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 < 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 < 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 < 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.

scholarly journals HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2919-2919
Author(s):  
Minoru Kanaya ◽  
Yasuo Morishima ◽  
Nobuyoshi Arima ◽  
Masahiro Hirayama ◽  
Souichi Shiratori ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Otsuka Pharmaceutical ◽  
The Impact ◽  
Cmv Reactivation

Abstract Background: HLA-B leader encodes methionine (M) or threonine (T) at position 2 and gives rise to TT, MT, or MM genotype. HLA-B M leaders promote higher HLA-E expression than T leaders, enhancing T cell and natural killer (NK) cell recognition on HLA-E via NKG2A and NKG2C related to cytomegalovirus (CMV) recognition. The dimorphic HLA-B leader informs acute graft-versus-host disease (GVHD) risk in HLA 1 allele mismatched unrelated hematopoietic stem cell transplantation (HCT) (Petersdorf EW et al. Lancet Haematol. 2020 and Blood. 2020) and haploidentical HCT (Fuchs EJ et al. 62nd ASH Annual Meeting 2020). However, the impact of the HLA-B leader genotype in HLA-matched related/unrelated donor HCT from the viewpoints of CMV reactivation has not been elucidated fully yet. We performed this retrospective study to explore the significance of HLA-B leaders in HLA-matched related/unrelated HCT in the Japanese population. Methods: All clinical data of 10,110 patients who underwent 8/8 HLA matched related/unrelated donor bone marrow/peripheral blood HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) between 1996 - 2019 were provided by the Japanese Data Center for Hematopoietic Cell Transplantation. All 8 alleles at HLA-A, -B, -C, and DRB1 were matched by genotyping, and sibling pairs whose genotype were unknown but matched 8/8 for HLA antigen at a serologic level were included. Study outcomes were overall survival (OS), relapse, non-relapse mortality (NRM), grade II-IV acute GVHD, grade III-IV acute GVHD, and chronic GVHD. Multivariable models using Cox regression analysis assessed transplant outcomes associated patient age, patient sex, patient performance status, donor sex, donor age, diagnosis, disease risk index (DRI), donor source (bone marrow or peripheral blood), related/unrelated donor, myeloablative (MAC)/reduced-intensity conditioning, patient CMV serostatus and patient/donor HLA B-leader (TT, MT, MM). In subgroup analysis, we adopted results of CMV antigenemia instead of CMV serostatus to evaluate the impact of CMV reactivation for HCT outcomes. All statistical analyses were performed with EZR. Results: This study included 5,212 AML patients (51.9%), 2,995 ALL patients (29.6%) and 1,864 MDS patients (18.4%). In DRI, low risk was 501 (5.4%), intermediate risk was 5,750 (61.6%), high risk was 2,711 (29.0%) and very high risk was 378 (4.0%). Median patients age was 44 (range 0-77) years. Bone marrow was the graft source in 7,183 recipients (71.0%). Related donors were 5,378 (53.2%). MAC was used in 5,891 (70.3%) patients. The number of TT patients/donor was 7,419 (73.4%), MT patients was 2,496 (24.7%) and MM patients was 195 (1.9%). MM patients was associated with significant lower OS (hazard ratio [HR] 1.329 [95% CI, 1.053 - 1.677]); p = 0.017 and higher NRM (HR 1.391, [95% CI, 1.018 - 1.902]); p = 0.039) compared to TT patients (Table). There was no significant correlation between MM patients and grade II-IV/III-IV acute GVHD. In subset analysis for each diagnosis, MM genotype didn't affect outcomes in AML patients, whereas MDS and ALL patients with MM genotype showed lower OS (MDS: HR 1.829, [95% CI, 1.070 - 3.128]; p = 0.023), (ALL: HR 1.638, [95% CI, 1.032 - 2.599]; p = 0.037) compared to TT genotype (Table). In subgroup analysis for HLA-B leader genotype, CMV reactivated patients were significant better for OS (HR 0.467, [95% CI, 0.266 - 0.819]; p < 0.001) and lower NRM (HR 0.342, [95% CI, 0.153 - 0.763], p = 0.009) only in MM patients. Conclusions: MM HLA-B leader genotype is a risk factor for worse OS and higher NRM compared to TT genotype in HLA matched related and unrelated HCT, particularly MDS and ALL patients in the study. On the other hand, CMV reactivation could be favorable for OS and NRM in MM leader patients suggesting that promoting NK cell reconstitution and education due to CMV reactivation might benefit MM leader patients. Figure 1 Figure 1. Disclosures Kanda: CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Amgen Astellas BioPharma: Honoraria. Ichinohe: Takeda Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; CSL Behring: Honoraria, Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Nippon Shinyaku Co: Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Repertoire Genesis Inc.: Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical Co.: Research Funding; Eisai Co.: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Meiji Seika Pharma Co, Ltd.: Honoraria; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria.

