scholarly journals CMV-Seropositive Recipients Are at Higher Risk of CMV Reactivation and NRM after Haploidentical-SCT with PT-Cy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4484-4484
Author(s):  
Jacopo Mariotti ◽  
Stefania Bramanti ◽  
Raynier Devillier ◽  
Barbara Sarina ◽  
Sabine Furst ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Multivariable Analysis ◽  
The Other ◽  
Time Dependent ◽  
Research Support ◽  
Free Survival ◽  
Increased Risk ◽  
Cmv Reactivation

Background: Cytomegalovirus (CMV) reactivation still represents a common complication after allogeneic stem cell transplantation and is associated with increased non-relapse mortality (NRM) and reduced overall survival (OS). Patients receiving T cell-replete haploidentical stem cell transplantation (haplo-SCT) with high dose post-transplant cyclophosphamide (PT-Cy) are considered at higher risk of developing CMV reactivation due to their particular immuno-suppressed status. Letermovir was recently shown to significantly reduce the frequency of CMV reactivation in a phase 3 clinical trial. We decided to perform a retrospective analysis among patients treated with haplo-SCT with PT-Cy in order to identify whether every patients should receive CMV prophylaxis with letermovir or it is possible to identify a particular subgroup that may benefit more of prophylactic treatment. Methods: We retrospectively analyzed 513 consecutive patients receiving Haplo-SCT with PT-Cy at our institutions between April 2009 and December 2018. Median age was 56 years old (range 15-77), main diagnosis was represented by acute myeloid leukemia (31%), Hodgkin lymphoma (22%), non-Hodgkin lymphoma (21%) and myelodisplastic syndrome (12%). Donor/recipient CMV serostatus was as follows: neg/neg (G1) 16%, pos/pos (G2) 50%, pos/neg (G3) 12% and neg/pos (G4) 22%. Conditioning regimen was non-myeloablative/reduced intensity in 90% of the cases, graft source was represented by bone marrow for 25% of the patients. Results: With a median follow-up of 35 months, 3-year OS was 57%, 3-year NRM 24% and 3-year graft-versus-host-disease (GVHD)/relapse free survival (GRFS) 43%. 180-days cumulative incidence of grade 2-4 acute GVHD was 23% and 2-year moderate-severe chronic GVHD was 9%. Median day of CMV reactivation was 41 days (range 10-275), 100-days and 1-year cumulative incidence of CMV reactivation was 43% and 48%, respectively. Cumulative incidence of CMV reactivation was more common among seropositive recipients: G1 1% vs G2 60% vs G3 32% vs G4 67% (Table I, p<0.001). Recipient CMV positive serostatus and increasing patient age (hazard ratio (HR): 1.01, p=0.033) were the only variables associated with increased risk of CMV reactivation. 3-year OS, 3-year progression-free survival (PFS) and 3-year GRFS were worse among seropositive recipients, and consistently 3-year NRM was higher for G2 and G4 (Table I). By a time-dependent analysis we investigated the impact of CMV reactivation on main outcomes. Only 180-day cumulative incidence of grade 2-4 acute GVHD, and none of the other analyzed outcomes, was more frequent after CMV reactivation (HR 2.064, p=0.001). By time-dependent multivariable analysis, positive recipient CMV serostatus, was an independent predictor of increased NRM (G2: HR 2.47 and G4 HR: 2.61, p=0.007) and worse GRFS (G2: HR 1.71, p=0.003 and G4 HR 1.32, p=0.183). Pre-transplant active disease and hematopoietic cell transplant comorbidity index (HCT-CI) ≥3 were the other independent variables affecting OS, NRM, PFS and GRFS by multivariable analysis. Based on landmark analysis at day 100, patients experiencing CMV reactivation had a higher NRM rate compared with those without reactivation (18% vs 10%, p=0.034) and a tendency for lower OS (72% vs 78%, p=0.065) and GRFS (50% vs 55%, p=0.061). Moreover, by multivariable analysis, CMV reactivation and increasing donor age were the main independent predictors of grade 2-4 acute GVHD: HR 2.21, (p=0.01) and 1.01 (p=0.016), respectively. Conclusion: Recipient positive CMV serostatus is associated with increased risk of CMV reactivation, increased rate of NRM and worse GRFS. CMV reactivation is associated with increased risk of developing grade 2-4 acute GVHD and higher NRM. We conclude that also in the platform of haplo-SCT with PT-Cy, letermovir prophylaxis should be given not to all patients, but mainly to CMV seropositive recipients, that probably may benefit the most in terms of CMV reactivation, acute GVHD incidence and NRM. Disclosures Chabannon: Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Genenta Science srl: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Novartis: Consultancy, Research Funding; MSD: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; BMS: Consultancy; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Abb-Vie: Speakers Bureau; Roche: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria.

