Preemptive Therapy Research Articles

Impact of Early Anti-Cytomegalovirus Therapy on the Incidence of Chronic Graft-Versus-Host Disease

Introduction: Cytomegalovirus (CMV) infections are associated with poor outcomes in recipients of allogeneic hematopoietic stem cell transplants (HSCTs). Therefore, preventive therapy or preemptive treatment have been developed. Ganciclovir (GCV) and foscarnet (FCN) are essential intravenous anti-CMV agents. A previous regional multicenter study revealed a significantly lower risk of chronic graft-versus-host disease (GVHD) in patients who received preemptive FCN therapy. To validate this observation and to investigate the mechanism or target, we executed a comprehensive nationwide study. Patients and Methods: We defined the early anti-CMV therapy as administration within 180 days after transplantation without evidence of target therapy for CMV infections. We retrospectively analyzed patients who received FCN or GCV as early anti-CMV therapy, and who are not received any anti-CMV agents (no anti-CMV) between June 2005 and December 2019. We excluded patients who received FCN, GCV, valganciclovir, or letermovir as prophylactic therapy; those who began anti-CMV therapy before the day of transplantation; those who received both FCN and GCV; those who underwent T cell-depleting treatment. Results: A total of 19536 adults with hematological malignancies who received their first allogeneic HSCT were included. We compared patients who received FCN (n = 1555) or GCV (n = 7335) as early anti-CMV therapy, and no anti-CMV recipients (n = 10646). FCN or GCV recipients showed higher incidence of acute GVHD than no anti-CMV recipients. The cumulative incidence of acute GVHD 200 days after transplantation were 46% (95% confidence interval [CI], 41%-51%), 47% (95% CI, 45%-50%), and 26% (95% CI, 25%-28%) for FCN, GCV, and no anti-CMV recipients, respectively (P < 0.001). The cumulative incidence of chronic GVHD three years after transplantation were 28% (95% CI, 26%-31%), 37% (95% CI, 36%-38%), and 29% (95% CI, 28%-30%) for FCN, GCV, and no anti-CMV recipients, respectively (P < 0.001). The cumulative incidence of extensive chronic GVHD three years after transplantation were 17% (95% CI, 15%-19%), 22% (95% CI, 22%-23%), and 16% (95% CI, 15%-26%) for FCN, GCV, and no anti-CMV recipients, respectively (P < 0.001) (Figure A). In multivariate analyses adjusted for acute GVHD or other important variables, the risks of extensive chronic GVHD among GCV recipients was higher than FCN recipients (hazard ratio [HR], 1.17; 95% CI, 1.01-1.34; P = 0.031), whereas no-anti CMV recipients and FCN did not showed statistically significance. In further investigations, we performed stratified analyses and revealed that the incidence of extensive chronic GVHD was significantly lower among the FCN recipients than among the GCV recipients only in stratifications that involved male recipients of female donor HSCT (according to sex compatibility). Comparing with GCV, the incidence of extensive chronic GVHD was significantly reduced among male recipients of female donor HSCTs who were taking FCN (HR, 1.63; 95% CI, 1.19-2.23; P = 0.002), but FCN did not affect the incidence of extensive chronic GVHD for other sex compatibility-based stratifications (HR, 1.05; 95% CI, 0.90-1.23; P = 0.51). Among male recipients of female donor transplants, the incidence of extensive chronic GVHD three years after transplantation were 13% (95% CI, 10%-17%), 27% (95% CI, 25%-29%), and 20% (95% CI, 18%-21%) for FCN, GCV, and no anti-CMV recipients, respectively (P < 0.001; Figure B). FCN and no anti-CMV recipients showed similar risk of extensive chronic GVHD (HR, 1.22; 95% CI, 0.89-1.66; P = 0.21). The incidence of extensive chronic GVHD was significantly reduced among FCN recipients who received HSCT from female donors, regardless of stem cell source, GVHD prophylaxis, or previous acute GVHD incidence, in male recipients. Conclusions: In this study, patients requiring early anti-CMV therapy were at a high risk of chronic GVHD, primary due to their increased incidence of acute GVHD. Remarkably, FCN could potentially mitigate the incidence of chronic GVHD for them. Especially, FCN would be beneficial for male recipients of female donor transplants who are typically at high risk for chronic GVHD. These findings pave the way towards a deeper understanding of the mechanism underlying chronic GVHD and overcome the unmet needs of allogeneic HSCT recipients.

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of <0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

A Real-World Efficacy of Letermovir Primary Prophylaxis for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single-Center Retrospective Analysis

Introduction: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. Methods: We retrospectively analyzed 167 consecutive patients who underwent allo-HSCT between August 2022 and May 2023, who received LET 240 mg/day, to evaluate the efficacy and safety of LET in primary prophylaxis for clinically significant CMV infection (csCMVi), defined as CMV disease or CMV viremia reactivation, in real-world situations in China. Results: Among the enrolled 167 patients, 95.21% (159/167) of patients underwent a haploidentical donor (HID) transplant and 4.79% (8/167) a matched unrelated donor (MUD) transplant. 96.41% of the recipients were CMV seropositive, and only 6 recipients were CMV seronegative but donor seropositive. The median interval from allo-HSCT to the administration of LET was 7 (2-55) days. A total of 121 patients received LET within 14 days after HSCT. With the median follow-up 162(74-397) days post-HSCT, the incidence of CMV viremia was 11.98% (20/167). 3 patients developed CMV viremia after discontinuation of LET medication. Among the 20 patients with CMV viremia, the median duration of preemptive therapy was 9 (3-28) days, and the peak level of CMV-DNA was 1867 (1228-22383) copies/ml. Only 1 patient developed refractory CMV viremia with prolonged preemptive anti-CMV treatment. No patients were diagnosed with clinically significant CMV disease. Patients who developed CMV viremia or not were similar with respect to the CMV IgG status of the recipient at HSCT, donor CMV IgG, and GVHD incidence. Notably, the CMV viremia incidences of patients who received LET within 14 days and after 14 days post-HSCT were 7.44% and 23.91%, respectively (p=0.005). The incidence of EBV viremia was 17.16% (29/169), and 9 developed PTLD. The six-month overall survival was 93.4±2.1% in all patients who received LET prophylaxis. Meanwhile, LET prophylaxis was well tolerated. No drug-related death or permanent discontinuation was reported due to toxicity. Conclusion: Letermovir was effective and safty as primary prophylaxis of csCMVi, particularly initiating early post-HSCT.

