scholarly journals Causes and Effects of Methotrexate Dose Alterations in Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2460-2460 ◽  
Author(s):  
Radha Ramanan ◽  
Andrew Boon Ming Lim ◽  
Kate Mason ◽  
Jeffrey Szer ◽  
David Ritchie
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
World Health ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Grade 3

Abstract Aim To identify the causes and consequences of omission and/or reduction of methotrexate (MTX) doses in graft-versus-host disease (GVHD) prophylaxis used during allogeneic hematopoietic cell transplantation (alloHCT). Method We conducted a retrospective medical record review of 125 alloHCTs performed between the years 2011 and 2013 at our hospital where MTX (15, 10, 10, 10 mg/m2 intravenously on day [D] +1, D+3, D+6, D+11 respectively) is used with cyclosporine as GVHD prophylaxis. The association of MTX dose omission with overall survival (OS), non-relapse mortality (NRM) and acute GVHD, measured from a landmark of D+12, was evaluated with univariate and multivariate analysis. Results 116 patients (median age 48, range 17-67, 59% male) were eligible for analysis. Commonest indications for alloHCT were acute leukemia (47%) and chronic lymphoproliferative disorders (28%). Conditioning was myeloablative in 54%, donors were siblings in 53%, and grafts were peripheral blood in 87%. 85 patients (73%) received all four full doses of MTX. 22 patients had a dose omission at D+11, and two at both D+6 and D+11. 43 patients were given folinic acid rescue. Documented reasons for MTX alteration were mucositis (n = 22; World Health Organisation mucositis grade 4 in 16 patients, grade 3 in 4 patients and grade 2 in 2 patients), fluid overload (n = 10), liver impairment (n = 8, median bilirubin 83 micromol/L, range 19-204 micromol/L, normal < 21 micromol/L), renal impairment (n = 8, median creatinine 138 micromol/L, range 67-276 micromol/L, normal 45-90 micromol/L) and sepsis (1). MTX omission was associated with poorer OS (48% vs 90%; hazard ratio [HR] for mortality 5.4, 95% CI 2.5-11.7, P < 0.001, Figure 1) and higher NRM (39% vs 5%, HR 10.2, 95% CI 3.4-30.8, P < 0.001, Figure 2) at 12 months post landmark. A pattern of ongoing NRM was observed beyond day 100. Strikingly, those patients who received all four full doses of MTX had NRM of 0% at 100 days post landmark. There was no difference in rates of grade 2-4 (24% vs 22%, P = .950) or grade 3-4 (9% vs 11%, P = .662) acute GVHD, or relapse (20% vs 17%, P = .514), at day 100 post landmark. Conclusion MTX dose reduction has no significant impact on GVHD development, suggesting that MTX omissions or other adjustments of GVHD prophylaxis did not lead to enhanced T cell activation. However, it seems that the need to reduce MTX indicates an increased risk of NRM, likely reflecting ongoing organ dysfunction. Older patients or those with pre-transplant co-morbidities may be better served by strategies that lower the likelihood of organ toxicity, including reduced intensity conditioning and lower initial doses of MTX. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Disclosures No relevant conflicts of interest to declare.

scholarly journals Safety and reactogenicity of the recombinant zoster vaccine after allogeneic hematopoietic cell transplantation

2021 ◽  
Vol 5 (6) ◽  
pp. 1585-1593
Author(s):  
Emily Baumrin ◽  
Natalie E. Izaguirre ◽  
Bruce Bausk ◽  
Monica M. Feeley ◽  
Camden P. Bay ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Zoster Vaccine ◽  
Varicella Zoster ◽  
Increased Risk ◽  
Adjusted Incidence Rate ◽  
Recombinant Zoster Vaccine ◽  
Grade 3

Abstract Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. A nonlive adjuvanted recombinant zoster vaccine (RZV) has been developed to prevent herpes zoster (HZ), but there are no recommendations for use in this population. In this single-center prospective observational cohort study, we assessed the safety and reactogenicity of RZV, as well as incidence of graft-versus-host disease (GVHD) and confirmed cases of HZ after vaccination. Between December of 2018 and June of 2020, patients aged ≥18 years received 2 doses of RZV between 9 and 24 months after HCT, with the doses separated by ≥8 weeks. One hundred and fifty-eight patients (mean age, 55 years; 42% women) received ≥1 dose (total vaccinated cohort), and 150 patients (95%) received 2 doses (modified total vaccinated cohort). Solicited reactions occurred in 92.1% of patients (grade 3, 32.5%), owing mostly to injection site pain, which occurred in 86% (grade 3, 16%). The cumulative incidence of GVHD in the peri-vaccination period was no different than in historical controls (adjusted incidence rate ratio, 1.05; 95% confidence interval, 0.8-1.38). There were 4 cases of HZ in the total vaccinated cohort (2.5%) and 3 cases in the modified total vaccinated cohort (28.3/1000 person-years). Among recipients of allogeneic HCT, RZV was safe, tolerable, and did not increase rates of GVHD. Future clinical trials are needed to determine the immunogenicity and efficacy of RZV in this population.

