Influence of KIR Genes and HLA Class I Ligands on Overall and Event-Free Survivals after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5509-5509
Author(s):  
Ekaterina G Khamaganova ◽  
Elena N. Parovichnikova ◽  
Larisa A. Kuzmina ◽  
Sergei M Kulikov ◽  
Valeriy G Savchenko
Keyword(s):  
High Risk ◽  
Hla Class I ◽  
Myelogenous Leukemia ◽  
Class I ◽  
Risk Category ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Hla Ligand ◽  
Risk Patients ◽  
Standard Risk

Abstract Acute myelogenous leukemia (AML) is the most sensitive to natural killer (NK)-cell reactivity among blood malignancies treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Function of NK cells is regulated by their inhibitory and activating surface receptors, including killer-cell immunoglobulin-like receptors (KIRs). KIRs with specificity to different HLA class I-encoded ligands seem to play a major role in allorecognition: HLA-C allotypes with asparagine at position 80 (HLA-C1ligands) are recognized by KIR2DL2/3, HLA-C allotypes with lysine at position 80 (HLA-C2 ligands) are recognized by KIR2DL1and KIR2DS1, and HLA-B allotypes with a polymorphic sequence motif at position 77-83 (Bw4 ligands) are recognized by KIR3DL1.There are numerous but sometimes contradictory data about the role of KIR genes and genes of their HLA ligands in outcomes after HLA-identical related and HLA-matched unrelated HCST in patients with AML. The goal of our prospective study was to evaluate the influence of KIR genes and HLA class Iligands on overall survival (OS) and event-free survival (EFS) after allo-HSCT in adult patients with AML. 35 patients with AML (median age 36 years, range 19-60) treated with allogeneic HSCT in our transplant center from HLA-identical related (n=19) and HLA-matched (10/10) unrelated (n=16) donors were included in the study. Median follow-up was 18 months (range, 5-56). The pre-transplantation risk category included standard or high risk. Patients in complete remission 1 (CR1) were categorized as standard risk (n=22), whereas patients in > CR1 were considered as high risk (n=13). In case of HLA-identical related HSCT donor KIR genotyping was performed simultaneously with HLA-typing. In case of HLA-matched unrelated HSCT donor KIR genotyping was performed in time of confirmatory HLA-testing or in day of HSCT. KIR genotyping was done using a PCR-SSP kit (Olerup, Sweden). Overall survival (OS) and event-free survival (EFS) were calculated by Kaplan-Meier method, and compared with log-rank test. OS was defined as survival without lethal event from any cause, EFS was defined as survival in complete remission without lethal event from any cause. The 3-year estimated OS and EFS in all patients were 66 and 43%, respectively. 10 patients died (29%), relapse (hematological and/or molecular) was diagnosed in 18 patients (51%). The pre-transplantation risk category was the main factor affecting OS and EFS after HSCT. The probability of the 3-year OS and EFS for standard-risk patients was 86 and 57%, respectively. Nobody of our patients with high risk lived more than18 months. Conditioning regimen, graft source and donor/patient gender combination had no significant effect on OS and EFS. The patients with unrelated HLA-matched donors had better (not significantly) EFS in comparison with recipients of related HLA-identical grafts (p=0.12). The influence of KIR and HLA- ligand genes on EFS after allo-HSCT was investigated in patients with standard risk. We did not find the immunogenetic factors (presence of B- haplotypes in donors, donor KIR B content, presence of centromeric or telomeric B- motifs in donors, presence of missing HLA ligand for any inhibitory KIR of donor), which significantly affected EFS, but we found two obvious tendencies. The patients with HLA-C1/C1 homozygosity had a tendency to improved EFS compared with patients having either HLA-C1/C2 or HLA-C2/C2 ligands (p=0.09). There was a tendency to better EFS in HLA-C1/x recipients of KIR2DS1 -positive allografts (p=0.09). Our data suggest that KIRs and their HLA class I ligands play role in the graft versus leukemia effect in AML. It seems that HLA-C1 homozygosity improves EFS in patients after allo-HSCT, and KIR2DS 1-positive donors are preferable for HLA-C1/x patients. Disclosures No relevant conflicts of interest to declare.