Real-World Experience with Selinexor -Containing Regimens in Post-Transplant AML/MDS Patients Who MRD Still Positive after First-Line Preemptive Treatment

Background: Hematopoietic stem cell transplantation (HSCT) is the only cure for acute myeloid leukemia (AML), but relapse is the most important cause of transplant failure. Patients with remission but measurable residual disease (MRD) positive have a higher probability of hematologic relapse. The MRD-directed preemptive treatments can spare some patients in remission from further therapy. The conventional first-line preemptive treatment has been ineffective in some patients, so it's necessary to find a new preemptive treatment to prevent relapse and improve the prognosis. Our study aimed to evaluate the efficacy and safety of selinexor-containing regimens in the preemptive treatment of MRD positive in post-transplant patients with AML or myelodysplastic syndrome (MDS). Methods: The study was conducted in Tongji Hospital from March 2022 to May 2023. The inclusion criteria of post-transplant AML/MDS patients included the followings: (a) Persistent MRD positive. (b) MRD turned negative after first-line preemptive treatment but was positive again. (c) Patients at high risk for hematologic relapse after transplantation; (d) AML-M4/5. The end of the follow-up was in June 2023. Bone marrow aspiration was assessed for MRD using multiparameter flow cytometry (MFC) combined with real-time quantitative polymerase chain reaction (RT-qPCR) as follows: 1) MRD assessed by MFC: MRD negativity was defined as <0.1%. 2) MRD assessed by RT-qPCR: Abnormal genes associated with prognosis were used for molecular MRD detection. 3) WT1 was used for molecular MRD assessment if no molecular marker was available at diagnosis. MRD negativity was defined as <0.6%. Results: A total of 11 patients were included in the study. There were 10 patients with AML and one patient with MDS, with a median age of 43 years old. Two patients had received autologous HSCT, nine patients had received allogeneic HSCT, of which two matched sibling donor, one matched unrelated donor, and six were haploidentical donor. All patients were WT1 positive and two of the cases were both WT1 and MFC positive. Seven patients with post-transplant MRD positive were treated with selinexor-containing regimens after first-line preemptive therapy (azacytidine, azacytidine combined with venetoclax, decitabine combined with venetoclax, etc.) failed or MRD positive again. The remaining four patients were treated directly with selinexor-containing regimens for personal reasons or with a diagnosis of AML-M4/5 may be resistant to venetoclax. The selinexor-containing regimens used in this study were either selinexor (35mg/m 2 biw) alone or in combination with other drugs (decitabine, azacytidine, venetoclax, low-dose cytarabine, and CAG (cytarabine, aclarubicin, G-CSF) regimen). MRD was evaluated after two weeks of the selinexor-containing regimens. And selinexor 20 to 40 mg per week was used as maintenance therapy after MRD converted to negative. Eight patients (72.7%) successfully cleared the MRD. Of the three patients who didn't clear the MRD, two patients successfully converted to negative after continuing the selinexor-containing regimens. It is worth mentioning that 7 of the 11 patients were treated with the selinexor-containing regimens after first-linepreemptive treatment failure, and six of them had successfully cleared the MRD (71.4%). At the end of follow-up, 10 (90.9%) patients survived and one (9.1%) died due to disease progression. In terms of hematological adverse events (AEs), grade 3-4 neutropenia occurred in nine (81.8%) patients, the median duration was 2 days (IQR 1,4). Grade 3-4 thrombocytopenia occurred in three (27.3%) patients, and the median duration was 5 days (range 4-7). Although the number of people with grade 3-4 neutropenia was large, the duration was short after using granulocyte colony-stimulating factor, and no patient developed a severe infection. Most of the non-hematological AEs were mild, including nausea (100.0%), fatigue (63.6%), hyponatremia (58.3%), and vomiting (45.5%). The AEs can be alleviated after symptomatic treatment and no patient discontinued treatment. Conclusion: Selinexor-containing regimens have been shown to be effective and well tolerated in post-transplant AML/MDS patients with MRD-positive, including those who have failed first-line preemptive treatment.

Treatment of Molecular Relapses in Pediatric AML Saves Toxicities Prior to Hematopoietic Stem Cell Transplantation (HSCT) - Results of AMoRe2017 Trial

