Risk of treatment-related death in carriers of pathogenic DPYD polymorphisms treated with fluoropyrimidine chemotherapy: A systematic review and patient-level analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15132-e15132 ◽  
Author(s):  
Karan Rai ◽  
Bhavina D O Batukbhai ◽  
Gabriel A. Brooks
Keyword(s):  
Systematic Review ◽  
Standard Dose ◽  
Patient Level Data ◽  
Risk Of Death ◽  
Patient Level ◽  
Level Data ◽  
Increased Risk ◽  
Risk Of Treatment ◽  
Treatment Related Mortality ◽  
Related Mortality

e15132 Background: Polymorphisms of the DPYD gene are present in 3-5% of the population and are associated with increased risk for grade ≥3 toxicity during treatment with fluoropyrimidine (FP) chemotherapy. Fatal toxicities in carriers of DPYD polymorphisms have been described in published reports, however reliable estimates of the risk of treatment-related mortality are lacking. Methods: We conducted a systematic review of the MEDLINE database to identify relevant manuscripts published before January 28, 2018. We searched for published studies of patients receiving standard-dose FP chemotherapy (5-fluorouracil or capecitabine) who had pre-treatment testing for ≥1 of 4 pathogenic DPYD polymorphisms (c.1236G > A/HapB3, c.1679T > G, c.1905+1G > A/*2A, and c.2846A > T) and who were systematically assessed for treatment-related toxicities. In the case of retrospective studies, we required that the cohort be defined by pretreatment characteristics (e.g., patients were not included on the basis of observed toxicity). Two reviewers extracted study- and patient-level data, with discrepancies resolved by consensus. The pooled data were analyzed to estimate the risk of treatment-related mortality among polymorphism carriers. Results: Of the 1290 references screened, 37 publications were included in the final analysis. Patient-level data identified 485 of 14,377 patients (3.4%) with pathogenic DPYD polymorphisms. There were 12 deaths among polymorphism carriers, resulting in a 2.5% risk of treatment-related mortality (95% CI 1.3-4.4%). Only 2 treatment-related deaths were reported in 13,892 patients without identified polymorphisms. Risk of death by genotype is shown in the table; two decedents were compound heterozygotes. Conclusions: Patients with pathogenic DPYD polymorphisms who are treated with standard-dose FP chemotherapy are at significant risk of death and can be prospectively identified through pharmacogenetic testing. [Table: see text]

Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2409-2416 ◽  
Author(s):  
Junya Kanda ◽  
Hiroh Saji ◽  
Takahiro Fukuda ◽  
Takeshi Kobayashi ◽  
Koichi Miyamura ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Hla Dr ◽  
Increased Risk ◽  
Related Donor ◽  
Risk Of Treatment ◽  
Standard Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)–matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell–replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P < .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases.

Immune-related acute myocarditis in patients treated with immune checkpoints inhibitors: Systematic review with individual patient-level data meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e24096-e24096
Author(s):  
Alexey Rumyantsev ◽  
Edgar Israelyan ◽  
Alexandra Tyulyandina ◽  
Elena Glazkova ◽  
Yury Sergeev ◽  
...  
Keyword(s):  
Systematic Review ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
High Dose ◽  
Autoimmune Myocarditis ◽  
Patient Level Data ◽  
Nccn Guidelines ◽  
Individual Patient Level ◽  
Patient Level ◽  
Level Data

e24096 Background: Immune checkpoint inhibitors can sometimes lead to fatal outcomes or significant morbidity due to immune-related adverse events (IRAE). Cardiac IRAE, especially myocarditis, are among the most fatal IRAE. There are scarce of the trials addressing the optimal therapeutic approaches for patients with IR-myocarditis. Initial therapy with high-dose steroids (1000 mg of prednisolone for 3-5 days) may be beneficial for many patients with this IRAE and this approach is endorsed by NCCN guidelines. We conducted a systematic review with individual patient-level data meta-analysis of published clinical cases to assess impact of various initial therapeutic modalities and adherence to NCCN guidelines on outcomes of immune-related myocarditis, associated with checkpoint inhibitors. Methods: We searched PubMed database for all full-text articles and abstracts on the treatment of patients with cardiac-related IRAE treated with various PD-1/PD-L1 or CTLA-4 inhibitors for years between 2012 and 2020 in English. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to ensure transparent reporting. Main study inclusion criteria were: 1) morphologically confirmed immune-related myocarditis or highly clinically suspected autoimmune myocarditis (based on Bonaca et al, 2019 criteria); 2) clear association of IRAE and administration of check-point inhibitors; 3) availability of individual patient and treatment data. Pooled analysis of outcomes and multiple logistic regression analysis were conducted. The primary outcome of this study was rate of major cardiac adverse events (MACE) due to immune-related autoimmune myocarditis according to adherence to NCCN guidelines. MACE was defined as death or persisting significant disabilities due to myocarditis (ie, chronic heart failure, rhythm abnormalities or deterioration leading to impossibility of further anticancer treatment). Results: We identified 277 articles and screened them for title and abstract. After the review process we selected 81 studies for further analysis which described treatment course for 111 patients. Overall, 26 and 85 patients were treated with high-dose and non-high dose steroids. Among patients treated high-dose steroids therapy and non-high dose steroids 10 (38.5%) and 57 (67.1%) of patients respectively experienced MACE (HR 0.185; 95% CI 0.07-0.47; p = 0.0091). Initial treatment failure was associated with high rate of morbidity; however, 9 patients were rescued with various immunosuppressive drugs (eg, tacrolimus, alemtuzumab, tocilizumab). Conclusions: Our results support use of high-dose pulse therapy as a preferred therapeutic approach for all patients with suspected or proven immune-related myocarditis.

Conditional Survival and Cause-Specific Mortality in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Hematologic Malignancy Over Three Decades

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 606-606
Author(s):  
Saro H. Armenian ◽  
Can-Lan Sun ◽  
Tabitha Vase ◽  
George Mills ◽  
Liezl Atencio ◽  
...  
Keyword(s):  
General Population ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
Mortality Rates ◽  
Conditional Survival ◽  
Risk Of Death ◽  
Increased Risk ◽  
Risk Of Relapse ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 606 Background: alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT. Methods: From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records. Results: As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table. Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD. Conclusions: The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Exceptional Responders in Oncology: An International Systematic Review and Meta-analysis of Patient Level Data

2019 ◽  
Vol 103 (5) ◽  
pp. E47
Author(s):  
Mackenzie Cummings ◽  
Eric J. Lehrer ◽  
Joseph Drabick ◽  
Niraj Gusani ◽  
Daniel M. Trifiletti ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Patient Level Data ◽  
Patient Level ◽  
Level Data
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