Hazard ratio (HR) 2.45, p = 0.02) and ≥30 mg/d (HR 2.20, p = 0.015) along with absolute lymphocyte count <0.2 × 109/L (HR 5.82, p < 0.001) and number of CARV episodes as a continuous variable per one episode increase (HR 0.48, p = 0.001) as independent risk factors for all-cause mortality. Degree of immunosuppression, rather than intrinsic CARV virulence, has the most significant impact on mortality in allo-SCT recipients with CARV-LRTD.

Outcome of Human Parainfluenza Virus infection in allogeneic stem cell transplantation recipients: possible impact of ribavirin therapy.

This retrospective study focused on analyzing community-acquired respiratory virus (CARV) infections, in particular human parainfluenza virus (hPIV) after allogeneic stem cell transplant (allo-SCT) in adults recipients. It aimed to assess the impact of ribavirin treatment, clinical characteristics, and risk factors associated with lower respiratory tract disease (LRTD) progression and all-cause mortality. The study included 230 allo-SCT recipients diagnosed with hPIV between December 2013 and June 2023. Risk factors for the development of LRTD, disease severity, and mortality were analyzed. Ribavirin treatment was administered at physician discretion in 61 out of 230 cases (27%). Risk factors for LRTD progression in multivariate analysis were corticosteroids > 30mg/day (Odds ratio (OR) 3.5, 95% Confidence Interval (C.I.) 1.3-9.4, p = 0.013), fever at the time of hPIV detection (OR 3.89, 95% C.I. 1.84-8.2, p < 0.001), and absolute lymphocyte count (ALC) < 0.2 × 109/L (OR 4.1, 95% C.I. 1.42-11.9, p = 0.009). In addition, the study found that ribavirin therapy significantly reduced progression to LRTD [OR 0.19, 95% C.I. 0.05-0.75, p = 0.018]. Co-infections (OR 5.7, 95% C.I. 1.4-23.5, p = 0.015) and ALC < 0.2 × 109/L (OR 17.7, 95% C.I. 3.6-87.1, p < 0.001) were independently associated with higher day + 100 after hPIV detection all-cause mortality. There were no significant differences in all-cause mortality and infectious mortality at day + 100 between the treated and untreated groups. ALC, corticosteroids, and fever increased the risk for progression to LRTD while ribavirin decreased the risk. However, mortality was associated with ALC and co-infections. This study supports further research of ribavirin therapy for hPIV in the allo-HSCT setting.

Abstract CT143: IFN-γ and donor leukocyte infusion to treat relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation

Abstract Introduction: Allogeneic stem cell transplantation (alloSCT) can provide a cure for myeloid malignancies partially through the graft-vs-leukemia effect (GVL), wherein donor-derived alloreactive T cells attack recipient leukemia cells. Preclinical data strongly suggested IFN-γ is crucial for effective GVL against myeloblastic leukemia. IFN-γ receptor gene-deficient myeloblastic leukemia were resistant to GVL in mouse models (Matte-Martone, Shlomchik JCI 2017). IFN-γ upregulated HLA expression in relapsed myeloblasts in vitro (Christopher NEJM 2018, Toffalori Nat Med 2019). We hypothesized that IFN-γ would sensitize myeloblasts to alloreactive T cells and promote GVL. Here, we present the results of a phase 1 study to evaluate the safety of IFN-γ combined with donor leukocyte infusions (DLI) for relapsed myeloblastic malignancies post-transplant (NCT04628338). Methods: HLA-matched donor alloSCT recipients with relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and no active graft-versus-host disease (GVHD) were eligible. Patients self-administered 100mcg IFN-γ (Actimmune, Horizon Therapeutics) three times a week for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Flow cytometry-based surface HLA expression and single-cell RNAseq (scRNAseq) were analyzed using bone marrow (BM) collected before and after IFN-γ. Results: Seven patients with high-risk diseases (2 MDS and 5 AML) were enrolled. There were no serious adverse events during IFN-γ monotherapy. After DLI, 5 patients developed grade I-II GVHD along with immune effector cell-associated neurotoxicity syndrome (grade 1 or 2; n=2) and idiopathic pneumonia syndrome (IPS; n=1). All immune-mediated toxicities, including IPS, resolved with corticosteroids. 4 out of 6 DLI recipients achieved minimal residual disease negative complete remissions and full donor hematopoietic cell reconstitution. The median overall survival was 579 days (range, 97-906) in responders. Myeloid blasts upregulated HLA-DR after IFN-γ, and enrichment of recipient malignant hematopoietic stem cells expressing CIITA was observed in post-IFN-γ BM by scRNAseq. Conclusions: This first in human use of IFN-γ to treat post-transplant relapse was safe, with a promising efficacy signal when combined with DLI. Correlative studies support our hypothesis that in vivo IFN-γ activates myeloblasts, manifest by HLA-DR upregulation and CIITA induction. We plan to design a phase 2 trial to formally test the efficacy of this novel immunotherapeutic approach to boost GVL in alloSCT. Citation Format: Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Scott N. Furlan, Warren D. Shromchik. IFN-γ and donor leukocyte infusion to treat relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT143.