Introduction The long-term survival for children with AML has increased to 70 % - but relapsed AML patients still have a poor prognosis (about 30 %). Recent data suggest that in AML residual leukemic cells below the 5 % limit required for a morphologic CR can adversely affect outcome and that increasing levels of Minimal Residual Disease (MRD) are almost always followed by clinical relapse. Early MRD detection provides an opportunity to implement pre-emptive therapies as a bridge-to-transplant approach, to potentially prevent hematological relapse and increase the probability of successful HSCT. A promising approach is the use of Azacitidine (Aza) for treatment of molecular relapse which we evaluated within the clinical trial “AMoRe2017”. Aza has been shown to reverse epigenetic changes in malignant cells, restoring the normal function of genes critical for differentiation and cell cycle control. The trials' primary objective was the evaluation of the effect of Aza treatment in AML subjects at molecular relapse after CR1 regarding molecular response prior to further treatment (reinduction/HSCT). Patients and Methods AMoRe2017 enrolled children with AML (N=20), >3 months < 21 yrs., of which n=1 dropped out due to laboratory measurement error. The median age was 10.9 yrs. (range 1.7-18.9 yrs.). N=10 (53 %) had a CBFB-AML, n=5 (27 %) KMT2A-rearrangement, n=1 (5 %) NUP98::NSD1, n=1 (5 %) FLT3-ITD, n=1(5 %) PICALM::MLLT10 and n=1 (5 %) NPM1. N=8 (42 %) were classified to subgroup M2, n=4 (21 %) to M5, n=3 (16 %) into M1 and n=4 (21 %) to M4/M4 Eo. At baseline, the white blood cell count averaged 3.8x10 9/l (range 0.1-6.6x10 9/l), without leukemic blasts in PB or BM. Each patient had at least one quantifiable genetic marker (rt-PCR), achieved CR with molecular remission, following initial therapy, and subsequently had a molecular relapse (defined as an increase of the MRD level by at least 1 log, less than 5 % BM myeloblasts and absence of proven extramedullary disease). Patients were treated for up to 6 cycles with 75 mg/m 2 i.v. Aza on days 1 to 7 in a 28-day cycle. Molecular response was categorized as molecular stabilization (< 1 log decrease or increase from baseline), molecular progression (≥ 1 log increase from baseline without hematological relapse), molecular improvement (≥ 1 log decrease from baseline), and hematological relapse (at least 5 % blasts in PB and/or BM and/or proven histological extramedullary relapse). Results During Aza treatment, 10 patients (53 %) had an open relapse, which occurred in n=9 after 1 st or 2 nd cycle. These patients were monitored for KMT2A::SEPTIN6 (n=1), KMT2A::MLLT3 (n=2), PICALM::MLLT10 (n=1), FLT3-ITD (n=1), NUP98::NSD1 (n=1), CBFB::MYH11 (n=1) and RUNX1::RUNX1T1 (n=3). 9 patients (47 %; RUNX1::RUNX1T1 n=5, CBFB::MYH11 n=1, NPM1 n=1, KMT2A::ELL n=2) showed a molecular response to Aza and proceeded to HSCT without receiving intensive re-induction treatment. 16 out of the 19 patients are alive (overall survival 84 %), 2 died from HSCT-associated side effects (VOD, infection), and 1 from disease progression. Considering genetics, 7 out of 11 patients with favorable genetics (core-binding leukemia n=10 or NPM1 n=1) responded to the Aza therapy ( RUNX1::RUNX1T1 n=5, CBFB::MYH11 n=1, NPM1 n=1). By contrast, in cases with KMT2A-rearrangements, NUP98::NSD1 or FLT3-ITD, 2 out of 8 patients showed improvement or stabilization. In total 152 adverse events (AEs) associated to Aza were reported, the majority classified as grade 1 or 2 (n= 114; 75 %). Mainly affected was the hematopoietic system (40 %), the gastrointestinal tract (15 %), kidney and liver (14 %). Cardiotoxicity was not reported. Discussion The use of Aza as pre-emptive “bridge-to-transplant” approach treating the molecular relapse showed efficacy in patients with RUNX1::RUNX1T1, CBFB::MYH11, NPM1, and KMT2A::ELL, who could be transplanted directly. This pilot provided proof of principle that molecular relapses could be treated, and MRD levels be reversed, at least in subgroups. In addition, avoiding intensive re-induction therapy prior to HSCT is feasible. Conversely, the relatively slow-acting mechanism of epigenetic therapy seems to be ineffective in highly proliferative subgroups of AML with KMT2A-rearrangements or FLT3-ITD. Further studies are mandatory to define treatment options for molecular relapses of non-favorable pediatric AML and to confirm potential improvement of outcome post-HSCT.

1506. Prevalence of Histoplasma Antigenuria among an outpatient Advanced HIV cohort in Kampala,Uganda

Abstract Background Histoplasmosis is a major cause of mortality in persons with advanced HIV disease (CD4< 200 cells/mcL) and areas of endemicity are evolving. Presenting symptoms of histoplasmosis may overlap with that of tuberculosis (TB). The true burden of histoplasmosis remains unknown in persons with advanced HIV disease, in part due to poor diagnostic capacity. We sought to evaluate the prevalence of Histoplasma antigenuria among outpatients with advanced HIV disease in Kampala, Uganda. Methods This prospective cohort study of outpatients with advanced HIV in Kampala, Uganda was nested within the ongoing ENCORE trial evaluating preemptive therapy and prophylaxis among outpatients with advanced HIV disease. Urine samples were obtained from participants at the time of enrollment and a Histoplasma galactomannan enzyme immunoassay (EIA) (Immy, Norman OK) was run on urine per manufacturer’s instructions. We obtained baseline characteristics and laboratory values, a statistical comparison by antigen status was not done due to a low number of positives. We calculated the prevalence of histoplasmosis in our cohort using EIA results. We obtained information on symptoms, TB diagnostics, and TB treatment for those with Histoplasma antigenuria. Results We tested 388 urine samples among participants with advanced HIV disease. Four samples were positive for Histoplasma antigen (1%). Baseline characteristics of participants are summarized in Table 1. Histoplasma antigen prevalence among participants with CD4< 100 cells/mcL was 2.5% (4/158). Of those that tested positive for histoplasmosis, the median CD4 count was 39 cells/mcL (interquartile range (IQR): 16–54), and median CRP was elevated at 29 (IQR 14-46). All four participants with Histoplasma antigenuria had a positive TB urine lipoarabinomannan (LAM, AlereLAM, Abbott, Palatine, IL, USA), though only two of four participants reported symptoms of cough, weight loss, and/or physical weakness. Three of four participants with positive Histoplasma antigen were started on anti-TB treatment. Patient symptoms resolved with no intervention. Conclusion Among outpatients with severe advanced HIV disease with CD4< 100 cells/mcL in Kampala, Uganda Histoplasma antigen prevalence was 2.5%. Disclosures All Authors: No reported disclosures

QuantiFERON-CMV as a Predictor of CMV Events During Preemptive Therapy in CMV-seropositive Kidney Transplant Recipients.

Prevention of cytomegalovirus (CMV) infection after kidney transplantation is costly and burdensome. Given its promising utility in risk stratification, we evaluated the use of QuantiFERON-CMV (QFCMV) and additional clinical variables in this prospective cohort study to predict the first clinically significant CMV infection (CS-CMV, ranging from asymptomatic viremia requiring treatment to CMV disease) in the first posttransplant year. A cost-effectiveness analysis for guided prevention was done. One hundred adult kidney transplant recipients, CMV IgG + , were given basiliximab induction and maintained on steroid/mycophenolate/tacrolimus with weekly CMV monitoring. Thirty-nine patients developed CS-CMV infection (viral syndrome, n = 1; end-organ disease, n = 9; and asymptomatic viremia, n = 29). A nonreactive or indeterminate QFCMV result using the standard threshold around day 30 (but not before transplant) was associated with CS-CMV rates of 50% and 75%, respectively. A higher QFCMV threshold for reactivity (>1.0 IU interferon-γ/mL) outperformed the manufacturer's standard (>0.2 IU interferon-γ/mL) in predicting protection but still allowed a 16% incidence of CS-CMV. The combination of recipient age and type of donor, along with posttransplant QFCMV resulted in a prediction model that increased the negative predictive value from 84% (QFCMV alone) to 93%. QFCMV-guided preemptive therapy was of lower cost than preemptive therapy alone ( P < 0.001, probabilistic sensitivity analysis) and was cost-effective (incremental net monetary benefit of 210 USD) assuming willingness-to-pay of 2000 USD to avoid 1 CMV disease. Guided CMV prevention by the prediction model with QFCMV is cost-effective and would spare from CMV surveillance in 42% of patients with low risk for CS-CMV.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

Preemptive versus prophylactic therapy using valganciclovir or ganciclovir in renal transplant recipients for the prevention of cytomegalovirus infection: a systematic review and meta-analysis

Preemptive versus prophylactic therapy using valganciclovir or ganciclovir in renal transplant recipients for the prevention of cytomegalovirus infection: a systematic review and meta-analysis

Slaying the "Troll of Transplantation"-new frontiers in cytomegalovirus management: A report from the CMV International Symposium 2023.

