scholarly journals Donor Clonal Hematopoiesis Increases Risk of Acute Graft Versus Host Disease after Matched Related Transplantation in AML and MDS Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 47-47 ◽  
Author(s):  
Betul Oran ◽  
Richard E. Champlin ◽  
Feng Wang ◽  
Nikeshan Jeyakumar ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Transplant Outcomes ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
The Impact ◽  
Homogenous Population

Background: After the introduction of reduced intensity conditioning (RIC) regimens, older patients became eligible for allogeneic hematopoietic stem cell transplantation (HSCT) with a parallel increase in the use of older sibling donors. Clonal hematopoiesis of indeterminate potential (CHIP) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. The impact of using older donors with CHIP on transplant outcomes have not been well-established. In this study, we investigated the association between donor-CHIP and transplant outcomes in acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) patients who underwent HSCT from older donors (age >= 55). Methods: Of 421 AML/MDS patients who underwent their first allogeneic HSCT from an older donor aged ≥55 from 2000- 2018, DNA samples were available from 363 healthy older donors at the time of stem cell donation. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CHIP using modified Mutect and Pindel algorithms. We excluded variants with allele frequency < 2%. After describing the distribution of CHIP among healthy older donors, we investigated the impact of donor CHIP on HSCT outcomes in a more homogenous population. We restricted clinical outcome analyses to 302 patients who underwent first allogeneic HSCT using a matched related donor (MRD), with peripheral blood stem cells (PBSCs) as the hematopoietic stem cell source. In this cohort, 90% of patients received tacrolimus/methotrexate for graft versus host disease (GvHD) prophylaxis. Results: Among 363 donors, 71 (20%) were found to have CHIP. The most frequently mutated genes as CHIP were DNMT3A (32/71, 45%), TET2 (18/71, 25%), PPM1D (8/71, 11%), and SXL1 (7/71, 10%). Of 71 CHIP donors, 63 (89%) had single mutation, while 8 (11%) had two mutations. There were no significant difference in recipients' disease status or transplant characteristics by donor CHIP status (Table 1). The presence of CHIP increased with donor age; the prevalence was 15% in donors aged 55-59, 16% aged 60-64, 32% aged 65-69 and 27% aged ≥70. Transplant outcomes including engraftment rate, time to neutrophil and platelet recovery, progression incidence, progression-free survival (PFS) and overall survival (OS) were comparable by donor CHIP status (Figure) in the 302 patients with older MRDs and PBSCs as the stem cell source. Of note, disease and transplant characteristics were similar for comparison groups. Cumulative incidence (CI) of grade 2-4 and 3-4 acute GvHD (aGvHD) at 6 months after transplant was higher with donor CHIP (HR=2.1, 95%CI=1.4-3.3, p<0.001 and HR=2.9, 95%CI=1.3-6.3, p=0.009) To further investigate the impact of donor CHIP on aGvHD, we investigated the interaction of donor CHIP with older donor age. Within healthy donors aged ≥65, CHIP increased the risk of grade 2-4 and 3-4 aGvHD (HR=2, 95%CI=1.1-3.5, p=0.01 and HR=3.5, 95%CI-1.1-10, p=0.03). The impact was similar in donors aged <65 with increased grade 2-4 and 3-4 aGvHD by CHIP (HR=2.1, 95% CI=1.1-4.4, p=0.04 and HR=2.4, 95%CI=0.6-9.5, p=0.2). Despite the increased aGvHD, we did not observe increased incidence of chronic GvHD by donor CHIP. Conclusion: In this relatively homogenous population of AML/MDS patients who were transplanted after RIC with PBSCs from older matched related donors and who received tacrolimus-based GvHD prophylaxis, donor CHIP was associated with significantly increased risk of grade 2-4 and 3-4 aGvHD. Engraftment, progression risk and overall survival were not affected. Further studies to investigate the molecular mechanism of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CHIP are warranted. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

scholarly journals Clinical Characteristics, Biological Markers and Comorbidity Indexes As Predictors of Transplant-Related Mortality after Allogeneic Hematopoietic Stem Cell Transplantation: Which One Should We Choose?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3478-3478
Author(s):  
Alienor Xhaard ◽  
Renato Cunha ◽  
Marc Busson ◽  
Marie Robin ◽  
Nathalie Dhedin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Telomere Length ◽  
Cell Transplantation ◽  
Research Funding ◽  
Disease Risk ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Recipient Age ◽  
The Impact