scholarly journals Superior Outcomes with Fludarabine-Busulfan (Flu/Bu) Based Conditioning for Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis - a Comparative Analysis By CIBMTR

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 912-912
Author(s):  
Guru Subramanian Guru Murthy ◽  
Soyoung Kim ◽  
Noel Estrada-Merly ◽  
Ronald M. Sobecks ◽  
Betul Oran ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Unrelated Donor ◽  
Free Survival ◽  
Grade 3

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapeutic modality for patients with myelofibrosis (MF). However, the optimal conditioning regimen for allo-HCT either in the myeloablative conditioning (MAC) or in the reduced intensity conditioning (RIC) setting is not well known. Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified adults aged ≥18 years with MF who underwent allo-HCT between the years 2008-2018. Donor types included matched sibling donor (MSD), 8/8 matched unrelated donor (MUD), and 7/8 MUD. Outcomes were compared separately in the MAC and RIC cohorts based on the most common conditioning regimens used in each setting - MAC [(Fludarabine/Busulfan (Flu/Bu) vs. Busulfan/cyclophosphamide (Bu/Cy)] or RIC [(Flu/Bu vs. Fludarabine/melphalan (Flu/Mel)]. Overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, acute and chronic graft versus host disease (GVHD) and GVHD-free relapse-free survival (GRFS) were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariable regression model included main effect (conditioning regimen) and covariates (patient age, gender, race, CMV match, disease subtype, DIPSS at HCT, comorbidities score (HCT-CI), Karnofsky performance status, prior therapy (ruxolitinib use/splenic radiation therapy/splenectomy), interval between diagnosis and transplant, conditioning intensity, stem cell source, donor-recipient HLA-match, GVHD prophylaxis, ATG/alemtuzumab use, transplant year, and center affect). All analyses were performed at a two-sided significance level of 0.05. Results: Of 872 patients who met the study criteria, 379 patients underwent allo-HCT using MAC (Flu/Bu=247, Bu/Cy=132) and 493 patients using RIC (Flu/Bu=166, Flu/Mel=327). Key baseline characteristics of the patients are summarized in Table 1. In multivariable analysis, significant differences in outcomes were observed in the MAC and RIC setting based on the choice of conditioning regimen (Table 2). In the MAC setting, Bu/Cy was associated with a higher risk of acute GVHD (grade 2-4 HR 2.33, 95% CI 1.67-3.25, p&lt;0.01; grade 3-4 HR 2.31, 95% CI 1.52-3.52, p&lt;0.01) and inferior GRFS (HR 1.94, 95% CI 1.49-2.53, p&lt;0.01) as compared to Flu/Bu. In the RIC setting, Flu/Mel was associated with inferior OS (HR 1.80, 95% CI 1.15-2.81, p&lt;0.01), higher risk of NRM (HR 1.81, 95% CI 1.12-2.91, p=0.01) and acute GVHD (grade 2-4- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade 3-4 HR 2.21, 95%CI 1.28-3.83, p&lt;0.01) as compared to Flu/Bu. These higher risks associated with Flu/Mel were primarily observed early post-transplant. The results were consistent when the outcomes were evaluated based on the two common melphalan doses employed in the RIC setting (100mg/m 2 vs 140mg/m 2). Conclusions: Our study demonstrates that the choice of conditioning regimen significantly influences the outcomes of allo-HCT in MF. The results favor Flu/Bu based conditioning in the MAC (lesser acute GVHD and better GRFS) and RIC (better OS, lower NRM, lower acute GVHD) setting. Hence, this aspect should be explored in future studies as the modification of conditioning strategies could lead to improved outcomes. Figure 1 Figure 1. Disclosures Guru Murthy: TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria; Qessential: Consultancy; Guidepoint: Consultancy; Techspert: Consultancy; Cancerexpertnow: Honoraria. Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saber: Govt. COI: Other.