The 2023 International CMV Symposium took place in Barcelona in May 2023. During the 2-day meeting, delegates and faculty discussed the ongoing challenge of managing the risk of cytomegalovirus infection (the Troll of Transplantation) after solid organ or hematopoietic cell transplantation. Opportunities to improve outcomes of transplant recipients by applying advances in antiviral prophylaxis or pre-emptive therapy, immunotherapy, and monitoring of cell-mediated immunity to routine clinical practice were debated and relevant educational clinical cases presented. This review summarizes the presentations, cases, and discussions from the meeting and describes how further advances are needed before the Troll of Transplantation is slain.

Pre-Emptive Use of Rituximab in Epstein-Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes.

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein-Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality.

Cytomegalovirus-Specific T Cells in Pediatric Liver Transplant Recipients.

Cytomegalovirus (CMV) infection is a major opportunistic infection after liver transplantation (LT) that necessitates monitoring. Because of the lack of studies in children, we aimed to investigate CMV-specific T cell immune reconstitution among pediatric LT recipients. The recipients were monitored for CMV infection and CMV-specific T cells from the start of immunosuppressive therapy until 48 weeks after LT. Clinically significant CMV viremia (csCMV) requiring preemptive therapy was defined as a CMV load of >2000 IU/mL. Peripheral blood CMV-specific T cells were analyzed by flow cytometry based on IFNγ secretion upon stimulation with CMV antigens including immediate early protein 1 (IE1) Ag, phosphoprotein 65 (pp65) Ag, and whole CMV lysate (wCMV). Of the 41 patients who underwent LT, 20 (48.8%) had csCMV. Most (17/20 patients) were asymptomatic and characterized as experiencing CMV reactivation. The onset of csCMV occurred approximately 7 weeks after LT (interquartile range: 4-12.9); csCMV rarely recurred after preemptive therapy. Lower pp65-specific CD8+ T cell response was associated with the occurrence of csCMV (p = 0.01) and correlated with increased viral load at the time of csCMV diagnosis (ρ = -0.553, p = 0.02). Moreover, those with csCMV had lower percentages of IE1-specific CD4+ and wCMV-reactive CD4+ T cells at 12 weeks after LT (p = 0.03 and p = 0.01, respectively). Despite intense immunosuppressive therapy, CMV-specific T cell immune reconstitution occurred in pediatric patients post-LT, which could confer protection against CMV reactivation.

Evaluation of Empirical and Preemptive Therapy Approaches of Invasive Mold Infections in Patients with Hematologic Malignancy

Evaluation of Empirical and Preemptive Therapy Approaches of Invasive Mold Infections in Patients with Hematologic Malignancy

Pre-Emptive Donor Lymphocyte Infusion As Optimal Treatment for Relapsed Acute Myeloid Leukemias and Myelodysplastic Syndromes Following Allogeneic Stem Cell Transplantation: Insights from a French-Italian Study on 134 Patients

Disease relapse after allogeneic stem cell transplantation (allo-SCT) is the main challenge in achieving a cure for acute myeloid leukemias (AMLs) and myelodysplastic syndromes (MDSs). The treatment of disease relapse can be offered in case of full hematological recurrence or in the presence of minimal residual disease (MRD) positivity and/or mixed chimerism. The latter approach is defined as pre-emptive therapy. Overall, treatment strategies may include chemotherapy, molecular-target drugs, hypomethylating agents (HMAs), donor lymphocyte infusions (DLIs) or even a second allo-SCT. We retrospectively analyzed a cohort of 553 AML and MDS adult patients consecutively allotransplanted between January 1, 2015, and December 31, 2021, at Saint-Antoine University Hospital, Paris (France) (n=420) and Spedali Civili di Brescia, Brescia (Italy) (n=133). 134/553 (24%) patients relapsed and were included in this study. 103/134 (77%) were subsequently treated. Among patients who received treatment, 40/103 (39%) were treated with a DLI-based regimen. In this group, 9 received DLIs alone, while the others also received HMAs (4 cases), HMAs+ venetoclax (12 cases), FLT3-inhibitors (3 cases), intensive chemotherapy (5 cases), a second allo-SCT (5 cases), or other therapies (2 cases). The remaining 63/103 (61%) patients were treated with regimens that did not include DLIs. Of these, 10 received HMAs, 27 HMAs+ venetoclax, 4 FLT3-inhibitors, 6 intensive chemotherapy, 9 a second allo-SCT, and 7 other therapies. With a median follow up of 1.6 years, the estimated 1-, 2- and 5-year OS rate of the 134 patients who relapsed after allo-SCT was 32%, 18 %, and 11 %, respectively. The OS of patients treated after allo-SCT relapse was 40 %, 20%, and 15% at 1, 2 and 5 years compared with 6 %, 3%, and 0 % for patients who did not receive therapy, respectively ( p&amp;lt;0.01).Moreover, the OS was significantly better in patients treated in a pre-emptive setting than in those treated for a morphological relapse (OS at 1, 2 and 5 years was 60%, 36% and 30%, respectively, for patients treated in a pre-emptive setting versus 26%, 12%, and 6%, respectively, for patients treated in hematological relapse ( p&amp;lt;0.01) (Figure 1A). Focusing on post-relapse treatment, patients who received DLI-based regimens had a 1-, 2- and 5-year OS of 55%, 32% and 32%, respectively, compared to 27%, 16% and 7% for patients treated with other therapies ( p&amp;lt;0.01). Among patients who received DLIs, 50% of patients were treated in the pre-emptive setting. Conversely, in the group of patients treated without DLI, only 22% were treated in the pre-emptive setting, reflecting the more advanced phase of relapse in this group. Finally, when patients were analyzed by the treatment strategy (pre-emptive therapy vs therapy in hematological relapse) and DLI administration (yes vs no), the best outcome was achieved when the relapse was promptly detected and pre-emptive therapy was started, particularly if a DLI was administered. Indeed, the 1-year OS of patients treated in the pre-emptive setting was 67% for those receiving a DLI and 54% for those treated without DLI, while for patients with hematologic relapse, the 1-year OS was 43% for those treated with the DLI-based regimen and 17% for those treated without DLI ( p&amp;lt;0.01) (Figure 1B). On multivariate analysis, treatment with DLI after relapse, and pre-emptive setting were independent factors associated with better OS ( p=0.03 and p&amp;lt;0.01), respectively. Our data showed that relapse treatment with pre-emptive therapies is associated with improved outcomes and this effect is more evident when combined with a DLI . These results confirm the primary role of the graft- versus leukemia effect in the treatment of relapse and underscore the importance of its early identification through MRD monitoring.