Donor KIR Tel-B Haplotypes Beneficially Affect Outcome after Allogeneic Stem Cell Transplantation in Patients with Myeloid Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5916-5916
Author(s):  
Ekaterina G Khamaganova ◽  
Elena N. Parovichnikova ◽  
Larisa A Kuzmina ◽  
Sergey M. Kulikov ◽  
Valeri G Savchenko
Keyword(s):  
High Risk ◽  
Nk Cell ◽  
Myelogenous Leukemia ◽  
Gene Content ◽  
Refractory Anemia ◽  
Risk Category ◽  
Myeloid Malignancies ◽  
Risk Patients ◽  
Lethal Event ◽  
Standard Risk

Abstract Introduction. Leukemia relapse after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains a major clinical issue. Myelogenous leukemias are the most sensitive to natural killer (NK)-cell reactivity among blood malignancies treated with allo-HSCT. NK-cell function is controlled by an array of inhibitory and activating receptors, including killer cell immunoglobulin-like receptors (KIRs), whose genes vary in number and content. Inhibitory KIRs recognize the HLA class I ligands and mediate tolerance to self when they encounter self-HLA molecules on putative target cells. HLA-C allotypes with asparagine at position 80 (C1 ligands) are recognized by KIR2DL2/3, HLA-C allotypes with lysine at position 80 (C2 ligands) are recognized by KIR2DL1. HLA-A and –B allotypes with Bw4 motif are recognized by KIR3DL1. The ligands and function of activating KIRs are not well identified with the exception of KIR2DS1which recognizes HLA-C2 ligand group. KIR A haplotypes have simple, fixed gene content; B haplotypes have variable gene content and one or more of the B-specific genes: KIR2DS1, 2, 3, 5 KIR2DL2, KIR2DL5.The KIR locus divides into centromeric (Cen) and telomeric(Tel) regions. In both regions there are two distinctive types of variable KIR gene content motif - Cen-A/Cen-B and Tel-A/Tel-B. The aim of our prospective study was to evaluate the influence of immunogenetic factors (KIRs and their HLA ligands) on the outcome after allo-HSCT in patients with myeloid malignancies. Methods. 29 patients with different clonal myeloid disorders who underwent allo-HSCT in Research Center for Hematology (Moscow, Russian Federation) in 2011-2013 from HLA-identical related (n=19) and HLA-matched unrelated (n=10) donors were included in the study. The pre-transplantation risk category included standard or high risk. Acute myelogenous leukemia (AML) in complete remission 1 (CR1, n=15), chronic myelogenous leukemia (chronic phase 1, n=4), and myelodysplastic syndromes (n=2) classified as refractory anemia/refractory anemia with ringed sideroblasts were categorized as standard risk (n=21), whereas AML > CR1were considered as high risk (n=8). KIR genotyping was performed before allo-HSCT simultaneously with HLA-typing using a PCR-SSP kit (Invitrogen, WI, USA). Overall survival (OS) and event-free survival (EFS) were calculated by the Kaplan-Meier method, and compared with the log-rank test. OS was defined as survival without lethal event from any cause, EFS was defined as survival in complete remission without lethal event from any cause. Results. We found that the 3-year estimated OS and EFS in all patients were 59.7 and 50.0%, respectively. Conditioning regimen and graft source (related or unrelated) had no significant effect on transplant outcome. The pre-transplantation risk category was the main factor influencing survival. The probability of the 3-year OS and EFS for standard-risk patients was 85.7 and 69.0%, respectively; all high-risk patients died during 20 months after allo-HSCT. For standard-risk patients there was better EFS in patients whose donors had KIR Tel-B haplotypes in comparison with patients whose donors had no KIR Tel-B haplotypes (87.5 vs. 58.3%, p=0.08). Standard-risk recipients with HLA-C1/C1 ligands (i.e., C1 epitope present on both HLA-C alleles) had a tendency to an improved EFS compared with patients having either C1/C2 or C2/C2 ligands (88.9 vs. 55.6%, p=0.15). Also there was a tendency to better EFS in patients lacking HLA-Bw4 ligands compared with patients having those ligands (88.9 vs. 55.6%, p=0.15). Conclusions. Our small one single-center prospective study supports the hypothesis about the specific, genetically determined role of NK cell in the graft versus leukemia effect in myeloid malignancies. We suggest that donors having KIR Tel-B haplotypes are preferable for patients with myelogenous leukemias, and selection of the donors with KIR Tel-B haplotypes can improve outcome after allo-HSCT for myelogenous leukemias. Disclosures No relevant conflicts of interest to declare.