Abstract Treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern and remains difficult to predict adequately. Several pre-transplant characteristics of patients and disease are associated with TRM. Comorbidity indexes, including pre-transplant assessment of mortality (PAM) and the hematopoietic cell transplantation comorbidity index (HCT-CI), have been developed in an attempt to predict TRM. Biologic markers, such as ferritin, C-reactive protein (CRP) and, more recently, telomere length, also correlate with TRM. However, the cumulative impact of these factors on TRM has not been addressed. Here, we investigated the impact of pre-transplant clinical factors, comorbidity indexes and biologic markers on TRM in 670 consecutive patients from a single center who received a first allogeneic HSCT between January 2006 and June 2012. Clinical factors considered were: year of transplantation, donor and recipient ages, gender and CMV serological status, disease risk (based on the American Society for Blood and Marrow Transplantation Request for Information 2006 risk scoring schema), stem cell source, and HLA matching. Comorbidities were evaluated by PAM and HCT-CI, and coded prospectively for all patients by a single observer. HCT-CI and PAM scores were ranked into previously published categories (0, 1-2, ≥3 for HCT-CI and 9-16, 17-23, 24-30 and 31-44 for PAM; Sorror, Blood 2005; Parimon, Annals Intern. Med. 2006). Ferritin, CRP and biological data for comorbidity indexes were recorded within 2 weeks prior to HSCT. Recipient telomere lengths were determined in peripheral blood leukocytes by qPCR and adjusted for age by the telomere attrition rate observed in donors.Our analysis categorized the population into quartiles and divided patients into 2 groups: shorter telomeres (first quartile) versus longer telomeres (upper 3 quartiles). The entire patient cohort was subsequently divided into 3 groups by data availability: Group 1 (G1), the entire population (n=670) for whom all clinical data were available; G2, 488 patients with clinical and comorbidity index data (pulmonary function tests were not systematically performed during the early study period); and G3, for whom pre-transplant telomere length was available (n=178). Univariate and multivariate methods developed by Fine and Gray for competing risks studies were used to assess prognostic TRM factors, with relapse as a competing event. Table 1 shows patient characteristics. Significant differences between G1 and G2 were found for mean donor and recipient ages, sex mismatch, HLA matching, stem cell source, disease risk, and year of transplantation. Median follow-up was 36 months, overall survival at 5 years for the entire cohort was 60%, and TRM was 18%. In G1, factors significantly associated with higher TRM in multivariate analysis were: recipient age (HR, 1.02, 95%CI [1.0-1.03], p=0.005), CMV seropositive recipient/seronegative donor (R+/D-) (HR, 1.98, 95%CI [1.34-2.92], p=0.001) and mismatched unrelated donor (MMUD) (HR, 2.28, 95%CI [1.38-3.74], p=0.001). In G2, the same factors [recipient age (HR, 1.01, 95%CI [1.00-1.03], p=0.027), CMV R+/D- (HR, 1.91, 95%CI [1.22-2.99], p=0.005), MMUD (HR, 2.55, 95%CI [1.48-4.42], p=0.001)] were associated with higher rates of TRM, whereas PAM showed a trend for higher TRM (HR, 1.41, 95%CI [0.99-1.99], p=0.05). HCT-CI, ferritin, and CRP were not associated with TRM. In G3, only MMUD (HR, 2.82, 95%CI [1.06-7.46], p=0.037) was associated with higher TRM. However, in analysis restricted to patients transplanted from an HLA-matched related or unrelated donor, recipient age (HR, 1.03, 95%CI [1.00-1.06], p=0.027) and telomere length (HR, 2.45, 95%CI [1.07-5.59], p=0.033) were independently associated with higher TRM. This is the first study to investigate the impact of clinical and biological pre-transplant factors and comorbidity indexes on TRM after allogeneic HSCT in a large cohort of patients. Best results were obtained with young patients transplanted from an HLA-matched donor, with CMV other than R+/D-. High comorbidity scores (evaluated by PAM) were marginally associated with higher TRM. In G3 (pre-transplant telomere length available), only HLA-mismatch was significantly associated with higher TRM. Disclosures Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Influence of Human Leukocyte Antigen Haplotypes on Acute Graft Versus Host Disease Incidence after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2887-2887
Author(s):  
Sameer Gupta ◽  
Charu Aggarwal ◽  
Philip L. McCarthy ◽  
Swaminathan Padmanabhan ◽  
Minoo Battiwalla ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Leukocyte ◽  
Hematopoietic Stem ◽  
Hla Alleles ◽  
Leukocyte Antigen ◽  
Graft Versus Host ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Hla Haplotypes