Comparable Survival and Transplant-Related Mortality Following Allogeneic Hematopoietic Cell Transplantation from HLA Allele-Matched Unrelated and HLA-Identical Sibling Donors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3146-3146 ◽  
Author(s):  
Thai M. Cao ◽  
Schickwann Tsai ◽  
Linda Kelley ◽  
Stephen C. Alder ◽  
Thomas C. Fuller ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
P Value ◽  
Unrelated Donor ◽  
Related Mortality

Abstract Comprehensive analyses of unrelated donor (URD) and recipient HLA-matching for allogeneic hematopoietic cell transplantation (AHCT) have demonstrated better outcomes when allele typing is performed using high-resolution nucleotide sequence-based techniques. To evaluate survival following myeloablative AHCT using allele-level HLA-matched URD as compared with HLA-identical sibling donors, we analyzed outcomes for 430 patients treated at our center between March 1991 and April 2005. Sequence-based allele typing was retrospectively performed for HLA-A, B, C, DR and DQ when not done at time of AHCT for URD (n = 124; 29%) and non-sibling related donors (n = 19; 4%). Donors were HLA-identical siblings (n = 276; 64%), HLA allele-matched URD (n = 52; 12%), single HLA-locus mismatched donors (n = 52; 12%), or > 1 locus mismatched donors (n = 50; 12%). The median age at transplant was 23.4 years (range: 0.2 – 61). The most common diagnoses were AML (n = 107; 25%), CML (n = 90; 21%), ALL (n = 86; 20%) and MDS (n = 50; 12%). Total body irradiation-based preparative regimens were used for 283 patients (66%). Bone marrow (BM) was the graft for 388 patients (90%) and GCSF-mobilized peripheral blood stem cells (PBSC) for the remaining 42 (10%). Graft-versus-host disease (GVHD) prophylaxes were cyclosporine and methotrexate (n = 327; 76%), long methotrexate (n = 42; 10%), T-cell depletion (n = 19; 4%), or other regimens (n = 42; 10%). With a median follow-up of 4.8 years (range: 0.2 – 12.1), the 5-year estimate of overall survival (OS) for the entire group was 48.2% (95% CI: 45.7 – 50.7) and transplant-related mortality (TRM) was 31.4% (95% CI: 28.8 – 34). As shown in the Table, OS and TRM were indistinguishable between AHCT performed with HLA-identical siblings compared with HLA allele-matched URD. There was also no difference in grade III – IV acute GVHD (P = .46) between these two groups whereas there was a trend towards more extensive chronic GVHD (HR 1.8; 95% CI: 0.9 – 3.6; P = 0.12) for the URD recipients. Using a multivariate analysis to adjust for advanced disease, age (> vs ≤ 30 years), graft (BM vs PBSC) and female-to-male gender mismatch, there remained no difference in OS between HLA-identical siblings and HLA allele-matched URD (P = 0.67). These results demonstrate that key outcomes (OS, TRM, and severe acute GVHD) are equivalent in recipients of grafts from either allele-level 10/10 HLA-matched URD or HLA-identical siblings. Overall Survival TRM Number Hazard Ratio 95% CI P value Hazard Ratio95% CI P value HLA-ID Sibling 276 1 - - 1 - - HLA-ID URD 52 1.1 0.7 – 1.7 0.67 0.8 0.4 – 1.6 0.58 1 Locus MM 52 1.3 0.9 – 2.0 0.19 1.4 0.8 – 2.4 0.25 > 1 Locus MM 50 2.0 1.4 – 2.9 < 0.001 2.6 1.7 – 4.1 < 0.001

scholarly journals Pembrolizumab for the Treatment of Disease Relapse Following Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3415-3415 ◽  
Author(s):  
Justin Kline ◽  
Hongtao Liu ◽  
Tallarico Michael ◽  
Andrew S Artz ◽  
James Godfrey ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Myeloid Sarcoma ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Disease Relapse ◽  
Grade 3

Abstract Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD > grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade > 2 toxicity related to pem, or development of > grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

scholarly journals Genetic Associations with Immune-mediated Outcomes after Allogeneic Hematopoietic Cell Transplantation

2022 ◽  
Author(s):  
Paul J. Martin ◽  
David Levine ◽  
Barry E Storer ◽  
Cassandra L. Sather ◽  
Stephen R. Spellman ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Increased Risk ◽  
Recurrent Malignancy

Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (GVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in sub-cohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of acute GVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect correlation with the level of HLA-DPB1 expression previously shown to affect the risks of acute GVHD and relapse in unrelated recipients. Our GWAS identified an association of chronic GVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.

scholarly journals The Prognostic Value of YKL-40 in Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1176-1176
Author(s):  
Brian Kornblit ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R. Spellman ◽  
Xiaochun Zhu ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Prognostic Value ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Plasma Concentrations ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Increased Risk ◽  
Comorbidity Index ◽  
The Impact