Molecular Relapse after First-Line Intensive Therapy in Patients with Core-Binding Factor and NPM1-Mutated Acute Myeloid Leukemia - a Filo Study

Background: Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) are considered as favorable or intermediate-risk according to the European LeukemiaNet (ELN) 2022 classification and allogeneic hematopoietic cell transplantation (HCT) is usually not considered in those achieving first complete remission (CR) with good molecular response. Close molecular monitoring by quantitative PCR has been widely implemented over time and approximately 30% of patients will experience molecular relapse. However, there is no recommendation on how to manage these patients due to the lack of data from large patient series or clinical trials. In this study, we retrospectively analyzed the outcome of CBF or NPM1-mutated AML patients who had MRD monitoring after having achieved first CR. Methods: All CBF and NPM1-mutated AML patients, aged 18-60 years, who had MRD molecular monitoring (RT-qPCR of RUNX1-RUNXT1 or CBFB-MYH1 transcripts or classical NPM1 mutations) after first-line therapy including induction therapy with daunorubicin/idarubicin and cytarabine followed by intermediate or high-dose cytarabine consolidation, without allogeneic HCT in first CR, were included. MRD measurements were generally performed every three months during follow-up for 24 months in either bone marrow (BM) or peripheral blood (PB). Molecular relapse was defined according to ELN recommendations (Heuser M, Blood 2021) as a conversion from MRD negativity to positivity or an increase in MRD copy numbers &amp;gt;1 log between two positive samples. Results: Between 2010 and 2019, 303 patients from 9 centers with newly diagnosed CBF or NPM1-mutated AML ( RUNX1-RUNX1T1, 19%; CBFB-MYH11, 27%; NPM1, 53%) and available MRD monitoring after first-line therapy were included. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse, with a median of 326 days (interquartile range [IQR]: 276-438) from initial diagnosis, and 55 (18%) had upfront morphologic relapse (i.e., without prior molecular relapse detected), with a median of 388 days (IQR: 280-559). Patients with molecular and upfront morphologic relapse had higher white blood cell (WBC) count at diagnosis (12 vs. 22 vs. 30 G/l in those without relapse, molecular relapse, and morphological relapse, respectively, P=0.003) and were more likely to have a FLT3-ITD mutation (7% vs. 25% vs. 19%, respectively, P=0.001). In addition, patients with upfront morphologic relapse had a lower log-reduction of MRD during first-line treatment (4.90 vs. 4.93 vs. 3.77, respectively, P=0.009) and were more likely to have CR with positive MRD at the end of treatment in peripheral blood (2% vs. 16% vs. 32%, respectively, P&amp;lt;0.001). Overall survival (OS) was significantly different according to whether patients never relapsed, had molecular relapse, or had upfront morphological relapse (three-year OS of 100% vs. 75% vs. 60%, P&amp;lt;0.001; Figure A). Among the 95 patients with molecular relapse, 53 (56%) received preemptive therapy (median of 48 days [IQR:24-68] from molecular relapse to treatment initiation) and 42 (44%) progressed to morphologic relapse before treatment was initiated (median of 58 days [IQR:36-134] from molecular to morphologic relapse). Patients who received preemptive therapy had a better OS than those who received salvage therapy after having progressed from molecular to morphologic relapse, and those who had upfront morphologic relapse (78% vs. 51% vs. 51% at three years, respectively, P=0.01; Figure B). Preemptive therapy included upfront allogeneic HCT (n=19), intensive chemotherapy (n=21), and non-intensive therapy (n=13) with different OS rates that did not reach statistical significance (92% vs. 79% vs. 58% at three years for upfront allogeneic HCT, intensive chemotherapy, and less intensive therapy, respectively, P=0.09). Conclusion: Up to 30% of patients with CBF or NPM1-mutated AML experienced molecular relapse in our cohort and more than 50% of them received preemptive therapy. Patients treated preemptively at molecular relapse had a better OS than those treated with active disease. Although these results need to be confirmed in larger studies, it supports molecular monitoring during follow-up to start preemptive therapy before overt morphologic relapse. Other techniques for MRD monitoring are urgently needed for AML patients who cannot be monitored by qPCR.

Improved Prevention and Treatment Strategy of Differentiation Syndrome Contribute to Reduce Early Death of Patients with Acute Promyelocytic Leukemia