Abstract There is increasing evidence that the Human Leukocyte Antigen (HLA) alleles may influence the incidence of acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). Differential presentation of recipient antigens to donor-derived T-cells by the respective HLA molecules may be a responsible factor. We have reported a decreased rate of aGVHD in HLA DR15 positive patients (pt) undergoing alloHSCT for myeloid malignancies (Blood, 2006; 107:1970). We investigated the influence of different HLA alleles and the three most common HLA haplotypes in US Caucasians on grade 2–4 acute GVHD (graded using published criteria) in HLA matched alloHSCT. We conducted a retrospective review of 195 related and 70 unrelated consecutive first myeloablative alloHSCT pt treated from 01/1992 to 4/2005 at our center. HLA typing was determined by either molecular (n=176) or serologic (n=89) methods. Pt characteristics included: AML (n=84), CML (n=62), NHL (n=47), ALL (n=41), MDS (n=20), HD (n=7) and CLL (n=4); median age 39 years (range 6–66), < 40 years (n=130); Male (n=168), Female (n=97); Caucasian (>95%); Donor-Recipient Sex Mismatch (n=112); Total Body Irradiation (TBI) conditioning regimens (n=205); Etoposide/Cyclophosphamide(Cy)/TBI (n=122), Busulfan(Bu)/Cy (n=28), Bu/TBI (n=27), Thiotepa/TBI (n=23), Cy/TBI (n=22), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=27) and peripheral blood stem cell source (n= 35). HLA Haplotypes analyzed for their effect on aGVHD were A1B8DR3 (n=25), A3B7DR15 (n=20) and A2B44DR4 (n=13). There was no significant difference in the pt characteristics (donor relation, conditioning regimen, donor-recipient sex match, diagnosis, age, gender, performance status, disease status at transplant, stem cell source and GVHD prophylaxis) by each of the three haplotypes. We analyzed prior published HLA alleles that were associated with an increased or decreased risk of aGVHD and pt characteristics for their effect on grade 2–4 aGVHD incidence. By univariate analysis, donor relation (unrelated vs. related, 52% vs. 38%, p=0.0002), HLA A2 (44% vs. 33%, p=0.05) and HLA B8 were associated with increased aGVHD (61% vs. 37%, p=0.005) whereas HLA B18 was associated with decreased aGVHD (19% vs. 43%, p=0.017) in contrast to prior reports using serological typing only. By multivariate analysis, HLA A2 (RR=1.5, 95%CI: 1.0 to 2.2, p=0.04), HLA B8 (RR=1.9, 95%CI: 1.1 to 3.0, p=0.01) and unrelated donor (RR= 1.9, 95%CI: 1.3 to 2.9, p=0.001) were associated with increased aGVHD. HLA haplotype multivariate analysis demonstrated increased risk of aGVHD with haplotypes A1B8DR3 and A2B44DR4 (A1B8DR3: 64% vs. 32%, RR 2.6, 95% CI: 1.1 to 5.9, p=0.012 and A2B44DR4: 61% vs. 39%, RR 3.5, 95% CI: 1.7 to 7.5, p=0.04) whereas haplotype A3B7DR15 had less aGVHD compared to others (18% vs. 42%, RR 0.31, 95%CI: 0.098 to 0.98, p=0.049). This is the first published report of the effect of HLA haplotypes on aGVHD incidence. Results of our haplotype analysis substantiate our findings of single allele effects of HLA A2, HLA B8 and HLA DR15 suggesting a differential effect on aGVHD incidence. The ability to predict aGVHD after alloHSCT using HLA haplotypes may improve outcomes by allowing for individualized GVHD prophylaxis regimens.