Abstract Although allogeneic hematopoietic cell transplantation (HCT) is a treatment option for a variety of malignant hematologic diseases, complications such as graft versus host disease (GVHD), infections and relapse are still major causes of morbidity and mortality. Prognostic scores such as the disease risk index and the HCT comorbidity index have proven useful in predicting relapse and treatment related mortality (TRM). However, to appropriately balance the likelihood of disease control against the risk of debilitating complications, still more accurate pretransplant markers are necessary to predict outcome. YKL-40 (chitinase-3-like-1 (CHI3L1)) is mainly secreted by cancer cells, macrophage and neutrophils. YKL-40 regulates vascular endothelial growth factor and has a role in angiogenesis and inflammation, cell proliferation and differentiation, and remodeling of the extracellular matrix. High plasma YKL-40 levels have been associated with poor prognosis in patients with different types of cancers and inflammatory diseases A previous study in HCT found that YKL-40 >95% age-adjusted level in recipients was associated with relapse and lower disease-free and overall survival. High YKL-40 levels in donors were associated with more grade II-IV acute GVHD. We investigated the prognostic value of pre-transplant plasma YKL-40 in a validation cohort of 784 recipients and donors undergoing allogeneic HCT for acute myeloid leukemia (AML) (n=626) or myelodysplastic syndrome (n=158) (MDS) with 8/8 matched unrelated donors after myeloablative (n=566) or reduced intensity (n=218) conditioning. Transplantations were facilitated through the National Marrow Donor Program (NMDP) and data collection and analysis were performed under the auspices of the Center for International Blood and Marrow Transplant Research (CIBMTR). Samples were provided by the NMDP/CIBMTR and obtained pre-transplant from recipients and prior to mobilization from donors. P<0.05 was considered significant for validation of previous observations. Mean recipient pre-transplant YKL-40 plasma concentrations were elevated in patients with HCT-comorbidity index (CI) scores ≥5 (HCT-CI 0: n=266, 106 (range 20-1446) ng/ml; HCT-CI 1-2: n= 244, 105 (range 20-1176) ng/ml; HCT-CI 3-4: n= 206, 106 (range 20-636) ng/ml; HCT-CI ≥5: n=68, 171 (range 20-4644) ng/ml; p<0.04). There was no difference (p=0.91) in YKL-40 concentrations between recipients with AML (111 (range 20-4644) ng/ml) and MDS (113 (range 20-714) ng/ml). There was no association between recipient YKL-40 concentrations and cytogenetics or AML disease status (first complete remission versus beyond first remission). In addition, MDS YKL-40 concentrations did not significantly increase with successively worse cytogenetics (p=0.67), IPSS (p=0.72) or Karnofsky score (p=0.86). Recipient YKL-40 levels above the age-adjusted 95% percentile were not associated with any outcomes (p>0.198). Donor YKL-40 levels >95% was associated with acute GVHD II-IV (HR 1.39, 95% confidence interval 1.00-1.92, p=0.0466) as observed in the previous study. There was no association between donor YKL-40 and other outcomes. When age-adjusted YKL-40 percentile was used as a continuous variable, recipient and donor pre-transplant elevated YKL-40 were not associated with any outcomes (p>0.088). Analyses were also conducted to investigate the impact of extremely low and high YKL-40 level expression and no associations were observed. In contrast to the prior study no association between recipient pre-transplant YKL-40 concentrations and clinical outcome were observed. However, in agreement with the previous study, donor YKL-40 concentrations were associated with increased acute GVHD, suggesting that donors with a higher degree of inflammation prior to mobilization could increase risk of post transplant complications. However, this did not translate into increased risk of TRM. Although it is not known whether the associations between YKL-40 and outcome are causal or just bystander effects, our observations suggest that an inflammatory biomarker, such as YKL-40, that potentially defines a higher-risk donor population could be a valuable tool complementing clinical risk scores in HCT. In conclusion, age adjusted YKL-40 levels in the donor, but not recipient, were a prognostic indicator for acute GVHD risk in this population. Disclosures No relevant conflicts of interest to declare.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

scholarly journals Poor Outcomes of HLA-Mismatched Allogeneic Hematopoietic Cell Transplantation and High Ferritin Levels after a Reduced-Intensity Conditioning Regimen in Patients with Advanced Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5742-5742
Author(s):  
Han Bi Lee ◽  
Jae-Ho Yoon ◽  
Gi June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Reduced Intensity

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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