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience

BackgroundWe aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). MethodsWe conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. ResultsThe median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. ConclusionsCMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Letermovir use may impact on the Cytomegalovirus DNA fragmentation profile in plasma from allogeneic hematopoietic stem cell transplant recipients.

Cytomegalovirus (CMV) DNA in plasma is mainly unprotected and highly fragmented. The size of the amplicon largely explains the variation in CMV DNA loads quantified across PCR platforms. In this proof-of-concept study, we assessed whether the CMV DNA fragmentation profile may vary across allogeneic hematopoietic stem cell transplant recipients (allo-SCT), within the same patient over time, or is affected by letermovir (LMV) use. A total of 52 plasma specimens from 14 nonconsecutive allo-SCT recipients were included. The RealTime CMV PCR (Abbott Molecular), was used to monitor CMV DNA load in plasma, and fragmentation was assessed with a laboratory-designed PCR generating overlapping amplicons (around 90-110 bp) within the CMV UL34, UL80.5, and UL54 genes. Intrapatient, inter-patient, and LMV-associated qualitative and quantitative variations in seven amplicons were observed. These variations were seemingly unrelated to the CMV DNA loads measured by the Abbott PCR assay. CMV DNA loads quantified by UL34_4, UL54.5, and UL80.5_1 PCR assays discriminate between LMV and non-LMV patients. Our observations may have relevant implications in the management of active CMV infection in allo-SCT recipients, either treated or not with LMV, although the data need further validation.

Impaired T cells and “memory-like” NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation

AbstractAllogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens, such as human cytomegalovirus (HCMV). Letermovir prophylaxis has revolutionized HCMV management, but the challenge of late HCMV reactivations has emerged. Immunological surrogates of clinically significant HCMV infection (csCMVi) after discontinuation of letermovir remain to be defined. Therefore, we studied natural killer (NK)-cell reconstitution along with the global and HCMV pp65-specific T-cell repertoire of 24 alloSCT recipients at 7 time points before (day +90) and after (days +120-270) cessation of letermovir prophylaxis. Patients who experienced csCMVi had lower counts of IFN-γ+ HCMV–specific CD4+ and CD8+ T cells than HCMV controllers. Furthermore, patients with csCMVi displayed late impairment of NK-cell reconstitution, especially suppression of “memory-like” CD159c+CD56dim NK-cell counts that preceded csCMVi events in most patients. Moreover, several surrogates of immune reconstitution were associated with the severity of HCMV manifestation, with patients suffering from HCMV end-organ disease and/or refractory HCMV infection harboring least HCMV–specific T cells and “memory-like” NK cells. Altogether, our findings establish an association of delayed or insufficient proliferation of both HCMV–specific T cells and “memory-like” NK cells with csCMVi and the severity of HCMV manifestations after discontinuation of letermovir prophylaxis.

Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study

BackgroundWe previously reported that the “Endothelial Activation and Stress Index” (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as...