scholarly journals Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation

2020 ◽  
Vol 4 (15) ◽  
pp. 3474-3485
Author(s):  
Jun Zou ◽  
Stefan O. Ciurea ◽  
Piyanuch Kongtim ◽  
Min Yi ◽  
Yudith Carmazzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Clinical Outcome ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Epitope ◽  
Class I ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Transplant Outcomes ◽  
The Impact

Abstract Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.

scholarly journals Investigating Antibiotic Exposure and Risk of Severe Acute Graft Versus Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4539-4539
Author(s):  
Razan Mohty ◽  
Remy Dulery ◽  
Giorgia Battipaglia ◽  
Eolia Brissot ◽  
Clemence Mediavilla ◽  
...  
Keyword(s):  
Stem Cell ◽  
Exposure Group ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Grade 3 ◽  
Severe Grade ◽  
Neutrophil Engraftment

Several studies have shown that alteration of the microbiota, particularly in the gastrointestinal tract, can be associated with graft-versus-host disease (GvHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) usually get exposed to antibiotics (ATB), mainly in the peri-transplant period. Moreover, ATB, specifically those that target anaerobic bacteria, can alter the microbiota in a variety of body organs. This, in turn, renders several organs vulnerable to injury making them more prone to developing diseases such as GvHD. In this study, we evaluate whether the use of ATB, characterized by duration, timing and type, in the peri-transplant period, is associated with an increased incidence of acute GvHD (aGvHD) and aGvHD-related mortality. In this retrospective study, we included 318 consecutive patients who underwent allo-SCT including haploidentical and cord blood transplantation between December 2012 and June 2018 at a single center. ATB exposure was collected and classified into 3 groups according to the date of initiation of ATB: from the start of conditioning to day - 1 of allo-SCT (early ATB exposure), from day 0 to neutrophil engraftment (late ATB exposure) and a third group of patients who did not receive ATB (no ATB exposure). ATB were only initiated if a patient develop fever or show signs of infection. Patients did not receive any prophylactic ATB. Exposure was further categorized as primary or adjunct. Primary exposure included the use of 4 classes of ATB: carbapenems, anti-pseudomonal penicillin, 4thand 5thgeneration cephalosporins and fluoroquinolones. Adjunct ATB comprised other ATB and was further divided into 2 groups according to anaerobic coverage. The median age at transplant was 55 years. The stem cell source was peripheral blood in 85%, bone marrow in 10% and cord blood in 5% of the patients. Ninety-nine percent of the patients received cyclosporine A as GvHD prophylaxis and 80% and 7% of the patients received (along with cyclosporine A), mycophenolate mofetil and methotrexate, respectively. In addition, 35% and 89% of the patients received post-transplant cyclophosphamide and anti-thymocyte globulin, respectively, as GvHD prophylaxis. The median time to neutrophil engraftment was 16 days post-transplant. The median follow-up was 85 months. 93.7% of the patients received ATB in the peri-transplant period with 64.5% of them in the early ATB exposure group, and 29.2% of them in the late ATB exposure group. The 2-year overall survival and progression free survival were 74.3% and 63.6% in patients with early ATB exposure, compared to 79.5% and 70.8% in patients with late ATB exposure (p=0.11 and p=0.07 respectively). The 2-year cumulative incidence of non-relapse mortality was 16.5% in patients with early ATB exposure, compared to 15.1% in patients with late ATB exposure (p=0.63). The 180-days cumulative incidence of grade 2-4 and 3-4 aGvHD were 23.8% and 12.2% in patients with early ATB exposure, compared to 27.2% and 5.4% in patients with late ATB exposure (p=0.64 and p=0.06 respectively). In multivariate analysis, including the most important parameters associated with GvHD (stem cell source and donors, conditioning regimen, sex mismatch and patients age), early ATB initiation was the only parameter associated with a significantly higher risk of severe grade 3-4 aGvHD [HR 0.51 (0.28-0.90); p=0.02]. In conclusion, in the absence of any ATB prophylaxis, early initiation of ATB, before graft infusion,is associated with a significantly higher risk of severe grade 3-4 aGvHD. Weighing risk of morbidity and mortality associated with infections versus later on risk of developing aGvHD is essential. Hence, new strategies should be developed to risk stratify patients with fever and thus to avoid early non necessary ATB exposure especially in those who develop fever during anti-thymocyte globulin infusion. Studies evaluating such strategies will be necessary in the next years. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Malard:Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Keocyte: Honoraria; Janssen: Honoraria; Therakos/Mallinckrodt: Honoraria.