Early CMV Reactivation Still Remains a Cause of Increased Transplant Related Mortality in the Current Era: A CIBMTR Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 47-47 ◽  
Author(s):  
Muthalagu Ramanathan ◽  
Pierre Teira ◽  
Minoo Battiwalla ◽  
A. John Barrett ◽  
Caroline A Lindemans ◽  
...  
Keyword(s):  
Research Funding ◽  
Negative Impact ◽  
Multivariable Analysis ◽  
Time Dependent ◽  
Positive Serology ◽  
Increased Risk ◽  
The Impact ◽  
Cmv Reactivation ◽  
Risk Of Relapse ◽  
Related Mortality

Abstract Introduction: Since the early days of allogeneic hematopoietic cell transplantation (HCT), positive serology for cytomegalovirus (CMV) in either the recipient or the donor, and CMV reactivation have been associated with poorer outcomes. In the 90’s, development of effective monitoring and potent antiviral drugs minimized and occasionally abrogated this negative impact. Recently, some studies have reported an unexpected association between early CMV reactivation and decreased incidence of relapse in AML. The Center for International Blood and Marrow Research (CIBMTR) sought to conduct a retrospective large scale study to reassess the impact of CMV serology and CMV reactivation in the current era. Methods: The analysis includes comprehensive data of 11,153 patients undergoing first allogeneic HCT between 2003 and 2010 reported to the CIBMTR. Separate analyses were conducted for each of the 6 patient categories: AML transplanted with bone marrow (BM) or peripheral blood stem cell (PBSC) (n=5310), AML transplanted with cord blood (CB) (n= 925), ALL with BM/PBSC (n=1883), ALL with CB (n= 759), CML with BM/PBSC (n=1079) and MDS with BM/PBSC (n=1197). CMV serology from the donor (D) or recipient (R), and reactivation of CMV (as a time-dependent co-variate) within the first year after HCT were analyzed as risk factors for outcomes. The median duration of follow up was 56 months (1 – 127 months). Results: The median time to CMV reactivation was 40 days (1 – 362 days) after HCT and 98% of reactivations occurred before day 100 (D+/R+ 32%, D+/R- 11%, D-/R+ 34%, D-/R- 4%). In multivariable analysis, throughout the 6 groups, a positive serology (D+/R+, D+/R-, D-/R+) vs a negative serology (D-/R-),had no effect on the risk of GVHD (acute or chronic) or the risk of relapse, except for an increased risk of chronic GVHD for BM/PBSC recipients with ALL. CMV positive serology was associated with a higher transplant related mortality (TRM) and a poorer overall survival (OS). For a R+ patient, a D- compared to a D+, had no negative impact except for ALL with BM/PBSC where a D- was associated with a poorer OS. After PBSC/BM transplantation, CMV reactivation was associated with a higher TRM for MDS (RR=1.61, p=0.0002), CML (RR=1.86, p=0.0004), AML (RR=1.68; p<0.0001) and ALL (RR=1.95; p<0.0001), translating into lower OS (range of RR from 1.27 to 1.49; p value from 0.003 to <0.0001). Only among AML patients following CB transplantation, CMV reactivation did not worsen OS. Moreover, CMV reactivation had no effect on the incidence of relapse irrespective of the diagnosis or the source of stem cells. Finally, we conducted a subset analysis focusing on the group of AML, transplanted with PBSC after a myeloablative conditioning regimen and with a GVH prophylaxis relying on Ciclosporine and Methotrexate only. In multivariable analysis, there was no difference in the risk of relapse based on CMV reactivation as a time-dependent co-variate [RR 0.96 (0.65 – 1.4), p=0.8385]. Conclusion: Positive D/R CMV serology still results in increased TRM and decreased OS after HSCT in the current era. Early CMV reactivation did not prevent relapse in patients with AML, MDS, CML or ALL after HCT. Disclosures Boeckh: Chimerix: Consultancy, Research Funding; Viropharma: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