Multiparametric Flow Cytometry Based Quantification of the Marrow Hematopoietic Stem and Progenitor Compartment in Post Allogeneic Stem Cell Transplant Recipients with Poor Graft Function to Evaluate Hematopoietic Stem Cell Quality and Predict Clinical Outcomes: A Pilot Study

Poor graft function (PGF) is a poorly defined, commonly occurring (estimated 5 to 27%) 1 and difficult to treat complication of allogeneic stem cell transplantation (Allo-HSCT). Thrombopoietin agonists such as eltrombopag (EPAG) or CD34-selected cell infusions are treatments offered for persistent cytopenias. However, with limited knowledge of pathophysiology, there is a lack of reliable prognostic biomarkers. We aimed to investigate if assessment of the BM hematopoietic stem and progenitor cell (HSPC) landscape by multiparametric flow cytometry (MP-FCM) could help evaluate stem cell quality and predict clinical outcomes in PGF patients. We screened the UHN biobank repository to identify banked BM samples of patients who underwent diagnostic BM aspirate for PGF post allo-HSCT. Patients who had progressive cytopenia in one or more lineages after achieving engraftment while having full donor chimerism were included. Relapse as a cause of cytopenia was excluded. Controls in 1:1 ratio were Allo-SCT recipients with stable counts with banked day 60 BM aspirate. The blinded BM samples were analyzed with a 14-parameter FCM adapted from panels previously utilized to assess HSPC and mature lineages in cord blood xenograft studies (2). We selected 12 each of PGF and controls. The mean age of all recipients was 50 years and donors was 30.5 years. 23/24 cases had AlloSCT for hematological malignancies with 15 having AML or MDS. There were 14 unrelated (9 matched, 5 mismatched) and 10 related (5 matched sibling, 5 haploidentical) donors. Mean cell dose of infused graft was 6.66(± 1.98)x 10E6/kg CD34 cells. The significant difference between PGF and controls were recipient age (median 57y vs 28y), allo-SCT number (3 vs 0 with 2 nd transplant), intensity of conditioning regimen (myeloablative in 16% PGF vs 83% controls), and incidence of ≥ grade 3 acute graft vs host disease (GVHD) (n=3 vs 0). Most common causes of PGF were GVHD (n=6), infections (n=4) and drug effects (n=5). 11 PGF patients were treated with EPAG with 5 patients (A3, B2, B3, B5, C4) showing complete response, 3 (A6, B6, C5) showing partial response, and 3 (A2, A4, C9) showing no response. Patient C1 showed complete recovery without the use of EPAG, while C9, who initially did not respond to EPAG, showed a slow spontaneous recovery almost a year later. Amongst non-responders A2 and A4 received CD34 boost; with A4 showing a good response to the second boost. Analyzing the HSPC population by MP-FCM, we found that the PGF vs control groups show significant differences in the percentage of CD34+CD19+ B-Lymphoid precursors (B-LP) and CD19+ B lymphocytes. The mean ± SD percentage of B Lymphocytes and B-LPs in the PGF cohort were 6.76% ± 0.096% and 0.39% ± 0.005% respectively, while in the control group they were 20.09% ± 0.136% and 1.17% ± 0.012% respectively. When the 50 th centile value of the B-LPs (0.375%) or CD19+ B cells (10.89%) was investigated as a cut off to predict the clinical syndrome, this strategy achieved a 75% success rate with 3 PGF (blue bars) or control (black bars) samples misclassified (Fig1). Next, we investigated if these HSPC fractions could help predict the clinical outcome of PGF cases. The cases A2 and A4 who demonstrated no count recovery and needed CD34 boost lie in the lower quartile of both B Lymphocytes as well as B Lymphoid precursors content (Fig 1 red arrows). Conversely the three PGF cases in the upper 50 centile of these cell populations (patient B3, C4 and C9) all showed either a spontaneous or EPAG induced recovery of counts. We further investigated if the proportion of immunophenotypic CD34+CD38-CD45RA-CD90+CD49f+ long-term HSC (LT-HSC) could provide additional prognostic information (Fig2). Again, patients A2 and A4 had LT-HSC in the lower 50 th centile. Patient C1 who showed a spontaneous recovery of counts without the need of EPAG had the highest proportion of LT-HSCs despite lying in the second quartile of the cohort for both B cells as well as B-LPs. In conclusion, MP-FCM based analysis of the HSPC landscape in PGF marrow could be a robust prognostic biomarker in Allo-SCT patients.