Purpose: All-trans retinoic acid (ATRA) with arsenic trioxide (ATO) has been the standard of care for acute promyelocytic leukemia (APL) with high efficacy in china.However,early death (ED) still remains the major reason for treatment failure.Severe differentiation syndrome (DS) with no response to full dose dexamethasone is one of direct or indirect important causes of ED.Therefore,to further optimize prevention and treatment strategy of DS is critical for APL therapy success. Patients and Methods： The APL-01 study was a prospective and single-arm clinical trial in patients with newly diagnosed APL from June 2019 to December 2021.111 eligible patients aged between 18 and 70 years classified as Low-risk APL (WBC count at diagnosis＜10*10 9/L n=78) or High-risk APL (WBC count at diagnosis≥10*10 9/L n=33) received induction therapy consisted of ATRA and intravenous arsenic trioxide or oral tetra-sulfide arsenic formulation (Realgar-Indigo naturalis formula,RIF) with chemotherapy-free or chemotherapy-substantially reduced protocol in China. During the course of induction therapy,we used different intravenous doses of dexamethasone to prevent DS according to the WBC count at presentation or after the initiation of ATRA.For example,if WBC counts≥ 5*10 9/l and &amp;lt;10*10 9/l,5mg per day;if ≥10 *10 9/l,10mg per day.And we gave patients dexamethasone 10mg per 12h as preemptive therapy once DS was suspected.Ruxolitinib was administered when steroids therapy were considerd insensitive. We evaluated the effect of selective steroids prophylaxis and preemptive therapy on the incidence and severity of DS,which contributed to increased early mortality rate. The safety and feasibility of Ruxolitinib as second-line therapy for DS was also explored. Results： In this study,41 of 111 patients (36.9%) experienced DS,16 (14.4%) were severe cases and 25 (22.5%) were moderate cases. Univariate analysis identified the following prognostic factors as regards developing DS（P-value&amp;lt;0.1）:age,sex and WBC count were included for exploring the difference between DS and Non-DS patients Increased WBC count (&amp;gt;4*10*109/l )(OR (95% CI)=1.241 (1.131-1.361)) were potential risk factors for patients with DS.We further investigated the difference between severe DS and moderate DS using age,sex,ECOG,WBC and PLT count.We found that only advanced age (over 40 years old)(OR (95% CI)=12.200 (1.640-90.772)) was associated with developing severe DS. Dyspnea (71%),weight gain (85%) and pulmonary infiltrates(78%) were the most common symptoms of patients with DS.Compared with moderate DS,severe DS patients had more frequency of dyspnea (Fishers exact P=0.013),pleuropericardial effusion (χ2=5.577, P=0.018)and acute renal dysfunction (Fishers exact P=0.018). Among the 41 patients with DS,23 patients were treated effectively with dexamethasone 10mg per 12h.18 patients with steroid resistance received Ruxolitinib to control the cytokine release storm（CRS）,12 of which showed immediate remission, however,the situations of the remaining 6 patients did not alleviate until ATRA was suspended temporarily.All of them（6/41）recovered with the help of noninvasive mechanical ventilation. The total 30-day mortality rate was 1.8% (2/111).During induction treatment,no death owing to DS or infection occurred.Two patients with high-risk APL died due to intracranial hemorrhage,one occurred on day 8 and the other on day 9 after ATRA were initiated. Of all the 109 patients evaluable,78 (100%)Low-risk patients and 31 (100%) high-risk patients achieved complete remission (CR)at the end of induction therapy,respectively.The median follow-up time was 34 months,estimated 2-year overall survival (OS) was 98.7% in the Low-risk group and was 93.9% in the High risk group. Conclusions: Our study suggests individualized steroids prevention,preemptive treatment and Ruxolitinib as second-line therapy for DS contribute to control DS,which in verse lessen the discontinuation of ATRA, consequently decreasing early death due to DS and hemorrhage in APL patients.(clinicaltrials.gov NCT04446806) Keywords: acute promyelocytic leukemia;early death;prophylaxis strategy;pulmonary hemorrhage;differentiation syndrome;retinoid acid syndrome;Ruxolitinib;steroid-resistance;cytokine release syndrome;

Letermovir Prophylaxis Reduced Cytomegalovirus Reactivation and Resistance Post Umbilical Cord Blood Transplantation

Objective: Umbilical cord blood transplantation (UCBT) has proved to be an effective treatment with its own unique advantages nowadays, while long-lasting immunosuppression and delayed immune recovery make the UCBT recipients susceptible to a range of infections. Human cytomegalovirus (HCMV) is the main cause of viral complications post transplantation, which is associated with poor prognosis. Although the implementation of pre-emptive therapy (PET) has significantly reduced the incidence of CMV disease, the long-time antigenemia and the toxicity of antiviral drug remains challenging and risky. Letermovir (LET), a kind of CMV DNA terminase complex inhibitor, is a relatively new antiviral drug for prophylaxis against CMV and has received positive opinion in adult CMV-seropositive recipients of allogeneic haematopoietic stem cell transplant (allo-HSCT). Nevertheless, the clinical efficacy of LET prophylaxis on CMV reactivation and resistance post UCBT remained unknown. Methods: We retrospectively analyzed 43 UCBT patients with hematological diseases at the First Affiliated Hospital of University of Science and Technology of China between August 2022 and May 2023, who received LET prophylaxis since the first day post transplantation until 100d or CMV reactivation occurred, whichever came first. A historical cohort of 208 UCBT patients also from our transplant center between 2021 and 2022 without LET prophylaxis was compared as control group. The CMV DNA testing was performed using the quantitative real-time PCR (RT-PCR) method and CMV monitoring was examined twice per week for at least 100 days and once a week for at least half a year after UCBT. The 180-day cumulative incidences of CMV reactivation (defined as DNA achieved 500 copies/ml or 1000 copies/ml) and refractory CMV infection (defined as CMV viral load remains the same level or increases after at least 2 weeks of appropriately dosed antiviral therapy) were compared between the two groups. To explore independent predictors of the development of CMV reactivation and resistance, univariate and multivariate analyses were performed by using Fine-Gray proportional hazard regression. Results: The two groups were similar in demographic and transplant characteristics, and in the LET group, patients received LET for a median of 100 days (range, 16-100). The 180-day cumulative incidence of CMV DNA achieved 500 copies/ml and 1000 copies/ml and refractory CMV infection in the LET group were significantly lower than that in the control group [500 copies/ml: 33.8% vs. 78.4%, P &amp;lt; 0.001; 1000 copies/ml: 30.2% vs. 74.0%, P &amp;lt; 0.001; refractory CMV: 4.7% vs. 31.7%, P &amp;lt; 0.001]. Furthermore, multivariate competing risk analysis identified LET prophylaxis as an independent protective factor for CMV reactivation (adjusted hazard ratio [HR] 0.27, 95% CI 0.15 to 0.48, P &amp;lt; 0.001) and refractory CMV infection ([HR] 0.16, 95% CI 0.04 to 0.62, P = 0.004). However no significantly lower incidences of CMV disease (4.7% vs. 8.8%, P = 0.542) and recurrent CMV infection (3.7% vs. 9.6%, P = 0.386) were found in LET group. Among the patients who developed CMV reactivation, there was no significant difference in the time from UCBT to CMV reactivation between two groups (39 days vs. 41 days, P = 0.367). LET prophylaxis was associated with a shorter duration of CMV DNAemia (median 27 days vs. 42 days, P = 0.014), and there was a trend towards lower peak CMV viral load in the LET group (median 2620 copies/ml vs. 5380 copies/ml, P = 0.165). Conclusion: We demonstrated that LET is highly effective at preventing CMV reactivation and resistance after UCBT, and its benefit for UCBT patients perhaps will be observed in a longer-time following time.