Evaluation of NIH Consensus Criteria for Classification of Late Acute and Chronic Gvhd in Reduce Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1139-1139 ◽  
Author(s):  
Jifang Zhou ◽  
Sylvain Thepot ◽  
Aurrore Perrot ◽  
Marie Robin ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Time Dependent ◽  
Increased Risk ◽  
Nih Consensus Criteria

Abstract Abstract 1139 Poster Board I-161 Background Chronic graft-versus-host disease (GVHD) occurs frequently after allogeneic stem cell transplantation (SCT) and has an impact on morbidity and survival. The National Institutes of Heath (NIH) consensus criteria for the diagnosis of GVHD, emphasized clinical manifestations of GVHD rather than the classical time of onset (day 100). Incidence and impact in term of relapse and no-relapse mortality (NRM) of this new classification is not well known after RIC. Methods We retrospectively reviewed 116 consecutive patients (pts) in Saint Louis' Hospital undergoing an SCT for hematologic malignancy and surviving at least day + 100 after RIC between August 2005 and December 2008. We evaluated non-relapse mortality (NRM) and recurrent malignancy. Cumulative incidence was computed using death as a competing event. Incidence of relapse and NRM was counted from 100 days post-transplant for patients without chronic GVHD or from chronic GVHD onset. Patients with relapse/progression before chronic GVHD onset were considered as not having chronic GVHD in these analyses. The association of occurrence of chronic GVHD with the risk of relapse and non-relapse death was analyzed using time-dependent covariates in cause-specific proportional hazards models. Results Among 116 pts ( M/F: 71/45), with a median age of 53 years old (19-68 years) 28 pts (24%) were transplanted for acute leukemia in, 11 pts (9%) for chronic leukemia, 27 pts (23%) for lymphoma, 30 pts (26%) for MPD/MDS and 20 pts (17%) for plasma cell disorder. Sixty-three pts (54%) received HLA-identical sibling transplantation, 53 pts (46%) received transplantation from unrelated donors. Source of stem cells was mobilized peripheral blood stem cell for 108 pts (93%), bone marrow for 4 pts (3%) and 4 cord blood (3%). After a median follow-up of 18 months (range 5-45 months), a total of 67 pts (58%) developed chronic GVHD according to the Seattle day 100 landmark criteria and when using NIH consensus criteria, 55 pts (47%) developed chronic GVHD, including 43 pts (53%) with classic chronic GVHD and 8 pts (10%) overlap syndrome. Patients reclassified included; 3 pts with late onset acute GvHD, 19 pts had recurrent and 8 had persistent acute GVHD (numbers do not to previous sentence because some of these patients latter developed chronic GvHD). The cumulative incidence of chronic GVHD at 36 months was 64% (95%CI; 53%-73%) when using Seattle criteria compared to 56% (95%CI; 45%-67%) with NIH chronic GVHD criteria. Two-year Cumulative incidences of relapse and NRM using both classifications are summarized in Table. In Cox model with GvHD as a time dependent covariate, the NRM was significantly higher in patients with late onset, persistent and recurrent acute GVHD compared to no GVHD (hazard ratio (HR) 31, 47 and 30; p = 0.005, p <0.0001, p <0.0001, respectively), whereas the NRM was statistically increased in case of chronic GVHD using Seattle day 100 criteria (HR: 2.8; P=0.034). Conclusion The cumulative incidence of chronic GVHD “decrease” about 10% when using NIH consensus criteria compared to Seattle criteria in our cohort of RIC. Most of the NRM occurred beyond 100 days after SCT was due to the increased risk of NRM in patients with late onset, recurrent or persistent acute GVHD. Disclosures No relevant conflicts of interest to declare.