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.

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.

scholarly journals Impact of Graft-Versus-Host Disease and Graft-Versus-Leukemia Effect Based on Minimal Residual Disease in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4522-4522
Author(s):  
Yu Akahoshi ◽  
Aiko Igarashi ◽  
Takahiro Fukuda ◽  
Naoyuki Uchida ◽  
Masatsugu Tanaka ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Multivariate Analyses ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Graft Versus Host ◽  
Graft Versus Leukemia ◽  
Grade 3 ◽  
Overall Mortality

[Background] Previous studies have shown that a graft-versus-leukemia (GVL) effect was augmented in patients who developed graft-versus-host disease (GVHD). The benefit of the GVL effect is counter-balanced by treatment-related mortality (TRM) due to GVHD. In addition, the development of the ability to detect minimal residual disease (MRD) has changed the landscape of risk stratification. Therefore, patients with positive-MRD require a more intensive GVL effect to reduce relapse, whereas a "mild" GVL effect may be sufficient in patients with negative-MRD. However, it is uncertain whether the influence of a GVL effect would differ depending on the MRD status at HSCT. Here, we conducted a nationwide retrospective study to evaluate the impact of GVHD and a GVL effect according to the MRD status for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) in the TKI era. [Patients & Methods] Clinical data were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). We examined 1022 recipients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive ALL in first complete remission between 2005 and 2017. We excluded patients who lacked MRD status at HSCT or who received in vivo T-cell depletion or high-dose post-transplantation cyclophosphamide. The impacts of acute GVHD (aGVHD) and chronic GVHD (cGVHD) as time-dependent covariates on transplant outcomes were analyzed while adjusting for other significant variables in multivariate analyses. In the analysis of cGVHD, only patients who survived at least 100 days without hematological relapse were included. This retrospective study was approved by the data management committee of TRUMP and by the Institutional Review Board of Jichi Medical University Saitama Medical Center. [Results] The median age at HSCT was 45 years (range, 16 to 71 years). MRD status at HSCT was negative in 791 (77.4%) and positive in 231 (22.6%). The median observation period of the survivors was 1505 days (range, 18 to 4944 days). To graphically illustrate the impacts of aGVHD and cGVHD, a Simon-Makuch plot were drawn in the whole cohort and in the groups limited to negative-MRD and positive-MRD at HSCT (Figure 1 and 2). The impacts of acute GVHD on overall survival, hematological relapse, and non-relapse mortality (NRM) were summarized in Table. In multivariate analyses, the HRs for hematological relapse with positive-MRD at HSCT (0.80 for grade 1-2 aGVHD and 0.31 for grade 3-4 aGVHD) were smaller than those with negative-MRD at HSCT (1.07 for grade 1-2 aGVHD and 0.45 for grade 3-4 aGVHD), respectively. In addition, the risk of hematological relapse gradually decreased proportionally to the severity of aGVHD. Because the risks of NRM for grade 1-2 aGVHD were not significant regardless of MRD-positivity, grade 1-2 aGVHD was not significantly associated with superior overall mortality. Grade 3-4 aGVHD was significantly associated with inferior overall survival in the whole cohort and in the group limited to negative-MRD at HSCT because of high NRM. Meanwhile, grade 3-4 aGVHD was not significantly associated with overall mortality due to the potent GVL effect in the analysis limited to positive-MRD at HSCT. In the analysis of cGVHD, although cGVHD reduced the risk of hematological relapse, the survival advantage of cGVHD was not significant regardless of MRD-positivity. Because the NIH severity score was not available in our database, further evaluations of cGVHD considering the severity score are needed. [Conclusion] Our study showed that both MRD status at HSCT and the severity of aGVHD might be associated with the intensity of a GVHD-associated GVL effect for Ph-positive ALL. However, because GVHD had no apparent survival benefit regardless of MRD-positivity at HSCT or the severity of GVHD, less intensive GVHD prophylaxis to obtain the GVL effect is not recommended for Ph-positive ALL. Disclosures Kanda: Nippon-Shinyaku: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Research Funding; Tanabe Mitsubishi: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Research Funding; Taiho: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; CSL Behring: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Asahi-Kasei: Research Funding; Taiho: Research Funding; Tanabe Mitsubishi: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Otsuka: Research Funding; Asahi-Kasei: Research Funding; Mochida: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria. Ichinohe:Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Tanaka:Bristol-Myers Squibb: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Kako:Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria.