Haploidentical Donor Transplants with Cytokine Release Syndrome Have Increased Risk of Clinically Significant Early CMV Reactivation Compared with Matched Donor Transplants Receiving Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) enables safe haploidentical stem cell transplantation by reducing graft-versus-host-disease (GVHD) but is associated with an increased risk of reactivation of Cytomegalovirus (CMV). PTCy has more recently been adopted for matched-donor transplants, where early CMV reactivation may also be more common. This suggests that CMV reactivation is a function of PTCy rather than donor source. However, other studies comparing the rates of CMV in transplants using PTCy-based prophylaxis suggested disparity in donor source may contribute to CMV reactivation. Aim: The goal of this single-centre, retrospective study was to determine if donor type had any impact on CMV reactivation in the setting of PTCy-based GVHD prophylaxis. Methods: The Alfred Hospital Bone Marrow Transplantation Unit has used PTCy for GVHD prophylaxis in both haploidentical and matched-donor allogeneic stem cell transplants (alloSCT) since 2015. A local database search identified 119 allogeneic peripheral blood alloSCT recipients receiving PTCy-based GVHD prophylaxis between February 2015 and December 2022. Matched-donor alloSCTs also received cyclosporin from Day +5 while haploidentical alloSCTs also received tacrolimus and mycophenolate from Day +5. One patient was excluded due to CMV viremia at the time of transplant. Recipients who were CMV seropositive received therapeutic dose valganciclovir 900 mg twice daily from the start of conditioning until the day prior to stem cell infusion. Prophylactic valganciclovir (900 mg daily) was planned upon engraftment for seropositive recipients and those receiving stem cells from a seropositive donor. CMV DNA PCR was performed weekly for the first 100 days post-transplant and beyond when clinically indicated. CMV viremia was defined as any positive CMV PCR (&amp;gt; 34.5 copies/mL) within the first 100 days post-transplant. Therapeutic valganciclovir was initiated for CMV viral loads (VL) &amp;gt; 1,000 copies/mL or earlier for rapidly rising VLs. Cytokine release syndrome (CRS) was defined as fever &amp;gt; 38 degrees Celsius between stem cell infusion and PTCy on Day +3 without an alternate explanation and graded according to CTCAE criteria. CMV donor and recipient negative transplants were excluded from the analysis of the impact of donor disparity on CMV reactivation. Statistical analyses included Fisher's Exact test, one-way ANOVA and Binomial Logistic Regression. Results: Transplant characteristics according to donor source were similar apart from conditioning intensity, where recipients of haploidentical stem cells were more likely to receive myeloablative conditioning (Table 1). The cumulative incidence of moderate-severe chronic GVHD was significantly higher in matched sibling transplants but overall, 12-month GVHD-free and relapse-free survival were similar. As previously reported, CRS (overall and grades II-IV) was significantly more common in haploidentical transplants. Day 100 CMV viremia rates were not statistically different between donor groups. However, haploidentical transplants trended for earlier CMV reactivation (p=0.08), and were significantly more likely to rise above 250 copies/mL (Table 1 and Figure 1). Consequently, haploidentical transplant recipients received significantly more anti-CMV therapy (p=0.009). Multivariable analysis identified haploidentical donor as a major risk factor for CMV &amp;gt; 250 (odds ratio, OR 1.24, p=0.011) and &amp;gt; 1,000 copies/mL (OR 1.41, p=0.032) while transplant for AML/MDS was negatively associated with CMV &amp;gt; 250 (OR 0.19, p=0.009) and CMV &amp;gt; 1,000 copies/mL (OR 0.16, p=0.003). CRS was significantly associated with CMV &amp;gt; 1,000 copies/mL (OR 3.33, p=0.032) but this was no longer significant in multivariable analysis due to the association with haploidentical donor transplantation. Conclusion: This single-center retrospective comparison of PTCy-based transplants shows that haploidentical transplants have increased risk of early and clinically significant reactivation of CMV. Potential explanations include increased immunosuppression with mycophenolate and the presence of CRS, where inflammatory cytokines may de-repress the CMV major immediate early promoter. Selecting this high-risk group (haploidentical transplants with CRS) may be a cost-effective use of letermovir, which can be initiated prior to engraftment.