The Bidirectional Relationship Between Cytomegalovirus Replication and Graft-Versus-Host Disease - a Retrospective Single Center Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2236-2236
Author(s):  
Nathan Cantoni ◽  
Hans H Hirsch ◽  
Nina Khanna ◽  
Dominik Heim ◽  
Joerg Halter ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Time Dependent ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Cmv Reactivation ◽  
Multiple Episodes

Abstract Abstract 2236 Poster Board II-213 Cytomegalovirus (CMV) infection and graft-versus host disease (GVHD) are important complications after allogeneic HSCT with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV reactivation. Data on CMV infection as a cause of GVHD, in contrast, are controversial. The association of pre-transplant CMV serology with GVHD development and reduced rates of chronic GVHD after preemptive CMV treatment are indicative of such an association. However, analyses of the direct impact of CMV infection on GVHD are rare; a recent small study found no effect of CMV replication on subsequent development of acute GVHD (Wang et al, BMT 2008). We analyzed in a single centre study the association of CMV reactivation with acute GVHD in 517 patients treated between 1993 and 2008. 59% of patients were male, median age was 42 years (range 16 to 70). Diagnoses were AML (31%), ALL (16%), CML (15%), MDS/MPN (13%), lymphoma (21%), and other (4%). Conditioning regimens were Cy/TBI ±/- etoposide (49%), Cy/Bu (17%), fludarabine and TBI (16%), or others (18%). GVHD prophylaxis consisted of CyA/MTX (78%) or CyA/MMF (21%). Donors were HLA-identical siblings (65%), other family members (4%), or unrelated donors (31%). We made use of a standardized CMV policy over the last decades. CMV reactivation was monitored using real-time polymerase chain reaction or pp65 antigenemia assay weekly in patients without infection, twice weekly in patients with CMV replication. CMV was preemptively treated with gancyclovir or foscarnet. To determine the correlation of CMV infection with acute GVHD, we used a stringent Cox regression model, in which CMV replication was modeled as a time-dependent covariate becoming positive on the day of the first detection of CMV and negative on the first negative assay thereafter. Multiple episodes of CMV replication were considered. Acute GVHD was modeled as a time-dependent covariate in models with CMV infection as endpoint. Hazard ratios (HR) were adjusted for patient age, disease, disease stage, donor type, stem cell source, conditioning regimen and GVHD prophylaxis. The analysis was restricted to the time from transplant to day 100. CMV reactivation was detected at least once in 16% (84/517) of patients at a median of 33 (range 1-95) days after HSCT. Median duration of CMV reactivation was 8.5 days (range 2-62). 19 patients showed multiple episodes of CMV replication. Donor and recipient serostatus significantly influenced the day 100 cumulative incidence of CMV infection: D-/R- (N=173) 6%; D±/R- (N=61) 10%; D±/R± (N=128) 25%; and D-/R± (N=99) 37%, p<0.001. The cumulative incidence for any acute GVHD (grade I-IV) was 67% (95% CI 56-78%) with a median onset time at day 14 (range day 5-94); the cumulative incidence for severe acute GVHD (grade II-IV) was 48% (95% CI 40-56%). When both endpoints (CMV, GVHD) were combined, 150 patients (29%) experienced neither GVHD nor CMV reactivation, 281 (54%) GVHD only, 19 (4%) CMV reactivation only, and 67 (13%) both CMV reactivation and GVHD. Of the 67 patients with both GVHD and CMV, 46 (69%) developed GVHD prior to CMV reactivation, 17 (25%) developed GVHD during CMV reactivation, and 4 (6%) developed GVHD after CMV reactivation. Cox modeling revealed that presence of GVHD grade II-IV increased the risk of CMV infection (HR 1.61, 95% CI 1.03-2.52, p=0.04). Similarly, patients were at increased risk of developing acute GVHD during phases of CMV replication (grades I-IV: HR 2.23, 95% CI 1.39-3.81, p=0.001; grades II-IV: HR 2.00, 95% CI 1.08-3.72, p=0.03). GVHD grade was not influenced by concomitant CMV reactivation (median grade II, in patients with or without CMV reactivation). The overall proportion of GVHD that occurred during phases of CMV replication was small (3% versus 64% occurring in CMV non replicating patients). Even if GVHD occurring after resolution of CMV reactivation was additionally taken into account, the majority of GVHD occurred without preceding CMV infection (63% versus 4%). These data describe the complex relationship between CMV infection and GVHD. We confirm previous studies that GVHD (and GVHD therapy) can induce CMV infection. We describe as well that patients with active CMV replication have a significantly higher risk of developing GVHD compared to patients without CMV replication. However, the proportion of GVHD that could be linked to CMV reactivation was small in this population with a low overall incidence of CMV reactivation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Non-Infectious Pulmonary Toxicity after Allogeneic Hematopoietic Cell Transplantation (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Sagar S. Patel ◽  
Kwang Woo Ahn ◽  
Manoj Khanal ◽  
Caitrin Fretham ◽  
Celalettin Ustun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lower Risk ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Marrow Transplant ◽  
Smoking History ◽  
Platelet Recovery ◽  
Increased Risk

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (&gt;500/mcL x 3 consecutive days), platelet recovery (&gt;20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS &lt;90. Median follow-up was 49 months. Per the HCT-Comorbidity Index (HCT-CI), 15% and 24% of pts had a severe (FEV1 and/or DLCO≤65%, dyspnea at rest, requiring supplemental oxygen) and moderate (FEV1 and/or DLCO 66-80%, dyspnea on slight activity) pulmonary comorbidity, respectively. Pre-transplant, 3% of pts had a history of mechanical ventilation, 5% had a history of pulmonary fungal infection, and 40% reported a smoking history. Most pts had a matched sibling or unrelated donor (68%) and received peripheral blood graft (71%). Myeloablative conditioning was used in 49% pts, and 39% received total body irradiation (TBI). Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p&lt;0.0001). Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

scholarly journals Analysis of Risk Factors Determining Incidence and Outcome of Infections in Children and Adults after Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3364-3364
Author(s):  
Jan Styczynski ◽  
Krzysztof Czyzewski ◽  
Sebastian Giebel ◽  
Jowita Fraczkiewicz ◽  
Malgorzata Salamonowicz ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Leukemia ◽  
Bacterial Infections ◽  
Acute Gvhd ◽  
Viral Infections ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Risk Of Death ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract BACKGROUND: Recent EBMT analysis showed that infections are responsible for 21% of deaths after allo-HCT and 11% after auto-HCT. However, the risk, types and outcome of infections vary between age groups. The aim of the study is the direct comparison of risk factors of incidence and outcome of infections in children and adults. PATIENTS AND METHODS: We analyzed risk factors for the incidence and outcome of bacterial, fungal, and viral infections in 650 children and 3200 adults who received HCT between 2012-2015. The risk factors were determined by multivariable logistic regression analysis. RESULTS: A total number of 395/650 (60.8%) children and 1122/3200 (35.0%) adults were diagnosed for microbiologically confirmed infection, including 345/499 (69.1%) and 679/1070 (63.5%), respectively after allo-HCT, and 50/151 (33.1%) and 443/2130 (20.8%) respectively, after auto-HCT. At 2 years after HCT, the incidences of microbiologically documented bacterial infection were 36.0% and 27.6%, (p<0.001) for children and adults, respectively. Incidences of proven/probable invasive fungal disease (IFD) were 8.4% and 3.7% (p<0.001), respectively; and incidences of viral infection were 38.3%, and 13.5% (p<0.001), respectively. Overall, 31/650 (4.8%) children and 206/3200 adults (6.4%) have died after these infections. The distribution of deaths was different in children (35.5% bacterial, 48.4% fungal, 16.1% viral) and adults (61.7% bacterial, 24.7% fungal, 13.6% viral). BACTERIAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=1.8; p<0.001). In allo-HCT patients, the risk was higher in children (HR=2.1; p<0.001), in patients with acute leukemia (HR=1.6; p<0.001), matched unrelated (MUD) vs matched family-donor (MFD) HCT (HR=1.6; p<0.001), mismatched unrelated (MMUD) vs MFD HCT (HR=2.0; p<0.001), myeloablative vs reduced-intensity conditioning (RIC) (HR=1.3; p<0.001), delayed (>21d) hematological recovery (HR=3.3; p<0.001), acute GVHD before infection (HR=1.7; p<0.001), and chronic GVHD before infection (HR=1.4; p=0.014). In auto-HCT patients, the risk was higher in children (HR=1.7; p<0.001), and in patients with delayed hematological recovery (HR=2.8; p<0.001). In patients with multiple myeloma (MM) the risk was decreased (HR=0.7; p=0.005). FUNGAL INFECTIONS: The risk of proven/probable IFD was higher after allo-HCT (HR=5.4; p<0.001). In allo-HCT patients, the risk was higher in children (HR=3.9; p<0.001), in patients with acute leukemia (HR=3.8; p<0.001), MUD vs MFD HCT (HR=1.5; p=0.013), MMUD vs MFD HCT (HR=2.5; p<0.001), delayed hematological recovery (HR=3.3; p<0.001), acute GVHD before infection (HR=1.5; p=0.021), and chronic GVHD before infection (HR=2.2; p<0.001). In auto-HCT patients, the risk was higher in children (HR=1.8; p=0.025). Patients with MM were at decreased risk of IFD (HR=0.6; p=0.005). VIRAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=6.1; p<0.001). In allo-HCT patients, the risk was higher in children (HR=1.3; p=0.010), in patients with acute leukemia (HR=1.7; p<0.001), MUD vs MFD HCT (HR=2.0; p<0.001), MMUD vs MFD HCT (HR=3.3; p<0.001), myeloablative vs RIC (HR=1.8; p=0.050), acute GVHD before infection (HR=1.5; p<0.001) and chronic GVHD before infection (HR=2.7; p=0.014). Among auto-HCT patients, diagnosis of MM brought decreased risk of viral infections (HR=0.5; p<0.001). DEATH FROM INFECTION: In allo-HCT patients, adults (HR=3.3; p<0.001), recipients of MMUD-HCT (HR=3.8; p<0.001), patients with acute leukemia (HR=1.5; p=0.023), chronic GVHD before infection (HR=3.6; p=0.014), CMV reactivation (HR=1.4; p=0.038) and with duration of infection treatment >21 days (HR=1.4; p=0.038) were associated with increased risk of death from infection. Among patients with bacterial infections, the risk was higher in G- infections (HR=1.6; p=0.031). Among auto-HCT patients, no child died of infection. In adults, the risk of death was higher if duration of treatment of infection was >21 days (HR=1.7; p<0.001). In patients with MM the risk was decreased (HR=0.4; p<0.001). CONCLUSIONS: The profile of infections and related deaths varies between children and adults. MMUD transplants, diagnosis of acute leukemia, chronic GVHD, CMV reactivation and prolonged infection are relative risk factors for death from infection after HCT. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.

scholarly journals Post-Transplant Cyclophosphamide after Matched Sibling, Unrelated and Haploidentical Donor Transplants in Patients with Acute Myeloid Leukemia, a Comparative Study of the ALWP EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3274-3274
Author(s):  
Jaime Sanz ◽  
Jaques-Emmanuel Galimard ◽  
Boris V Afanasyev ◽  
Emanuele Angelucci ◽  
Fabio Ciceri ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Free Survival ◽  
Increased Risk ◽  
Matched Sibling ◽  
Grade Ii

Introduction: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. Although PTCy-Haplo has been compared with different transplant platforms, there is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods:We retrospectively analysed outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n=215), MUD (n=235) and Haplo (n=789) donors registered in the EBMT database between 2010 and 2017. The median follow up period of the entire cohort was 2 years. Results: Median age of patients was 52 years (range, 18-76), 693 (56%) were male and 928 (78%) were CMV seropositive. AML was de novo in 1,046 (84%) patients, while 47 (6%),543 (66%) and 239 (29%) had standard, intermediate and high risk cytogenetics, respectively. Peripheral blood (PB) was used as the stem cell source in 814 (66%) patients. Regarding conditioning, 962 (78%) were chemotherapy based regimens and 500 (41%) patients received reduced intensity conditioning (RIC). Preferred conditioning regimens were thiotepa, busulfan, fludarabine for Haplo (n= 371; 47%) and busulfan, fludarabine for MSD (n= 83; 39%) and MUD (n= 102; 43%). Patients received a variety of PTCy containing immune suppressive regimens, the most frequently used being PTCy, calcineurin inhibitor and mycophenolate mofetil in Haplo (n= 684; 87%) and PTCy and calcineurin inhibitor alone in MSD (n= 52; 24%) and MUD (n= 74; 31%). In-vivo T-cell depletion (TCD) was used in 164 (13%) patients. Compared to MSD and MUD, Haplo patients were older and less frequently received RIC, TCD and PB but the distribution of cytogenetic risk group was similar between the donor types. Cumulative incidence of neutrophil recovery at 60 days was 95% (95% CI 94-96). The cumulative incidence of 100 day acute GVHD grade II-IV and III-IV, and 2-year chronic and chronic extensive GVHD were 25% (95% CI 23-28), 9% (95% CI 7-10), 31% (95% CI 28-34) and 12% (95% CI 10-14), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS) and overall survival (OS) were 25% (95% CI 22-28), 19% (95% CI 17-21), 56% (95% CI 53-59) and 63% (95% CI 60-66), respectively. On multivariable analysis, outcomes were not significantly different for MSD and MUD. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) but the risk was not significant for chronic GVHD (HR 1.2; 95% CI 0.8-1.8). Haplo-SCT carried a higher risk of NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no change in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). The most frequent cause of death was relapse for MSD (n= 36, 53%) and MUD (n= 41, 48%) and infection for Haplo (n = 107, 39%). Interestingly, the use of PB was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). Other variables that had an impact on LFS were: poor risk cytogenetics (HR 1.4; 95% CI 1.1-1.7), use of MAC-Chemo (HR 0.7; 95% CI 0.6-0.9), Karnofski performance status <90 (HR 0.8; 95% CI 0.6-0.99), older patient age (HR 1.1 by 10 year increase; 95% CI 1.02-1.2) and CMV seropositivity of recipient (HR 1.3; 95% CI 1.0-1.6). Conclusions:The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD and Haplo is safe and effective and rates of GVHD are low, especially chronic. HLA mismatch in Haplo has a negative impact on acute GVHD and NRM in this setting but also offers increased anti-leukemic efficacy. As seen in other transplant scenarios, PB is associated with more GVHD and less relapse. Figure Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Celltransplantation for Patients with Primary or Secondary Myelofibrosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 169-169
Author(s):  
Gabriela Hobbs ◽  
Haesook T. Kim ◽  
AJ S. Bottoms ◽  
Michael T. Byrne ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cumulative Incidence ◽  
Interim Analysis ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Grade 3 ◽  
Neutrophil Engraftment

Abstract Background: Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease. Methods: This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis. Results: This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD. As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing. Discussion: The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. Figure 1 Figure 1. Disclosures Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Will describe the use of ruxolitinib in the ongoing clinical trial.

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2285-2285
Author(s):  
Simona Pagliuca ◽  
Antonio M Risitano ◽  
Sylvie Chevret ◽  
Flore Sicre de Fontbrune ◽  
Alienor Xhaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

scholarly journals Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4662-4662
Author(s):  
Jacopo Peccatori ◽  
Serena Albanese ◽  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Fabio Giglio ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

scholarly journals Cytomegalovirus Gastroenteritis in Patients with Acute Graft-Versus-Host Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3918-3918
Author(s):  
Yu Akahoshi ◽  
Shun-ichi Kimura ◽  
Yuma Tada ◽  
Toshihiro Matsukawa ◽  
Masaharu Tamaki ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Multivariate Analyses ◽  
Time Dependent ◽  
Chugai Pharmaceutical ◽  
Graft Versus Host ◽  
Otsuka Pharmaceutical ◽  
Cmv Disease ◽  
The Impact ◽  
Cmv Reactivation

Abstract [Background] A pre-emptive strategy has successfully decreased the incidence of cytomegalovirus (CMV) disease after allogeneic hematopoietic cell transplantation (HCT). However, it is difficult to completely prevent breakthrough CMV gastroenteritis, especially after acute graft-versus-host disease (GVHD) because a routine monitoring test with antigenemia or PCR assay often shows negative results before the development of CMV gastroenteritis that is considered as a localized infection initially. Actually, gastroenteritis is the predominant CMV disease in a pre-emptive strategy era. In addition, letermovir has recently been available for prophylactic strategies against CMV in clinical practice. However, little is known about the incidence, prognostic factors, and impact of subsequent CMV gastroenteritis after acute GVHD under recent advances in HCT including the introduction of letermovir. [Methods] This nationwide retrospective study evaluated adult patients who received their first allogeneic transplantation between 2008 and 2019 and developed grade II-IV acute GVHD (G24GVHD). Patients with a CMV-seronegative donor and recipient were excluded. Weekly monitoring using pp65 antigenemia assay was performed from the time of engraftment. A diagnosis of CMV gastroenteritis was made by gastrointestinal symptoms with histological proof of CMV on biopsy samples. The day when patients developed G24GVHD was considered as day 0 in all analyses. Nonrelapse mortality (NRM) by day 365 was set as the primary end-point. Cox proportional hazards regression models were used in all multivariate analyses. The impact of CMV reactivation and gastroenteritis as a time-dependent covariate were graphically plotted using a Simon-Makuch method. This study was approved by the data management committee of the Japan Society for Transplantation and Cellular Therapy (JSTCT) and by the Institutional Review Board of Jichi Medical University Saitama Medical Center. [Results] In total, 3759 patients with G24GVHD fulfilled eligibility and were included in this analysis. The median age at HCT was 50 years (range, 16 to 74). Of the 3759 patients with G24GVHD, 1120 (29.8%) developed grade III-IV acute GVHD. Letermovir prophylaxis was administered in 275 patients (7.3%), and the median start timing was 1 day after HCT (range, -8 to 36). The median duration of letermovir administration was 91 days (range, 2 to 332). The median observation period of survivors with letermovir prophylaxis was 320 days from the development of G24GVHD. By day 365, 207 patients developed CMV gastroenteritis and the cumulative incidence was 5.7% (95% CI, 5.0-6.5%). The median duration between the development of G24GVHD and CMV gastroenteritis was 22 days (range, 1 to 235). Before the onset of CMV gastroenteritis, 37 (17.9%) did not develop CMV reactivation. In multivariate analyses, advanced age (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.16-2.22; P = 0.004), GVHD prophylaxis using mycophenolate mofetil with calcineurin inhibitor (HR, 1.73; 95% CI, 1.08-2.77; P = 0.024), lower-gut acute GVHD at the development of G24GVHD (HR, 2.17; 95% CI, 1.58-2.98; P &lt; 0.001), and use of systemic steroids (HR, 1.78; 95% CI, 1.16-2.74; P = 0.008) were independent risk factors for cytomegalovirus gastroenteritis. Moreover, CMV prophylaxis with letermovir was significantly associated with a decreased risk of CMV reactivation (HR, 0.25; 95% CI, 0.20-0.32; P &lt; 0.001) and cytomegalovirus gastroenteritis (HR, 0.50; 95% CI, 0.25-0.99; P = 0.047). Then, we evaluated the impact of cytomegalovirus gastroenteritis on NRM by day 365. We found that patients who developed cytomegalovirus gastroenteritis (time-dependent covariate) had a higher risk of NRM (HR, 1.89; 95% CI, 1.50-2.39; P &lt; 0.001) (Figure A). Meanwhile, letermovir prophylaxis reduced the risk of NRM (HR, 0.72; 95% CI, 0.52-0.99; P = 0.043). We illustrated the adjusted cumulative incidence of NRM in patients with and without letermovir prophylaxis in Figure B. [Conclusion] To our knowledge, this is the largest study summarizing the characteristics and outcomes of cytomegalovirus gastroenteritis after acute GVHD. Our findings underscore the importance of more stringent surveillance with endoscopy and prevention with letermovir based on a comprehensive risk assessment. Figure 1 Figure 1. Disclosures Kimura: SymBio Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Nippon Kayaku: Honoraria; Eisai: Honoraria; Ono Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria. Uchida: Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb　Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Kanda: Sanofi: Research Funding; MSD: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Murata: GlaxoSmithKline: Honoraria; Asahi Kasei: Honoraria; Miyarisan Pharmaceutical: Honoraria; Astellas: Honoraria; JCR Pharmaceutical: Honoraria; Novartis: Honoraria; Toyama Chemical: Honoraria; FUJIFILM: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Kyowa Kirin: Honoraria; MSD: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria. Nakasone: Eisai: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

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