scholarly journals A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2003-2003
Author(s):  
Omer Jamy ◽  
Racquel Innis-Shelton ◽  
Susan Bal ◽  
Ravi K. Paluri ◽  
Samina Karim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Research Support ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Background: The use of post-transplant cyclophosphamide (PT-Cy) in combination with other immunosuppressive agents for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. PT-Cy mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. Extrapolating from the success of PT-Cy in haplo transplants, we investigated the benefit of PT-Cy (at a lower dose than that used in haplo HSCT) in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial between September 2013 and June 2018 of PT-Cy for GVHD prophylaxis following myeloablative MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 till day +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. Approval for the study was obtained from the Institutional Review Board. Results: There were 39 patients enrolled in the study (Table 1). The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). Based on disease risk index (DRI) assessment, 6 (15%) patients were DRI high, 32 (82%) were intermediate and 1 (3%) was low. The most commonly used myeloablative conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. Three patients with NHL received Fludarabine and Melphalan. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV (Table 2). The overall incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of them were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. Conclusion: We report a low incidence of acute severe GVHD with the combination of one dose of PT-Cy in combination with MMF and tacrolimus following myeloablative PBSC MUD HSCT. The single dose of PT-Cy may explain the modest control over chronic GVHD with this regimen. We also report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD HSCT and may play a vital role in mismatched unrelated donor transplants as well. Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; GSK: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals Central Nervous System Complications after Allogeneic Hematopoietic Stem Cell Transplantation: The Role of Calcineurin Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4601-4601
Author(s):  
Elisa Sala ◽  
Stephanie von Harsdorf ◽  
Verena Wais ◽  
Thanh Mai Anne Nguyen ◽  
Raphael Beck ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Research Funding ◽  
Calcineurin Inhibitors ◽  
Neurological Manifestations ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Prophylaxis Therapy