Incidence of Invasive Fungal Infections in CAR T-Cell Therapy Recipients: A Single-Center Retrospective Analysis

Background: CAR T-cell therapy has transformed the treatment of hematologic malignancies, but challenges persist due to toxicities like cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Rates of invasive fungal infections (IFI) post CAR T-cell therapy are estimated to range from 1% to 7% (Haidar et al. Clin Infect Dis, 2020). Some centers use positive fungal biomarkers, such as serum (1à3)-β-D-glucan (B-DG) and galactomannan (GM), alongside surveillance radiographic imaging to guide preemptive fungal therapy in this population. The objective of the study was to assess the diagnostic performance of surveillance B-DG and GM for the diagnosis of IFI in recipients of BCMA and CD19-directed CAR T for multiple myeloma (MM) and non-Hodgkin lymphoma (NHL), respectively. Methods: We conducted a retrospective analysis on adult patients who received BCMA-directed CAR T therapy for MM or CD19-directed CAR T for NHL at our institution between 2018-2023. IFI was defined using the Revised European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria (Donnelly et al. Clin Infect Dis, 2020). Only patients with proven or probable infection were included in the analysis. The choice of antifungal prophylaxis was determined based on the treating physician's discretion. In the most cases, B-DG and GM monitoring was done prior to apheresis, before CAR T infusion, and subsequently every 14 days for a duration of 6 months. All patients were followed until 7/12/2023, or until their data were censored at the last follow-up. The cumulative incidence was calculated using Kaplan-Meier method, considering the time to IFI, with IFI-free death and disease relapse as competing risks. Statistical analysis was performed using IBM SPSS (version 29.0). Result: Among the 148 subjects in this study, 51 patients (34.5%) received BCMA CAR T, and 97 (65.5%) received CD19 CAR T therapy. The median age at CAR T infusion was 66 years (range 36-78) in the BCMA cohort and 65 years (range 27-83) in the CD19 cohort (p=0.64). The BCMA cohort had a higher number of prior therapies, with a median of 6 (range 2-15) compared to the CD19 cohort, which had a median of 4 (range 2-12) (p&amp;lt;0.001). The median follow-up from CAR T infusion was 9.5 months (range 0-63) in both cohorts, with 12 months (range 0-63) in the BCMA cohort and 8 months (range 0-49) in the CD19 cohort. All patients received prophylactic antifungal agents, including anti-yeast (fluconazole, n=95), and anti-mold (micafungin n=5, isavuconazole n=1, or Posaconazole n=52). Among the BCMA cohort, 92% of the patients received anti-yeast prophylaxis, while 8% were given anti-mold prophylaxis. In the CD19 cohort, 49.5% received anti-yeast prophylaxis, while 50.5% received anti-mold prophylaxis. Out of the 148 patients, 21 individuals (14%) exhibited elevated B-DG levels, while only 2 patients (1%) showed elevated GM levels. However, 20 out of 21 (95%) cases with positive B-DG, and all cases with positive GM were deemed to be false positives. Among these false positives, 60% were attributed to IVIG administration, while the cause for the remaining cases remained unknown (Table 1). Only one patient in this study developed IFI. The patient received anti-yeast prophylaxis (Fluconazole) at CAR-T and had a disseminated Rhizopus infection on day 13 post CD19 CAR T, which ultimately resulted in the patient's death. The 1-year cumulative incidence of IFI, considering competing risks, was 0.7% (95% confidence interval [CI], 0- 2.1). The median progression-free survival (PFS) in the overall cohort was 11.7 months (95% CI, 6.9-16.6), with 8.6 months (95% CI, 3.2-13.97) in the BCMA cohort and 14.6 months (95% CI, NR-NR) in the CD19 cohort (p=0.324). The median overall survival (OS) of the study cohort was 32.4 months (95% CI, 16.3-48.4), with 41.4 months (95% CI, 16.74-66.08) in the BCMA cohort and 23.98 months (95% CI, NR-NR) in the CD19 cohort (p=0.260). Conclusion: The rate of IFI in our cohort was low (0.7%) post-CAR T therapy. The diagnostic performance of serial monitoring of B-DG and GM for the diagnosis of IFI is poor in recipients of BCMA-directed CAR T therapy for MM or CD19-directed CAR T for NHL.

Low-Dose ATG Has the Same Risk of CMV Reactivation after Allogeneic PBSCT As Ptcy, but Letemovir Is Effective in Preventing CMV Reactivation