scholarly journals Who Is the Best Donor for the Second Transplant?: HLA Discrepancy between Graft and Host Rather Than That Graft and First Donor May Impact the Second Transplant Outcome from the JSHCT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4635-4635
Author(s):  
Yoshinobu Maeda ◽  
Tomotaka Ugai ◽  
Eisei Kondo ◽  
Kazuhiro Ikegame ◽  
Makoto Murata ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Immunological Responses ◽  
Increased Risk ◽  
Significant Difference ◽  
Otsuka Pharmaceutical ◽  
Risk Of Relapse ◽  
Grade Iii

Abstract For patients with malignant hematological diseases that relapse after allogeneic hematopoietic stem cell transplantation (HSCT), a second HSCT is thought to be a curative option. A second donor is usually searched for due to HLA discrepancy between the graft and the host. However, it is unclear whether HLA discrepancy between the graft and the first donor has an impact on the outcome of second HSCT. To address this issue, we focused on second HSCT patients who had received first HSCT from an HLA-mismatched (MM) donor and compared the effects of HLA discrepancy between graft and first donor with those between graft and host. We retrospectively analyzed 646 patients receiving second HSCT between 1994 and 2016 after an initial HLA-MM transplantation. With regard to the graft versus host results, the one-allele mismatch (1 MM) group (relative risk [RR], 1.88; 95% confidence interval [CI], 0.79-4.45; p=0.163) and more than one-allele mismatch group (≥ 2 MM) (RR, 1.84; 95% CI, 0.75-4.51; p=0.182) had higher risks of grade III-IV acute GVHD compared to the HLA-matched (0 MM) group, although the results were not significant. In contrast, almost no difference in risk of acute GVHD was found among the 0, 1, and ≥ 2 MM group with respect to graft vs. first donor. Furthermore, with regard to graft vs. host, the ≥ 2 MM group showed a significantly higher risk of treatment-related mortality (TRM) (RR, 1.90; 95% CI, 1.04-3.50; p=0.038) compared to the 0 MM group. In contrast, the risk of relapse was slightly lower in the ≥ 2 MM group (RR, 068; 95% CI, 0.44-1.06; p=0.086). Consequently, no significant difference in OS was found among the three groups. In the analysis of each HLA allele MM, B allele MM between graft and host was associated with an increased risk of grade III-IV acute GVHD (RR 2.87; 95% CI, 1.42-5.79; p=0.003) and DR allele MM between graft and host was associated with a lower risk of relapse (RR, 0.75; 95% CI, 0.58-0.95; p=0.018) and higher risk of TRM (RR, 1.44; 95% CI, 1.03-2.00; p=0.033). In contrast, with regard to graft vs. first donor, there were no significant differences in relapse, TRM, or OS among the three groups, and also analysis of each HLA allele MM indicated no associations with relapse, TRM, or OS. These findings suggested that HLA discrepancy between graft and host, rather than between graft and first donor may induce transplant-related immunological responses in second HSCT leading to an increase in TRM. In conclusion, HLA-MM donor is an option after initial HLA-MM transplantation, however, TRM remains a challenge, particularly with a ≥ 2 MM donor regarding to graft versus host. In this study, the biological effects of HLA discrepancy between the graft and the first donor on the outcome appeared negligible, and our findings shed light on the role of nonhematopoietic APCs on transplant-related immunological responses. Figure. Figure. Disclosures Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Ichinohe:Mundipharma: Honoraria; Eisai Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; CSL Behring: Research Funding; Novartis.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding. Kanda:Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; Taisho-Toyama: Research Funding; MSD: Research Funding; Novartis: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; CSL Behring: Research Funding; Asahi-Kasei: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