Abstract Introduction Despite its curative potential, the outcome after allogeneic hematopoietic stem cell transplantation (SCT) strongly depends on transplant-related mortality. Neurological complications, especially those affecting the central nervous system (CNS), are often associated with a significant rate of morbidity. Commonly used immunosuppressive drugs are calcineurin inhibitors (CNI) such as cyclosporinA (CsA) and tacrolimus (TAC) which are associated with an increased risk of neurotoxicity. So far no direct comparison between CsA and TAC has been performed to identify the better option in terms of "neurologic tolerability" in the setting of SCT. Patients and Methods We performed a retrospective analysis of consecutive patients (pts) who underwent SCT for different hematological malignancies and developed one or more CNS complications between 1999 and 2018 at the University Hospital of Ulm (Germany) and received CsA or TAC as Graft versus Host Disease (GvHD) prophylaxis/therapy. During post transplant follow up, in case of neurological manifestations, neurological evaluation, brain imaging (CT-scan or MRI), electroencephalography and, if necessary, a lumbar puncture (including microbiological analysis) were performed. Results We identified 60 out of 1256 pts who experienced a total of 79 CNS complications. Pts' characteristics are listed in Table 1. Seventy-four of 79 (94%) complications occurred in pts receiving CNI (n=58/60 pts): 51/74 (69%) were detected during or after TAC administration, while in 23/74 cases (31%) CsA was used. No statistically significant differences were observed in the two subgroups with regard to conditioning regimen (myeloablative vs reduced intensity), donor type (matched related vs matched unrelated vs mismatched related), and incidence of severe GvHD (both acute and chronic). In both cohorts early complications (within 1 month after SCT) were mostly represented by vascular events and metabolic encephalopathy (sepsis or chemotherapy-related). As intermediate complications (2-6 months after SCT) we observed a trend towards increased infections of herpes encephalitis in the TAC cohort (p=0.08), CNI-neurotoxicity and CNS symptoms due to severe transplant-associated microangiopathy (TMA). As late effects (>1 year (y) after SCT) we detected secondary CNS neoplasms, CNS relapse or neurologic effects of chronic GvHD. Comparing the time of onset of all complications, we observed a median time of 6 months after SCT in the TAC-cohort (range: day -1 - 13y) and of 11 months in the CsA-cohort (range: day 0 - 4y). The frequency of the different types of CNS complications was similar in the two cohorts with exception for the occurrence of neurological manifestations related to TMA (Figure 1), which was statistically significant higher (p=0.01) in pts receiving TAC. These changes were reversible in 33% of cases (4/12) after discontinuation of TAC (which, at the time of TMA onset, was within or below the therapeutic ranges in 91% of cases) or after specific treatment (e.g. Eculizumab, plasma exchange). Conclusions Our data suggest a possible increment of neurologic complications in pts undergoing GvHD prophylaxis/therapy with TAC, especially related to the development of severe TMA, which is known to promote mental status changes. Although these findings need to be further explored and validated in larger prospective cohorts, they could have clinical relevance, such as avoiding TAC in pts at high risk of developing TMA as well as a stricter TMA monitoring in pts undergoing GvHD prophylaxis with TAC to minimize the development of severe TMA forms with neurological involvement. Disclosures Döhner: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding.

scholarly journals ORAL CYCLOSPORINE AS AN ALTERNATIVE FOR INITIAL STANDARD PROPHYLAXIS IN ALLOGENEIC STEM CELL TRANSPLANTATION WHEN INTRAVENOUS FORMULATION IS UNAVAILABLE

2018 ◽  
Vol 11 (12) ◽  
pp. 108
Author(s):  
Eucario Leon-rodriguez ◽  
Monica M Rivera-franco
Keyword(s):  
Stem Cell ◽  
Care Center ◽  
Tertiary Care ◽  
Gender Disparity ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Oral Group ◽  
Acute Graft