[Introduction] Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a curative treatment for hematological malignancies but has a risk of a chronic graft-versus-host disease (GVHD) compared to other donor sources. Post-transplant cyclophosphamide (PTCY) has been spread rapidly worldwide from HLA haploidentical-SCT (Haplo-SCT) to HLA matched-SCT. Although PTCY was theoretically thought to preserve non-alloreactive T cells which can contribute to fight infection, recent studies showed that PTCY was associated with the increased incidence of cytomegalovirus (CMV) infection. Letermovir (LTV), a novel anti-CMV agent, was useful for the prevention of CMV reactivation after SCT including Haplo-SCT using PTCY. On the other hand, low-dose antithymocyte globulin (ATG) is an alternative and useful option for GVHD prophylaxis in allo-PBSCT and often used in Japan. However, the risk of post-transplant CMV reactivation and the protective effect of LTV when using low-dose ATG remain to be elucidated. [Methods] We retrospectively analyzed 222 recipients who received allo-PBSCT using PTCY or low-dose ATG at Hokkaido University Hospital from January 2013 to July 2021. Of the 121 patients who underwent PBSCT with PTCY, 69 (all patients underwent Haplo-PBSCT) were without LTV prophylaxis and 52 (34 patients, Haplo-PBSCT) were with LTV. On the other hand, of the 101 patients who underwent PBSCT with low-dose ATG, 66 (12 patients, Haplo-PBSCT) were without LTV and 35 (2 patients, Haplo-PBSCT) were with LTV. LTV was administered on the day 0 at a dosage of 480 mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least weekly from neutrophil engraftment to discharge and after discharge monthly until day 180 after SCT. CMV reactivation was defined as the start of CMV preemptive therapy, generally initiated when there are 2 or more CMV antigen positive cells per 50000 white blood cells. Moreover, CMV disease was defined by organ dysfunction attributable to CMV. [Results] Baseline characteristics of the patients are summarized in Table 1. Although more patients in ATG group compared to PTCY group received myeloablative conditioning regimen significantly, there was no significant difference between the groups in terms of sex, age, underlying disease, disease risk at SCT, and CMV serostatus. GVHD prophylaxis in PTCY consisted of CY (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5), whereas that in ATG consisted of ATG at a total dose of 2-3 mg/kg around day -2, tacrolimus (from day -1) and short-term methotrexate. LTV prophylaxis significantly reduced the cumulative incidence of CMV reactivation at 180 days after SCT in PTCY group (69.6% without LTV vs. 22.4% with LTV, p&amp;lt;0.001) and ATG group (62.6% without LTV vs. 18.9% with LTV, p&amp;lt;0.001; Figure 1.). Importantly, although CMV disease were occurred in 2 patients in PTCY (1 gastritis and 1 retinitis) and 8 focuses in 7 patients (3 pneumoniae, 3 enteritis, 1 retinitis, and 1 glossitis) in ATG without LTV prophylaxis, none of the patients receiving LTV developed CMV disease in both group. Moreover, LTV did not affect overall survival, the cumulative incidence of non-relapse mortality, relapse, acute GVHD, and engraftment of neutrophil and platelet. Interestingly, the cases of early CMV reactivation within 100 days after SCT under LTV prophylaxis was significantly more frequent in ATG than in PTCY (p=0.0345). [Conclusion] CMV reactivation occurred with similar frequency after allo-PBSCT with low-dose ATG as after that with PTCY. LTV was effective for prevention of CMV reactivation in both GVHD prophylaxis methods. CMV breakthrough reactivation may be likely to occur in PBSCT with low-dose ATG compared to that with PTCY even under LTV prophylaxis, and careful CMV monitoring may be required.

Development of a Stacked Ensemble Model for Risk Stratification of Chronic Gvhd after Allogeneic HSCT: Trump Cohort Study

Background Effective risk stratification is vital for selecting donors and developing treatment strategies for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several pretransplant risk models have been proposed to predict post-transplant patient outcomes from pretransplant risk factors. However, it is still challenging to predict mid-to-long-term prognosis. To establish a novel and user-friendly tool for predicting chronic graft-versus-host disease (cGVHD), non-relapse mortality (NRM) and overall survival (OS), we used a Stacked Ensemble Model (SEM) designed to handle right-censored data and competing risk events (Iwasaki et al., 2021). Methods Using Japanese registry data, the Japanese Transplant Registry Unified Management Program, we analyzed 21,840 patients who underwent their first allo-HSCT between 2010 and 2018 for hematologic malignancies. Of these, 14,430 patients were alive without cGVHD and relapse on day 100 post-transplantation. Primary endpoint was cGVHD and secondary endpoints were NRM and OS. Data were randomly split into the training set (70% of the dataset) and the validation set (30%). We treated patient age and time from diagnosis to transplant as continuous variables and performance status, ABO type matching, sex matching, disease/status groups based on refined Disease Risk Index, Hematopoietic Cell Transplantation-specific Comorbidity Index, usage of total body irradiation, conditioning intensity, T cell depletion in vivo, human leukocyte antigen (HLA) locus matching, the number of HLA mismatching and CMV serostatus as categorical variables. To evaluate predictive accuracy at day 30, 60 and 100 posttransplant, we considered acute graft-versus-host disease (aGVHD) and its treatment, including grade 2 to 4 aGVHD occurrence, grade 3 to 4 aGVHD occurrence, stage of aGVHD before and after treatment, corticosteroid treatment, anti-thymocyte globulin treatment and treatment response of 1 st line therapy for aGVHD. Results The median age of the patients at transplantation was 51 years (inter quartile range (IQR): 39 - 60). The sources of stem cells were HLA-matched related bone marrow (BM) in 967 patients, HLA-matched related peripheral blood (PB) in 1,998 patients, haploidentical BM in 172 patients, haploidentical PB in 778 patients, unrelated BM in 5,539 patients, unrelated PB in 366 patients, and cord blood in 4,237 patients. Myeloablative conditioning was administered in 9,390 patients and reduced-intensity conditioning in 5,040 patients. The most common indication of HSCT was intermediate-risk acute myeloid leukemia (AML) in complete remission (CR, n=3,233) followed by acute lymphoblastic leukemia in first CR (n=2,164) and intermediate-risk AML in non-CR (n=1,618). Median follow-up period of survivors was 2.2 years (IQR: 0.9-4.5). The overall performance of SEM was superior across the endpoints evaluated, cGVHD, NRM and OS, while XGBoost showed a slightly higher C-index for cGVHD, demonstrating its robustness and reliability (Table 1, the C-index for cGVHD/NRM/OS-SEM: 0.567/0.635/0.607, Cox-PH: 0.550/0.624/0.602, Random Survival Forest: 0.555/0.632/0.597, XGBoost: 0.573/0.624/0.604, and Dynamic Deephit: 0.549/0.614/0.589). C-index of SEM for cGVHD, NRM, and OS were gradually improved as time goes by (Table 1, the C-index for cGVHD/NRM/OS: at day 30-0.589/0.643/0.635, at day 60-0.598/0.655/0.640, at day 100-0.598/0.688/0.640). Kaplan-Meier curves 100-day post-transplantation confirmed the accuracy of our predictions, effectively stratifying patients into four risk groups (Figure 1). SHapley Additive Explanations showed contribution of variables for predicting specific outcomes. Grade 3 to 4 aGVHD and stage of aGVHD after treatment influenced non-relapse mortality. Particularly, grade 3 to 4 aGVHD showed significant impact on OS in line with pretransplant risk factors including sex matching, donor source and disease/status groups. Grade 2 to 4 aGVHD and treatment response of 1 st line therapy for aGVHD influenced cGVHD. Conclusion Our study emphasizes the importance of aGVHD events in mid-to-long-term post-transplantation outcomes and presents SEM-based prediction models that account for early-phase post-transplantation events. We are currently developing a user-friendly web application tool for cGVHD, aiming to enhance post-transplant risk stratification and preemptive therapy for cGVHD.