scholarly journals Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2007-2007
Author(s):  
Dujardin Adèle ◽  
Pierre Morel ◽  
Alexis Caulier ◽  
Magalie Joris ◽  
Amandine Charbonnier ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Time Dependent ◽  
Viral Reactivation ◽  
First Episode ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Ebv Reactivation ◽  
Cmv Reactivation

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia <1G/L persisted at day 100 for 42/51 patients evaluated. In these 57 patients, ruxo was given for 62 episode of GVHD (acute: 21 [which 95% for an acute grade III-IV GVHD]; chronic: 36; overlap syndrome: 5). Response rates to ruxo were 48% for acute GVHD, 60% for overlap syndrom and 58% for chronic GVHD. The overall GVHD related-death rate was 33% (19% for acute GVHD and 14% for chronic GVHD). Our median follow-up was 30 months (range, 9 to 42) after HSCT. Main non-infectious adverse events were cytopenias (17/57) and hepatic cytolysis (6/57) leading to discontinuation or tapering of ruxo in 12 patients. EBV reactivation (> 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p<0,05) as well as first episode of CMV reactivation (HR: 1,747, p<0,05) after first episode of GVHD. Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Predictors and Outcomes of Flares in Chronic Graft-Versus-Host Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Grigori Okoev ◽  
Daniel J. Weisdorf ◽  
John E Wagner ◽  
Bruce R. Blazar ◽  
Margaret L. MacMillan ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Board Of Directors ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Time Dependent ◽  
Advisory Committees ◽  
Graft Versus Host ◽  
Day Range ◽  
Similar Risk ◽  
Fund Research