Objective: The objective of the study was to compare the incidence of acute graft versus host disease (aGVHD) between oral and intravenous (IV) initial standard cyclosporine A (CsA) prophylaxis in a tertiary care center in Mexico.Methods: A total of 117 consecutive patients who underwent allogeneic hematopoietic stem cell transplantations (HSCT) were retrospectively analyzed. GVHD prophylaxis consisted of CsA and methotrexate (MTX). CsA was administered IV, until 2005, when it was withdrawn from the market, and CsA was administered orally.Results: Most of the patients were male (55%), with a median age of 33 years (range, 15–63). 92 patients (79%) received CsA orally, and 25 (22%) intravenously. There were no significant differences in CsA concentrations during weeks 1, 2, 3, and 4 between the oral and IV group. From the entire cohort, 1 patient (4%) from the IV group and 16 (17%) from the oral group developed aGVHD, respectively. Sex, gender disparity, and HSCT source were statistically associated with aGVHD in the multivariate analysis.Conclusions: Using oral instead of IV CsA for aGVHD prophylaxis is feasible and could be financially efficient; nonetheless, our results showed a higher incidence of aGVHD in the oral group; however, our study has limitations and further prospective studies including a larger cohort are encouraged.

Low Incidence of Pulmonary Graft-Versus-Host Disease in Older Patients After Reduced Toxicity Conditioning with FBM Prior to Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4660-4660
Author(s):  
Jesus Duque-Afonso ◽  
Antje Prasse ◽  
Ralph M. Waesch ◽  
Hartmut Bertz ◽  
Jürgen Finke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Pulmonary Function ◽  
Older Patients ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Reduced Toxicity

Abstract Abstract 4660 Allogeneic hematopoietic stem cell transplantation (HSCT) of older or comorbid patients has become feasible due to new protocols for reduced toxicity/intensity conditioning. Particularly using fludarabine, BCNU and melphalan (FBM) as preparative regimen confers reduced toxicity with substantial anti-leukemic activity, therefore allowing allogeneic HSCT in patients up to ages well above 70. Nevertheless, chronic Graft-versus-Host disease (cGvHD) of the lung remains a serious non infectious, late onset pulmonary complication, contributing to treatment related morbidity and mortality of the older patients. Since the clinical entity of pulmonary cGvHD in an older population after reduced toxicity/intensity conditioning has not yet been well characterized, we performed a retrospective analysis of patients, who were transplanted after FBM conditioning at the University Hospital Freiburg between 2003 and 2005 and were alive at least 100 days after HSCT. 92 patients were enrolled in this study (median age of 60 years (range 29-71)). All patients received conditioning with fludarabin (4-5 × 30 mg/m2), BCNU (or carmustin, patients&gt; 55 years: 2×150 mg/m2, &lt;55 years: 2×200 mg/m2) and melphalan (patients &gt;55 years 1×110mg/m2, &lt;55 years: 1×140 mg/m2, fo). Peripheral stem cell grafts were used in most of the cases together with cyclosporin based GvHD prophylaxis. Seven patients (8.2%) developed a pulmonary cGvHD as defined by NIH criteria with a median time after HCT of 13.3 months (range 7-19m). In those patients, pulmonary function tests prior to HCT and on day +100 (prior to pulmonary GvHD) revealed a significant reduction in mean % of predicted value in FEV1 (88 v. 71 %), and of absolute values in MEF50 (3.33 v. 1.91) and MEF25 (0.96 v. 0.42) as characteristic changes. The patients with pulmonary GvHD showed at the time of diagnosis in comparison to values before HSCT a mixed pattern of obstruction (% of predicted FEV1 71 v. 50 %), restriction (mean % of predicted VCmax 78 v. 64 %) and changes in diffusions capacity (% of predicted TLCOc SB 79 v. 62%). In univariate analysis, risk factors for developing pulmonary cGvHD were: unrelated donor, chronic GvHD, smoking and lung disease (e.g. infections) after HCT. The latter emphasizes the importance of infections due to immunosuppression for the development of pulmonary GvHD in this patients. Interestingly, uncontrolled disease status or pre-existing lung disease per se did not increase the risk for the development of pulmonary GvHD. In conclusion, we found several risk factors and changes in pulmonary function test associated with developing pulmonary GvHD in HCT after reduced toxicity conditionig. These findings might help to identify a risk population in older patients and therefore result in personalized measures for GvHD prophylaxis. Disclosures: Marks: Novartis: Research Funding.

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