Lower Cumulative Incidence of Relapse but Higher Incidence of NRM in Patients with Poor Graft Function Following Allogeneic Stem Cell Transplantation

Introduction Poor Graft Function(PGF), defined as multilineage cytopenias in the setting of complete donor chimerism is a significant complication of allogeneic stem cell transplantation (alloSCT). Recently our group, in a published retrospective analysis of 929 patients, demonstrated that the following factors were associated with the development of PGF: Non matched sibling donor, ICU admission/ positive blood cultures within 1 st 30 days of alloSCT, severe graft versus host disease (GVHD), CMV viremia (Prabahran et al 2021). We extended our prior cohort study to validate risk factors previously associated with PGF and describe outcomes such as recovery from PGF, relapse and non-relapse mortality following a diagnosis of PGF. Methods This was a retrospective analysis of alloSCT recipients at our institution from 2017-2020. Patients 17 years and older were included. Patients who died prior to D60 of alloSCT were excluded as chimerism data was often not available prior to this timepoint. PGF was defined as follows: 1) ≥95% donor chimerism at last reading OR ≥95% CD3 negative chimerism; 2) ≥2 Lineage cytopenias defined as: Thrombocytopenia :≤30x10 9 /L from D40-D60 OR ≤50 x10 9/L from D60 onwards; neutropenia requiring filgrastim support at any time post D40; Hb &amp;lt;80g/L. Factors associated with PGF were evaluated using a logistic regression, with development of PGF being the dependent variable. The predictive power of the subsequent logistic regression model was validated utilizing bootstrapping re-sampling procedure and testing of the concordance index (C-index). Variables associated with PGF were also evaluated in a cox-proportional model and coded as time-dependent covariates. Relapse and non-relapse mortality (NRM) were evaluated in a competing risk model from a landmark of 200 days post alloSCT, performed as per the method of Fine and Gray. Results 308 patients were included in the analysis of which 259 patients did not have PGF (nPGF) and 49 had PGF. Baseline variables of nPGF and PGF patients were matched for median age (53 versus 56 p=0.28), recipient sex (68% versus 65% male, p=0.74)), median CD34 dose (5.00 versus 5.2 x10 9/L p=0.49), donor source (p=0.12) and CMV serostatus (p=0.23). In multivariate analysis, ICU admission within 30 days (p=0.002), non-CMV viral infections (p=0.032) and GVHD (p&amp;lt;0.001) were associated with the development of PGF. The c-index of the model at baseline was 0.77 and 0.75 after bootstrapping validation indicating reasonable predictive performance of this model. ICU admission, non-CMV viral infections and GVHD were still significantly associated with the development of PGF when utilised as time dependent variables in a cox-regression model. Patients with PGF had worse 2-year survival compared to nPGF (60 versus 75% p=0.02). PGF patients without marrow recovery at last follow up had a 6-month OS of 20%. Twenty three out of 49 patients recovered marrow function at last follow up with a median duration of cytopenias of 142 days (51-789). The cumulative incidence (CI) of recovery was 44% and 53% at 1- and 2-years following onset of cytopenias respectively. From a landmark of 200 days (33 patients excluded due to death prior to this timepoint) PGF patients had a higher CI of NRM (Figure 1A =0.001) but lower CI of relapse (Figure 1B p=0.027) compared to nPGF patients. Conclusions PGF is strongly associated with early ICU admission, severe GVHD and non-CMV viral infections. Survival is inferior in patients with PGF particularly those with poor marrow recovery and this is mainly driven by non-relapse mortality. The lower CI of relapse in PGF is a novel finding of this study and may suggest a protective effect of PGF against the development of relapse but this finding requires further validation in external cohorts.

Risk Factors Associated with Survival Following Ganciclovir Prophylaxis through Day +100 in Cytomegalovirus At-Risk Pediatric Allogeneic Stem Cell Transplantation Recipients: Development of Cytomegalovirus Viremia Associated with Significantly Decreased 1-Year Survival