scholarly journals Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML

2019 ◽  
Vol 3 (7) ◽  
pp. 1103-1117 ◽  
Author(s):  
Renato Bassan ◽  
Tamara Intermesoli ◽  
Arianna Masciulli ◽  
Chiara Pavoni ◽  
Cristina Boschini ◽  
...  
Keyword(s):  
High Risk ◽  
Odds Ratio ◽  
High Dose Chemotherapy ◽  
Hazard Ratio ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Risk Patients ◽  
Standard Risk

Abstract Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Lack of HLA Class I Ligands for Autologous Inhibitory KIR Is Associated with Improved Survival Following Autologous Stem Cell Transplant for Children with Neuroblastoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3322-3322
Author(s):  
Jeffrey M Venstrom ◽  
Junting Zheng ◽  
Reenat S Hasan ◽  
Karen E Danis ◽  
Irene Y Cheung ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
High Risk ◽  
Nk Cells ◽  
Progression Free Survival ◽  
Hla Class I ◽  
Class I ◽  
Free Survival ◽  
Hla Ligand ◽  
Myeloablative Chemotherapy

Abstract Background: In hematopoietic stem cell transplantation (HSCT) for hematologic malignancies, natural killer (NK) cells contribute to tumor eradication such that leukemia patients lacking the HLA class I ligand for the donor NK inhibitory killer Ig-like receptors (KIR) have lower relapse rates and longer survival. Since myeloablative chemotherapy followed by autologous HSCT (ASCT) improves survival for children with high risk neuroblastoma (a tumor sensitive to NK killing) we hypothesize that NK cells may be active in this setting and that KIR-HLA combinations where the patient lacks HLA class I ligands for autologous KIR may be associated with improved clinical outcomes. Methods: 155 children with high risk neuroblastoma received myeloablative chemotherapy followed by ASCT between 1992 and 2004. Most patients received anti-GD2 antibody 3F8 and 13-cis-retinoic acid following ASCT. HLA and KIR genotyping was performed. Patients were segregated according to those with or without HLA class I ligand for autologous inhibitory KIR. We examined the 3 inhibitory KIR groups with identified class I ligands: KIR2DL2/2DL3, which recognize HLA-CAsn80(HLA-C1 group), KIR2DL1 recognizing HLA-C Lys80(HLA-C2 group), and KIR3DL1 recognizing HLA-Bw4; as well as 6 activating KIR and 2 KIR haplotype groups. Overall survival and progression-free survival were estimated by Kaplan-Meier method and hazard ratios by Cox regression. No adjustments were made for multiple comparisons. Comparisons of each end point were based on the log-rank statistics. Results: 66% of the 155 children lacked at least 1 HLA ligand for his/ her inhibitory KIR. With median followup of 66.8 months, patients lacking a KIR ligand (n=103) had a 45% lower risk of death compared with patients with all HLA ligands present (n=52) (HR 0.55; 95% CI 0.33–0.90; P=0.015). Similarly, for progression-free survival, the risk of relapse or death was 39% lower for patients lacking an HLA ligand for inhibitory KIR (HR 0.61; 95% CI 0.39–0.97; P=0.035). In particular, patients lacking the HLA-C1 ligand for KIR2DL2/2DL3 experienced an overall survival benefit (HR 0.34; 95% CI 0.11–1.09; P=0.060). Activating KIR and KIR haplotypes were not associated with survival. Conclusion: Among children with high risk neuroblastoma undergoing ASCT, improved overall and progression-free survival is associated with the absence of one or more HLA class I ligands for the patient’s NK cell inhibitory KIR receptor. KIRHLA immunogenetics may therefore be a novel genetic indicator of prognosis for patients undergoing ASCT. Mechanistically, these findings imply that NK tolerance is modified after ASCT, and that KIR-HLA genotypes may also play a role in antibodybased immunotherapy, since most of these patients received 3F8 antibody. These findings require confirmation in a larger prospective study. Figure Figure