Introduction: Chronic Graft-versus-Host Disease (cGvHD) frequently requires prolonged immune suppressive therapy (IST) with &gt; 50% still on IST at 5 years. The IST typically involves a slow taper of steroids often with flare of cGvHD, necessitating augmentation of previous therapy or addition of new IST. Studies describing cGvHD flares are limited. We analyzed patients with cGvHD who flared during the treatment with systemic IST, their overall survival (OS) and non-relapse mortality (NRM). Methods: This study included all adult patients with cGvHD (n=145) following an allogeneic transplant (2010 - 2017) from a matched sibling donor peripheral blood stem cell transplant (MSD, n=104 (72%) or double/single umbilical cord blood transplant (UCBT, n=41 (28%). The 2014 NIH Consensus Criteria were used to classify organ/overall cGvHD severity. Flare of cGvHD was defined as progression in cGvHD manifestations (after initial response), which was less severe than at diagnosis. Multivariate regression of flares was based on the Prentice, Williams and Peterson model for ordered multiple events (flares). Time-dependent effects on OS and NRM were analyzed by Cox and Fine and Gray regression with propensity scoring to control for confounding. Results: Flares occurred in 87 patients; the cumulative incidence of flares was 60% (95% CI: 51-70%) at a median of 188 days (range 16-751) after diagnosis of cGvHD. The median dose of prednisone was 1 mg/kg/day (range 0-4.2) at diagnosis of cGvHD. At the diagnosis of flare, 36 (41%) of the patients were off prednisone, 50 (57%) were receiving 0.1-0.5 mg/kg /day, and 2 patients &gt; 0.5 mg/kg /day. Thirty two of the 87 (36%) patients experienced multiple flares (2 to 4). The most common organs involved at cGvHD flare were skin (n=45; 51%), mouth (n=27; 31%), GI tract (n=22; 25%) and liver (n=12; 14%); often in combinations of skin/mouth in 11 cases (13%), skin/GI in 6 (7%) and liver/mouth in 4 (5%) cases. Treatment for flare was mostly increase in dose of prednisone to 0.5 mg/kg/day (range 0.3-1.0) in 77 patients (88%) plus the addition of another line of IST in 48 patients (55%). In multiple regression analysis, only donor type was significant predictor of flare in cGvHD. UCBT was associated with 2-fold lower probability of flaring (HR 0.5; 95% CI: 0.3-0.9; p=0.03) compared to MSD. cGvHD severity, organ involvement, platelet count at diagnosis and type of onset were not significant predictors of cGvHD flares. At 2 years after the initial flare, the OS was 77% (95% CI: 66-84%) and NRM 19% (95% CI: 11-28%). Multiple regression analysis evaluating OS and NRM from onset of cGvHD comparing flare to non-flare were performed using flare as a time dependent variable. Compared to cGvHD patients without flare at 2 years, those with flare of cGvHD had a similar risk of NRM (HR 1.2; 95% CI: 0.2-6.1, p=0.86) and OS (HR 0.9; 95% CI: 0.4-2.3, p=0.85). At 2 years from cGvHD onset, the cumulative incidence of resolved cGvHD (durable discontinuation of steroids for ≥ 6 consecutive months) was 31% (95% CI: 21-41%) in those who flared vs. 86% (95% CI: 75-96%) in those without flare. Conclusions: Though cGvHD patients with flare had similar risk of NRM and OS as those without a flare, patients with flare required extended steroids, along with clinical monitoring and intensified IST. cGvHD after UCBT was associated with significantly lower risk of flaring compared to MSD. The ongoing burden of IST, risk of infection and morbidity of cGvHD is substantial and needs better approaches than chronic slow taper of steroids. Disclosures Weisdorf: Incyte: Research Funding; FATE Therapeutics: Consultancy. Wagner:Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Magenta Therapeutics: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees. Blazar:Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. MacMillan:Mesoblast: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Talaris Therapeutics, Inc: Consultancy; Fate Therapeutics, Inc.: Consultancy. Holtan:Generon: Consultancy; BMS: Consultancy; CSL Behring: Other: Clinical trial data adjudication; Incyte: Consultancy. Brunstein:AlloVir: Other: Advisory board; Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Bachanova:FATE: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Arora:Fate Therapeutics: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding.

scholarly journals Elimination of Acute GvHD with Three Doses of Abatacept Prophylaxis Combined with Post-Transplant Cyclophosphamide after Myeloablative Treosulfan-Based Conditioning in the HLA Identical Sibling and Unrelated (10-12/12) Peripheral Blood Stem Cell Donor Setting: Improved Safety and Efficacy Compared to Alemtuzumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4540-4540
Author(s):  
Amit Patel ◽  
Jun Yong
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Safety And Efficacy ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Secondary Outcomes ◽  
Cmv Reactivation