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and nonrelapse mortality (NRM) in pediatric allogeneic stem cell transplantation (alloSCT) recipients. Approximately 80% of CMV seropositive alloHCT recipients will experience CMV reactivation without prophylaxis. The impacts of ganciclovir prophylaxis and subsequent CMV viremia on 1-year survival and 1-year NRM are unknown. The primary objective of this study was to determine the effect of CMV viremia on the probability of 1-year survival and 1-year NRM in pediatric alloSCT recipients receiving 100 days of ganciclovir prophylaxis. The secondary objective was to determine the effect of other risk factors on 1-year survival and 1-year NRM. All patients age 0 to 26 years who underwent alloSCT between June 2011 and May 2020 and received ganciclovir prophylaxis for 100 days at Westchester Medical Center, an academic medical center, were analyzed. Ganciclovir was administered to at-risk alloSCT recipients (donor and or recipient CMV+ serostatus) as 5 mg/kg every 12 hours from the first day of conditioning through day -1 (recipient CMV+ only) followed by 6 mg/kg every 24 hours on Monday through Friday beginning on the day of an absolute neutrophil count >750/mm3 and continuing through day +100. National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria were used to grade toxicity. NRM was analyzed using competing survival analysis with relapse death as a competing event. The log-rank and Gray tests were performed to compare the 1-year survival probabilities and NRM cumulative incidence between patients who experienced CMV viremia post-alloSCT and those who did not. Univariate Cox regression analysis was performed for the following risk factors: CMV viremia, donor source, sex, malignant disease, disease risk index, conditioning intensity, receipt of rabbit antithymocyte globulin (rATG)/alemtuzumab, graft-versus-host disease (GVHD) prophylaxis, CMV donor/recipient serostatus, grade II-IV acute GVHD, and grade 3/4 neutropenia necessitating discontinuation of ganciclovir, treating the last 3 factors as time-dependent covariates. Those with P values < .2 were included in the multivariate Cox regression analysis. Eighty-four alloSCT recipients (41 males, 43 females; median age, 10.8 years [range, .4 to 24.4 years]) were analyzed. Multivariate analysis showed significantly lower 1-year survival and significantly higher 1-year NRM in patients who developed CMV viremia compared to those who did not (P=.0036). No other risk factors were significantly associated with 1-year survival or 1-year NRM. One-year survival was significantly decreased and 1-year NRM was significantly increased in pediatric alloSCT recipients who developed CMV viremia following ganciclovir prophylaxis. No other risk factors were found to be associated with 1-year survival or 1-year NRM. Alternative CMV prophylaxis regimens that reduce CMV viremia should be investigated in pediatric alloSCT recipients at risk for CMV infection.

Donor-related EDTA dependent pseudothrombocytopenia after allogeneic stem cell transplantation. Can it be real?

Hematopoietic stem cell transplantation (HSCT) may take place in the form of an autologous or allogeneic transplant depending on the indication for transplantation. Because of the myeloablative conditioning regimens preceding HSCT, deep thrombocytopenia is experienced by most of the stem cell recipients in whom replenishment of leukocytes and platelets is expected within the first month following the transplantation. Prolonged thrombocytopenia, on the other hand, usually develops as a delayed complication of allogeneic stem cell transplantation (allo-SCT) and is associated to the source of stem cells, quantity of the infused CD34+ cells, graft-versus-host-disease (GVHD), insufficient engraftment, relapse of the malignancy, microangiopathy, alloimmunisation, medications, or viral infections. In an attempt to explain pathogenesis leading to post-HSCT thrombocytopenia, two main theories have been proposed. First one is the peripheral destruction caused by anti-platelet antibodies, splenic sequestration, or other factors. The latter blames insufficient platelet generation due to impaired thrombopoiesis. Nevertheless, most of the clinical conditions arise with overlapping of both mechanisms.Here we present a pseudothrombocytopenia case induced by donor-related ethylene-diamine-tetra-acetic acid (EDTA) as an unanticipated cause of thrombocytopenia to which most recipients of allo-SCT are prone to.

Developing a supportive and palliative care intervention for patients with allogeneic stem cell transplantation: protocol of a multicentre mixed-methods study (allo-PaS)

IntroductionAlthough allogeneic stem cell transplantation (allo-SCT) is a curative treatment for many haematological malignancies, it is often associated with a high morbidity and mortality. Yet, little is known about the...

The graft-versus-leukemia effect of prophylactic donor lymphocyte infusions after allogeneic stem cell transplantation is equally effective in relapse prevention but safer compared to spontaneous graft-versus-host disease.

Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS.