scholarly journals Whole Exome Sequencing in Severe Aplastic Anemia Identifies Unrecognized Inherited Subset with Inferior Survival after Hematopoietic Cell Transplant

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 605-605
Author(s):  
Lisa J. McReynolds ◽  
Maryam Rafati ◽  
Youjin Wang ◽  
Bari Ballew ◽  
Valencia Owens ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Research Funding ◽  
Autosomal Recessive ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Survival Difference ◽  
Whole Exome ◽  
Telomere Biology

Abstract Background: It is important to identify inherited bone marrow failure syndromes (IBMFS) in patients with aplastic anemia in order to provide appropriate therapy. IBMFS are diagnosed through genetic or other diagnostic testing but can also go unrecognized, particularly in adults who may lack classic IBMFS features. This is particularly critical in light of increasing identification of individuals with variants of uncertain significance (VUS) and those with single pathogenic variants in an autosomal recessive (AR) gene or X-linked recessive (XLR) gene in females (SPVR) ("carriers") during evaluation. In this study of patients diagnosed with acquired severe aplastic anemia (SAA), we evaluated putatively causal variants in IBMFS genes to determine the frequency of patients with an unrecognized IBMFS or SPVR and assessed their association with outcomes after hematopoietic cell transplant (HCT). Methods: We used pre-HCT blood samples and clinical data from the Transplant Outcomes in Aplastic Anemia study (TOAA; a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research). Germline whole exome sequencing was performed on 732 patients with acquired SAA who received HCT between 1991-2015. A total of 104 IBMFS genes, (51 autosomal dominant (AD), 46 AR, 3 both AR and AD, 4 XLR) were evaluated for both single nucleotide (SNV) and copy number variants (CNV). All variants were curated using ACMG/AMP criteria, and a subset were validated by Sanger sequencing. Variants classified as VUS according to ACMG/AMP criteria and with a damaging score prediction in 3 of 5 in silico meta-predictors were categorized as deleterious VUS. Patients were divided into 3 groups based on known inheritance patterns of identified genes into those with 1) unrecognized IBMFS 2) SPVR or 3) neither (presumed acquired SAA). For telomere biology genes with AD/AR inheritance, we used telomeres <10 th percentile for age (by qPCR) to distinguish IBMFS from SPVR. For statistical analysis, we used the Kaplan-Meier estimator to calculate the probability of overall survival. The log-rank test was used to compare the survival distribution across patient categories. Cox proportional hazard models were used for multivariable analysis. Results: We identified 309 variants of them 156 were pathogenic or likely pathogenic (P/LP) (112 (71.8%) loss of function SNVs, and 10 CNVs), and 153 were deleterious VUS. Patients with deleterious VUS did not have different survival compared with those with no variants, and these were not considered for designating unrecognized IBMFS and SPVR cases Our analysis showed that 6.7% (N=49/732) of patients had variants consistent with an unrecognized IBMFS; 22 were AR (21 compound heterozygous, 1 homozygous), 26 AD and 1 XLR. Approximately half of those patients (22/49, 45%) had P/LP variants in hematopoiesis genes, and 31% in telomere biology genes (Figure 1A). We identified 79 patients with an SPVR, most in SBDS and FANCM. Patients with an unrecognized IBMFS had worse overall survival when compared with patients with presumed acquired SAA (log-rank p=0.0098) (Figure 1B). Multivariable analysis confirmed this association (HR=2.11, 95% confidence interval (CI)=1.38-3.22, p=0.001). The observed survival difference was not mitigated by lower conditioning regimen intensity (HR=2.1, p=0.01 in myeloablative condition (MAC), and HR=2.3, p=0.016, in reduced intensity regimens (RIC)). Patients with an SPVR had no post-HCT survival difference than presumed acquired SAA regardless of conditioning regimen (overall HR=0.96, p=0.85; MAC HR=1.4, p=0.27; RIC HR=0.3, p=0.1). Conclusions: A sizable subset of patients (6.7%) with reported immune mediated acquired SAA had unrecognized inherited disorder and 33% were adults at HCT. Unrecognized IBMFS was associated with statistically significant poorer survival after HCT. In contrast, post-HCT survival in patients with an SPVR ("carriers") was not different than those with acquired SAA. This work underscores the importance of identifying SAA patients with clinically meaningful underlying inherited disorders to enable the use therapeutic approaches to minimize regimen toxicity and late complications. It further highlights that identification of a single pathogenic variant in an autosomal recessive gene or X-linked gene in females and VUS are associated with post-HCT survival similar to acquired SAA. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; JANSSEN: Other; AstraZeneca: Research Funding; Takeda: Research Funding; Novartis: Other: clinical trials, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Incyte: Research Funding.

scholarly journals Impact of TBI-Based Conditioning Regimen on Outcomes of Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplant: Systematic Review and Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4773-4773
Author(s):  
Mudit Dutta ◽  
Rahul Mhaskar ◽  
Hany Elmariah ◽  
Taiga Nishihori ◽  
Bijal Shah ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Inclusion Criteria ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Conditioning Regimens

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation(TBI)-based and chemotherapy only (non-TBI) transplant conditioning regimens have been utilized. But the optimal conditioning regimen for all-HCT in ALL remains unclear. We performed a systematic review to assess the totality of evidence pertaining to the efficacy of TBI-based vs- non-TBI conditioning regimens. Methods: We searched PubMed and Embase databases for all studies comparing TBI-based vs. non-TBI conditioning regimens in patients who received allo-HCT for ALL. Two authors independently reviewed all references for inclusion and extracted data related to overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), relapse, acute- and chronic graft-versus-host disease (GVHD) whenever available. We restricted inclusion criteria to studies published only as peer-reviewed manuscripts which included ALL only patients (both T-ALL and B-ALL) who received a myeloablative conditioning; pediatric only studies were excluded. We also assessed outcomes in subgroups of patients 16 years of age and older which were majority of the included studies. Results: Seven studies were included in the final analysis that met our inclusion criteria. The quality assessment rating for each study was good based on its study type. The results for all patients in these observational studies revealed that TBI-based regimen was significantly favorable (all p<.05) to non-TBI conditioning regimen with regards to OS (HR=0.74, 95% CI [0.62, 0.88], 6 studies, 4300 patients), PFS (HR=0.72, 95% CI [0.61, 0.85], 6 studies, 4300 patients), and relapse (RR=0.73, 95% CI [0.61, 0.86], 5 studies, 4664 patients). The TBI-based regimen did not increase (all p>.05) the risks of NRM (RR=1.09, 95% CI [0.75, 1.58], 6 studies, 4251 patients), grade II-IV acute GVHD (RR=1.11, 95% CI [0.90, 1.36], 5 studies, 4725 patients) or grade III-IV acute GVHD (RR=1.20, 95% CI [0.89, 1.63], 2 studies, 3248 patients). However, TBI-based regimen increased the risk of chronic GVHD (RR=1.12, 95% CI [1.02, 1.23], 5 studies, 4219 patients). Subgroup comparison of patients 16 years of age and older (range 16-70) showed similar results as shown in Table 1a-d. Conclusion: This meta-analysis represents evidence supporting the use of TBI-based conditioning regimens for allo-HCT in patients with ALL as it offers significantly lower risk of relapse and better survival yet acceptable NRM as compared to non-TBI regimens. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bejanyan:Kiadis Pharma: Other: advisory board.

Pretransplant Factors That Influence Intravenous Busulfan Kinetics in Adult Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3350-3350
Author(s):  
Ali McBride ◽  
Karen Fancher ◽  
Jongphil Kim ◽  
Donn Davis ◽  
Michelle Conwell ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasma Concentrations ◽  
Multivariable Analysis ◽  
Population Based ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Time Curve ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Concurrent Use ◽  
Artery Disease

Abstract Abstract 3350 Poster Board III-238 We performed a retrospective review of intravenous busulfan (Bu) pharmacokinetic (PK) parameters and pretransplant characteristics on patient receiving Bu and fludarabine (40mg/m2/day x 4) (BuFlu) prior to allogeneic hematopoietic cell transplant (HCT) in order to determine the predictive value of pretransplant characteristics on Bu area under the concentration time curve (AUC). Included in this analysis are 265 pts transplanted between 7/04 and 12/08 who received 130 or 145mg/m2/day for 2 doses then had doses 3 and 4 adjusted based on first dose PK parameters (from 5 plasma concentrations) to achieve a target AUC of 5300 micromole*min/L. Pretransplant variables collected included: gender, age, ethnicity, height, actual body weight (ABW), body surface area (BSA), body mass index (BMI), underlying diseases states (hypertension, diabetes mellitus, coronary artery disease and liver disease), transplant diagnoses, prior chemotherapy, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), serum creatinine (SCr), measured creatinine clearance (CrCl) and concomitant medications administered up to 24 hours prior to first Bu dose. Median first dose AUC was 5252 micromole*min/L (2633-21400 micromole*min/L). Univariable and multivariable analyses were utilized to identify prognostic factors that may affect AUC levels based on first dose kinetics. In univariable analyses, BMI and CrCl were negatively correlated with Bu AUC while AST and SCr were positively correlated. In addition, the use of azole antifungals, metronidazole proton pump inhibitors, doxycycline, and choice of antiseizure prophylactic medication also had a significant effect on Bu AUC. Multivariable analysis demonstrated BMI and CrCl were negatively associated with AUC (p=0.008 and 0.005, respectively) while AST was positively associated (p=0.035). The use of fluconazole, metronidazole and doxycyline was associated with higher AUCs (p=0.011, 0.021, and 0.004, respectively) while concurrent use of voriconazole was associated with lower AUC (p=0.011). Based on these data, pts with large BMI, increased CrCl, or on concomitant voriconazole may require larger doses of busulfan to achieve a target AUC whereas pts with an elevated AST or taking fluconazole, metronidazole and doxycyline may require less. In order to validate these findings, we are developing a population based dosing model that will require testing in a prospective pt sample. Disclosures: Field: PDL BioPharma: Research Funding. Perkins:PDL BioPharma: Research Funding. Off Label Use: IV busulfan and fludarabine for pretransplant conditioning.

Analysis of Impact of Comorbidities Constituting the HCT-CI Score on the Outcome of Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3201-3201
Author(s):  
Fotios V. Michelis ◽  
Hans A. Messner ◽  
Naheed Alam ◽  
Vikas Gupta ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
P Value ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Cardiac Disorder

Abstract The Hematopoietic Cell Transplant Co-morbidity Index (HCT-CI, Sorror et al 2005) was developed as a prognostic tool for overall survival (OS) and non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (HCT) patients. The prognostic significance of the score for patients with acute myeloid leukemia (AML) undergoing HCT has been demonstrated, however reports are conflicting. The purpose of this single-center study was to retrospectively investigate the prognostic impact of the individual component co-morbidities of the HCT-CI on the outcome of 418 patients that underwent HCT for AML at our center between 2000 and 2013. Patients underwent HCT in first (CR1, n=303) and second (CR2, n=115) complete remission. Median age at HCT was 50 years (range 18-71), 212 (51%) patients were female. Myeloablative conditioning (MAC) was used in 283 (68%) patients, reduced-intensity (RIC) in 135 (32%) patients. Donors were related for 236 (56%) patients, unrelated for 182 (44%) patients. Grafts were peripheral blood stem cells (PBSC) in 339 (81%) patients and bone marrow in 79 (19%) patients. Median follow-up of patients alive was 62 months (range 12-168). Cytogenetics at diagnosis were available for 84% of patients, of which 31 (7%) were favorable, 246 (59%) were intermediate and 74 (18%) were unfavorable risk (MRC classification). HCT-CI scores were grouped as 0 (n=109, 26%), 1-2 (n=157, 38%) and ≥3 (n=152, 36%). A total of 171 patients (41%) underwent HCT during the years 2000-2006 and 247 patients (59%) during the years 2007-2013. The observed frequency of the co-morbidities composing the HCT-CI is summarized in Table 1. Univariate analysis for OS demonstrated the following significant variables: Age (HR=1.02, 95%CI=1.01-1.03, p=0.0002), CR status (HR=1.42 for CR2, 95%CI=1.08-1.87, P=0.01), donor type (HR=0.73 for related, 95%CI=0.57-0.94, p=0.02), HCT-CI group (overall p-value=0.004). For OS, univariate analysis of the impact of individual co-morbidities was performed for the components of the HCT-CI score that were observed in ≥5% of the patients (Table 1). All variables with a p-value ≤0.2 were introduced into the multivariable analysis (not including the HCT-CI itself), and these included cardiac disorder (CAD, CHF, MI or EF≤50%) (HR=1.65, 95%CI=1.17-2.32, p=0.004), prior solid tumor (HR=1.56, 95%CI=1.06-2.30, p=0.02) and diabetes (HR=1.40, 95%CI=0.89-2.19, p=0.14). In the multivariable analysis for OS, none of the aforementioned co-morbidities demonstrated independent prognostic relevance. For NRM, univariate analysis demonstrated cardiac disorder (HR=1.89, 95%CI=1.27-2.81, p=0.002), diabetes (HR=1.94, 95%CI=1.20-3.12, p=0.007) and moderate pulmonary (FEV1 and/or DLCO 66-80% or dyspnea on slight activity) (HR=1.31, 95%CI=0.93-1.84, p=0.12) to meet the significance criteria for inclusion in the multivariable analysis, which finally demonstrated diabetes (HR=2.17, 95%CI=1.31-3.60, p=0.003) and cardiac disorder (HR=1.78, 95%CI=1.15-2.76, p=0.01) to be independent predictors of NRM post-transplant. In conclusion, among the pre-transplant co-morbidities included in the HCT-CI, diabetes and cardiac dysfunction are independent prognostic indicators for NRM but not for OS. Pulmonary dysfunction does not seem to negatively influence outcomes in this cohort of patients. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

5-Day Decitabine with Mini Fludarabine and Busulfan Yields Comparable Outcomes to Mini Flu/Bu but with Increased Incidence of Severe Acute GvHD

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3422-3422
Author(s):  
Melissa Baker ◽  
Tracy Andrews ◽  
Scott D. Rowley ◽  
Andrew L. Pecora ◽  
Alan P Skarbnik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Advisory Committees ◽  
Disease Response

Abstract Background: Studies have shown that hypomethylating agents (HMAs), including 5-AZA and decitabine (Dac) are well-tolerated antileukemic agents (Kantarjian et al, JCO, 2012). Despite its myelosuppressive effect, Dac has low extramedullary toxicities, making it an attractive drug for allogeneic hematopoietic cell transplant (HCT). Reports suggest that HMAs selectively upregulate tumor associated antigens (TAAs) on malignant cells without expression in healthy tissue (Cruijsen, 2016). We previously reported on a series of 20 patients (pts) in a phase I study of 5-day Dac plus mini fludarabine and busulfan (DacMiniFluBu) in elderly or medically infirm pts (Baker et al, Blood, 2012). In the current analysis, we compared updated results from our DacFluBu study with a historical MiniFluBu control group in pts with MDS or AML. Methods: Pts were evaluated to assess engraftment, toxicity, disease response, PFS and OS. Pts received Dac 20 mg/m2/day on days (d) -15 to -11, Flu 30 mg/m2/day, on d -7 to -3 and Bu 130 mg/m2 on d -4 and -3. The control group received Flu 30 mg/m2 on d -6 to -2 and Bu 130 mg/m2 on d -3 and -2. Both groups received thymoglobulin 2 mg/kg IV on d -3, -2 and -1, followed by infusion of donor stem cells on d 0. Immunosuppression consisted of tacrolimus starting on d -2 and MTX 5 mg/m2 IV on d +1, 3, 6, and 11. Results: 107 pts were analyzed between 5/2009 and 8/2015; 36 pts received DacMiniFluBu; 17 with MDS, and 19 with AML. 23 (64%) had unrelated donors (URD); 13 (36%) had sibling donors. 71 pts were included in the MiniFluBu control group for comparison; 33 with MDS, and 38 with AML. 53 (75%) had URD; 18 (25%) had sibling donors. Median age was 68.5 yrs compared to 66 yrs, respectively. Cohorts were comparable for gender, disease and graft source. The incidence of severe (gr III/IV) acute GVHD (aGvHD) was 22% compared to the control group of 6% (p=0.0195). Moderate or severe cGVHD was seen in 7 pts vs 22 in the control group (p=0.2535). The median follow-up in the DacMiniFluBu group was 262 d, OS was 35%, relapse incidence was 28%, and NRM at 6 mos was 22%. In the control group, the median follow-up was 424 d (p=0.2213), OS was 34%, relapse was 41%, and NRM was 15%. Median time to relapse in the study vs control group was 142 and 149 d (p=0.8722). There were 22 deaths after DacMiniFluBu and 43 after MiniFluBu (p=0.7382). 6 pts in the study group received DLI at a median of 170 d post HCT for either relapse (n=3) or falling chimerism (n=3) compared to 16 pts in the control group at a median of 183 d. Multivariate analysis was performed to estimate the cumulative incidence of severe aGvHD by regimen. Results showed that conditioning regimen (HR=3.98, 95% CI, p=0.0197), degree of match (HR=1.365, p=0.039) and non-hematologic (heme) gr IV events (HR= 4.266, p=0.029) were all significant independent factors predicting a higher incidence of severe aGvHD. Conclusions: There were no significant differences in the cumulative incidences of relapse or survival between pts receiving DacMiniFluBu and MiniFluBu. However, the risk of severe aGvHD was 4 times greater in DacMiniFluBu recipients when controlling for infections, degree of match, and non-heme gr IV events. Findings were confirmed in univariate and multivariate analyses. This may be explained by the increased expression of TAAs in healthy tissues in response to Dac, which evoke T cell responses. This is the first report showing that adding Dac to the MiniFluBu regimen was an independent risk factor for severe aGvHD. Other findings in our analysis linking age, risk stratification, and degree of match to GvHD are consistent with prior reports. The differences between our results and those of other studies warrant larger validation analyses. Dac as part of a conditioning regimen should only be used in context of a clinical trial. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Skarbnik: Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau.

scholarly journals Impact of conditioning regimen on peripheral blood hematopoietic cell transplant

2019 ◽  
Vol 10 (2) ◽  
pp. 86-97
Author(s):  
Michael Burns ◽  
Anurag K Singh ◽  
Carrie C Hoefer ◽  
Yali Zhang ◽  
Paul K Wallace ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

scholarly journals Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity

2018 ◽  
Vol 2 (16) ◽  
pp. 2095-2103 ◽  
Author(s):  
Mary Eapen ◽  
Ruta Brazauskas ◽  
Michael Hemmer ◽  
Waleska S. Perez ◽  
Patricia Steinert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Clinical Remission ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Key Points ◽  
Acute Myeloid

Key Points Bu4/Cy, Flu/Bu4, and Flu/Mel are optimal regimens for patients with AML in clinical remission or those with MDS. Flu/Mel, considered a less-intense regimen, is ideal for less fit patients.

scholarly journals Impact of donor age and kinship on clinical outcomes after T-cell–replete haploidentical transplantation with PT-Cy

2020 ◽  
Vol 4 (16) ◽  
pp. 3900-3912 ◽  
Author(s):  
Jacopo Mariotti ◽  
Anna Maria Raiola ◽  
Andrea Evangelista ◽  
Angelo Michele Carella ◽  
Massimo Martino ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Clinical Outcomes ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Cell Transplant ◽  
Donor Age ◽  
Hematopoietic Cell Transplant ◽  
The Impact ◽  
Risk Of Relapse

Abstract Donor selection contributes to improve clinical outcomes of T-cell–replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P &lt; .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index &gt;3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

Association of Iron Overload with Survival and Complications in Allogeneic Hematopoietic Cell Transplant Recipients: Prospective Cohort Study Using R2-MRI Measured Liver Iron Content

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1961-1961
Author(s):  
Bryan J Trottier ◽  
Todd E. Defor ◽  
Linda J Burns ◽  
Sarah Cooley ◽  
Navneet S. Majhail
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Liver Iron ◽  
Allogeneic Hct ◽  
Liver Iron Content ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 1961 Elevated pre-transplant ferritin levels have been associated with increased mortality and transplant-related complications in hematopoietic cell transplant (HCT) recipients. However, attempts to define the impact of iron overload on transplant outcomes using ferritin are confounded by its lack of specificity. Using liver magnetic resonance imaging (R2-MRI) to quantify liver iron content (LIC), we designed a prospective cohort study to determine the impact of iron overload on outcomes following allogeneic HCT. Our primary study objective was to determine the impact of pre-transplant iron overload on overall survival (OS); secondary objectives included cumulative incidence of non-relapse mortality (NRM) and post-HCT complications. Adult patients with hematologic malignancies being considered for allogeneic HCT were recruited for this study. Enrolled patients underwent baseline, pre-transplant ferritin measurements; patients with ferritin levels > 500 ng/ml had LIC quantified using liver R2-MRI. Patients were defined as no-iron overload (ferritin ≤ 500 or LIC ≤ 1.8 mg/gdw) and iron overload (LIC > 1.8). Of the 112 patients recruited for the study, 24 were excluded (disease progression=12, unable to complete MRI=9, transplant delays due to pre-HCT complications=3) and 88 were included in the final analysis (no-iron overload=28, iron overload=60). Four patients had ferritin >500, but on MRI had LIC ≤ 1.8 and were included in the no-iron overload group. Median ferritin in the two groups was 290 (range, 52–2023) and 1732 (range, 510–7137), respectively. The median LIC in the iron overload group was 4.3 (range, 1.9–25.4). Baseline ferritin moderately correlated with LIC (Spearman's R=0.58). There was no significant difference in recipient age, conditioning intensity, graft source, or HCT comorbidity index scores between the two groups. Patients with iron overload were more likely to have acute leukemia (55% vs 15%) and less likely to have high risk disease (40 vs 75%). We observed no significant difference in OS, NRM, relapse, acute or chronic graft-versus-host disease, organ failure, bacterial infections, viral infections, or fungal infections among patients without and with iron overload (see Table). We also found no difference in the composite endpoint of NRM, any infection, organ failure or hepatic veno-occlusive disease (1 yr cumulative incidence 71% vs 80%, P=0.44). In multivariate analyses that adjusted for other important prognostic variables, iron overload status did not impact risks of overall mortality (relative risk 2.3 (0.9–5.9) for iron overload vs. no-iron overload). We also evaluated outcomes based on an LIC threshold of ≤ 5 vs > 5 and observed similar results (see Table). Immune reconstitution studies were done in 55 patients at 3, 6 and/or 12 months post-HCT (no-iron overload=19, iron overload=36). On generalized linear mixed modeling, presence of iron overload was not associated with delay in recovery of absolute lymphocyte count, total NK cells, total T cells, CD4 cells, CD8 cells, or regulatory T cells. In conclusion, we did not find an association between pre-transplant iron-overload defined by R2-MRI measured LIC and OS, NRM, complications or immune reconstitution after allogeneic HCT in adults. Pre-transplant ferritin levels only moderately correlated with LIC. Future studies of iron overload in HCT should consider LIC to define iron overload instead of ferritin. Table. Outcomes by Iron-Overload Status Prob (95% CI) Prob (95% CI) P-value Ferritin ≤ 500 or LIC ≤ 1.8 LIC > 1.8 N 28 60 2 yr OS 78% (57–90) 58% (44–70) 0.12 2 yr NRM 18% (4–33) 21% (10–32) 0.91 1 yr Bacterial Infection 11% (0–22) 13% (5–22) 0.72 1 yr Fungal Infection 7% (0–17) 12% (4–20) 0.49 LIC ≤ 5.0 LIC > 5.0 N 65 23 2 yr OS 62% (49–73) 73% (49–87) 0.42 2 yr NRM 20% (10–30) 19% (3–35) 0.82 1 yr Bacterial Infection 12% (4–20) 13% (0–27) 0.98 1 yr Fungal Infection 12% (4–20) 4% (0–12) 0.28 Disclosures: Burns: Novartis Pharmaceuticals: Research Funding. Majhail:Novartis Pharmaceuticals: Research Funding.

Activity and Tolerability of Azacitidine in Patients Who Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS): a Survey from the European Society for Blood and Marrow Transplantation (EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2506-2506 ◽  
Author(s):  
Charles Craddock ◽  
Myriam Labopin ◽  
Mohamed Houhou ◽  
Marie Robin ◽  
Juergen Finke ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Unrelated Donor ◽  
Disease Relapse ◽  
Post Transplant ◽  
Significant Difference ◽  
Grade 3

Abstract Disease relapse is the most common cause of treatment failure after allo-SCT for high risk AML and MDS. Treatment options for patients with recurrent disease are extremely limited and re-induction chemotherapy, when administered, is often either poorly tolerated or ineffective. Azacitidine (AZA) is a DNMT inhibitor which is well tolerated and clinically active in high risk AML/MDS. Of interest AZA also up-regulates the expression of tumor antigens and plausibly augments a graft-versus-leukemia effect. A number of small studies have suggested clinical activity of AZA in patients who relapse after an allograft for AML/MDS but both overall response rate and predictors of response remain unknown. We report the first systematic study of the activity and tolerability of AZA in patients who relapsed after allo-SCT for AML/MDS. 204 patients who relapsed at a median of 6.5 months (range, 1-49) after an allograft for AML (n=130) or MDS (n=74) were studied. The median age was 58 years (range 22-76). 89 patients were transplanted using a matched sibling donor and 115 from an adult unrelated donor. 47 patients received a myeloablative and 157 a reduced intensity conditioning regimen. AZA was administered for 5-7 consecutive days every month. The median duration of AZA treatment was 68 days (inter-quartile range 24-154 days). 66 patients received additional donor lymphocyte infusions (DLI) at a median of 43 days after commencement of AZA. AZA was well tolerated in the majority of patients. 57 patients developed Grade 3-4 non-hematological toxicities 47 of which were infectious complications and likely also attributable to relapsed disease. 4 patients developed Grade 3-4 acute GVHD after AZA treatment. 45 (22%) patients achieved a complete remission (CR) or partial remission after AZA administration at a median of 114 days after commencement of treatment. 31 (15%) patients achieved a CR. The median number of courses of AZA to achieve a clinical response was three. In multivariable analysis the only significant factor determining improved response to AZA was relapse occurring more than 12 months post-transplant. The median overall survival (OS) for all patients was 6 months after the commencement of AZA therapy. In patients who achieved a CR the 2 year OS after commencement of AZA was 38.5% versus 11% for the whole population (p= 0.001). In multivariable analysis OS was determined by the occurrence of disease relapse more than 6 months post-transplant and achievement of a CR after AZA therapy. Of note, there was no significant difference in response rates to AZA between patients with relapsed AML or MDS. Concurrent administration of DLI did not improve either response or survival rates. In conclusion, these data confirm the ability of AZA to salvage a proportion of patients with AML or MDS who relapse after an allogeneic SCT and identify prognostic factors of response. The response and survival rates achieved with salvage AZA are comparable to those previously reported with either intensive chemotherapy or DLI. We conclude AZA represents an important and relatively well-tolerated new treatment option in the management of selected patients with AML and MDS who relapse after allo-SCT. Disclosures Craddock: Celgene: Grants Other, Honoraria. Kroger:Celgene: Research Funding. Mohty:Celgene: Research Funding.

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