Background. Acute graft versus host disease (GvHD) remains a major cause of treatment failure post allogeneic stem cell transplantation (HSCT). CD28-CD80/CD86 axis T cell co-stimulation blockade with CTLA4-Ig using abatacept (AB) is an emerging acute GvHD prophylaxis strategy1. After myeloablative conditioning (MAC), together with methotrexate and calcineurin inhibition, four doses of AB commencing day (d)-1 is being investigated in the unrelated HLA 7/8 and 8/8 mismatched/matched donor settings, mostly in children2. It is unknown if AB can be de-escalated in adults to three doses for HLA matched sibling (SIB) or unrelated 10-12/12 donors (MUD), or combined with post-transplant cyclophosphamide (PT-CY) GvHD prophylaxis3, or combined with treosulfan (TREO)-based MAC4, which are other emerging transplant strategies. We investigated the safety and efficacy of this combination, and compared outcomes to a standard anti-CD52 directed IgG1 alemtuzumab (CH) prophylaxis regimen5 in a reduced intensity conditioning (RIC). Methods. We report a single centre consecutive cohort study using peripheral blood stem cells from SIB or HLA 10-12/12 MUDs, for HSCT in adults with blood cancer indications (intuitional registration: 1920-31). One group received AB GvHD prophylaxis while the other group received CH. During 2018-2019, the AB cohort received MAC with IV fludarabine 150 mg/m2, IV TREO 42 mg/m2, and 2 Gy total body irradiation (TBI). GvHD prophylaxis comprised three doses of IV AB 10 mg/kg on d+5, +14, and +28. This was combined with IV PT-CY 50 mg/kg on d+3 and +4, IV tacrolimus 0.03 mg/kg/d infusion from d+5, and IV mycophenolate mofetil 15 mg/kg tds from d+53. The MAC AB cohort was compared to a RIC CH cohort, chosen to be biased against AB. During 2017-2018 the CH cohort received RIC with IV fludarabine 150 mg/m2and IV melphalan 140 mg/m2. GvHD prophylaxis comprised IV CH 10 mg on d-7 to d-3, and IV ciclosporin 1.5 mg/kg bd from d-1. The primary outcome measure was the incidence of acute GvHD6 at d100 and 180 post HSCT. Secondary outcomes measures were the incidence of graft failure, mixed donor chimerism, donor lymphocyte infusion (DLI), CMV reactivation, relapse, overall survival, at d100 and 180. The AB and CH cohorts were indirectly compared. Results. A total of 39 patients were included in this study, with 15 consecutive patients in the AB group (Table). The AB group had a median Karnofsky score of 70% and HCT-CI of 6; significant comorbidity greater than other reports1,2. The major cancer indications were acute leukaemia and myelodysplastic syndrome (MDS). The AB and CH groups were largely balanced. There were no AB related infusion reactions. As expected for MAC, the AB group had a numerically but not clinically significantly slower time to engraftment relative to the RIC CH group. There was no AB group graft failure. Remarkably, the AB group did not experience acute GvHD compared to the CH group by d100 (P=0.03) and d180 (P<0.01). In contrast, by d100, 29% in the CH group experienced acute GvHD after a median of 59 days post HSCT. No AB group patients experienced mixed donor chimerism (P<0.01), nor required a DLI (P<0.01) compared to the CH group, where all had <99% T cell or whole blood values at d100. Consequently, 45% of the CH cohort without acute GvHD were treated with DLI, with all patients experiencing acute GvHD at a median of 39 days post DLI (Table). Other secondary outcomes were similar. The AB group experienced a CMV reactivation rate of 67% in IgG seropositive patients. Unfortunately, 93% of CMV IgG positive patients in the CH group experienced CMV reactivation. No relapses were observed by d180 in the AB group, whereas in the CH group, 8% of patients experienced relapse. Mortality at d180 was 20% in the MAC AB group, and 21% in the RIC CH group. Conclusions. Acute GvHD prophylaxis with only three doses of AB and PT-CY post TREO-based MAC appears to be safe and efficacious in the SIB and MUD settings, in a highly co-morbid adult blood cancer population. This AB approach seems favourable compared to CH despite RIC, where acute GvHD without DLI or post DLI remains significant. A prospective multicentre clinical trial with AB in this setting seems warranted to confirm these remarkable findings of patient benefit. References. 1. Biol Blood Marrow Transplant (BBMT) 2013;19:1638-49. 2. NCT01743131. 3. Lancet Haematol 2019;6:e132-43. 4. Cancer 2017;123:2671‐79. 5. BBMT 2017;23:805-12. 6. BBMT 2016;22:4-10. Table Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Abatacept, alemtuzumab, cyclophosphamide all the for the indication of graft versus host disease (GvHD) prophylaxis.

High Levels of Donor Chimerism Early after Non-Myeloablative Transplantation Predictive of Overall and Progression Free Survival but Not Risk of Acute Graft Versus Host Disease for Patients with AML or MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 185-185
Author(s):  
Edwin P. Alyea ◽  
Shuli Li ◽  
Haesook Kim ◽  
Vincent T. Ho ◽  
Corey Cutler ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Early Stage ◽  
Progression Free Survival ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Chimerism ◽  
The Impact

Abstract Non-myeloablative (NST) transplantation is increasingly used in the treatment of patients with AML and MDS who are not candidates for myeloblative transplant. Relapse of disease remains a major cause of treatment failure after NST. Predictive factors to identify patients at high risk of relapse are needed to identify patients who would benefit from additional interventions. Attainment of a high degree of donor engraftment achieved early after transplantation may indicate the presence of a more significant allo-immune effect. We have performed a retrospective analysis of 64 patients with AML and MDS receiving NST, assessing the impact of donor chimerism when measured early after transplantation on outcome. Overall survival (OS), progression free survival (PFS) and risk of graft versus host disease (GVHD) were compared for patients achieving ≥90 % or <90% donor derived hematopoiesis when measured 1 month after transplant. All patients received fludarabine 30 mg/m2/day x 4 days and intravenous busulfan (Busulfex)0.8 mg/kg/day x 4 days for conditioning. All patients received calcineurin-inhibitor based GVHD prophylaxis. All patients received PBSC with G-CSF at 5 mcg/kg beginning day 1 after transplantation. Chimerism was measured using FISH for sex mismatched patient donor pairs or by STR analysis. 37 patients had ≥90% donor derived hematopoiesis, 27 patients had <90% donor derived hematopoiesis after transplantation. The two groups had similar characteristics with a median age of 57 yrs (range 21–70) for patients ≥90% and 58 yrs (range 32–69) for patients <90%. Of patients achieving ≥90%, 23 patients had AML and 14 MDS. Of patients <90%, 13 had AML and 14 with MDS. 7 of 16 (44%) patients with early stage disease(AML in CR1 or early stage MDS) achieved ≥90% donor hematopoiesis, while 30 of 48 (63%) patients with advanced disease achieved ≥90%. 17 of 29 (59%) patients with unrelated donors achieved ≥90% donor derived hematopoiesis, while 20 of 33 (61%) patients with matched related donors achieved ≥90% donor derived hematopoiesis. 21 of 32 (66%) patients with donor-recipeint sex mismatch achieved ≥90% while 16 of 32 (50%) patients with same sex donors were ≥90%. The median follow-up for surviving patients achieving ≥90% donor chimerism was 12 months and 15 months for those <90%. Patients achieving ≥90% donor chimerism had a significantly improved 1-year (71% versus 41%) and 2-year (39% versus 19%) OS (p=0.05). Similarly, for patients achieving ≥90% donor chimerism, there was a trend toward an improved PFS at 1-year (49% versus 30%) and 2-years (32% versus 19%) (p=0.08). There was no difference in the risk of developing stage 2–4 acute GVHD, 19% for both patients above and below 90%. Achieving high levels of donor chimerism when measured early after NST predicts for an improved overall survival and there is a trend toward an improved progression free survival. This may represent the presence of an enhanced graft versus leukemia effect in these patients. The degree of donor chimerism does not predict the development of acute GVHD. These results suggest that patients with <90% donor derived hematopoiesis may be candidates for strategies to enhance donor chimerism.

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