Outcome of Adult AML at First Relapse Following a Risk-Oriented Strategy: An Update of the Northern Italy Leukemia Group (NILG) Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4385-4385 ◽  
Author(s):  
Irene Cavattoni ◽  
Enrico Morello ◽  
Elena Oldani ◽  
Tamara Intermesoli ◽  
Ernesta Audisio ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Risk Category ◽  
High Dose ◽  
High Risk Patients ◽  
Risk Patients ◽  
First Relapse ◽  
Group 2 ◽  
Standard Risk ◽  
Group 1

Abstract INTRODUCTION The impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) was retrospectively analyzed in 172 patients (patients) with relapsed non-APL AML, who had been initially treated with standard induction and risk-adapatiented consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All 172 patients were at first recurrence following consolidation of CR1 with high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinical-cytogenetic criteria) or allo-SCT in case of high-risk prognostic profile. Median age at relapse was 55 y (range 21–70). CR1 duration was <6 months in 50 patients (29%), ranging from 0.6 to 52,7 mo (median 9,1). High risk patients were 128/172 (74%) and 43/172 patients (25%) had an unfavourable cytogenetics (CG). One hundred-eleven patients (64%) received HiDAC and 24 (14%) an allo-SCT according to study design. RESULTS 140 patients (81%) received salvage treatment. The remaining 32 patients (19%) received palliation and all of them died. The median OS was 17.1 mo, with a 2yOS of 34%. Favorable prognostic factors identified by univariate analisys were: favourable or intermediate CG (p=0,007), standard risk category according to first line protocol (p=0.004), availibility of a HLA matched donor (p= 0.048), achievement of an early CR1(p=0,000), HiDAC as first line therapy(p=0,000), alloHSCT perfomed at relapse (p=0,000) and a DFS from CR1>12 mo (p=0,000). In multivariate analysis favourable or intermediate CG and DFS >12 mo were confirmed as independent prognostic factors (p=0,036 and p=0,001 respectively). Among the 140 patients, 50 received an allo-SCT following relapse (36%, group 1), and the remaining 90 (64%, group 2) received high dose chemotherapy alone (85), autologous SCT (2), or DLI (3, in case of previous alloSCT). Both groups were comparable regarding age >55 y, prior allo-SCT and risk class at diagnosis. After salvage therapy, 44 patients(88%) in the group 1 achieved CR2, compared to 26 patients (29%) in the group 2. The median duration of CR2 was 9 mo (range 2–64) and 3 mo (range 1–34) in group 1 and 2 respectively. NRM was 17/140: 12 patients (24%) in the allo-SCT group and 5 (6%) in group 2. The 2yOS was 57% and 23% respectively (p=0,000). Moreover, among 50 alloSCT patients, survival was affected by risk category at diagnosis: 2yOS of 19 (38%) standard risk patients was 83% compared to 42% in 31 high risk patients (62%) (p=0.01). This risk stratification has no impact on OS in the group 2. CONCLUSIONS DFS > 12 mo and standard risk category at diagnosis, according to NILG protocol, are the most important independent positive prognostic factors impacting OS of AML relapsed patients. The availibility of a HLA matched donor and a subsequent intensification with alloSCT may offer substantial salvage rates and its outcome is affected by the risk stratification at diagnosis. Nevertheless, high risk patients could benefit from alloSCT, reaching an 2yOS of 42%.

Identification of High Risk HLA Class I Amino Acid Substitutions in Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3050-3050
Author(s):  
Susana R Marino ◽  
Sang M Lee ◽  
T Andrew Binkowski ◽  
Michael D Haagenson ◽  
Martin Maiers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Amino Acid ◽  
High Risk ◽  
Hematopoietic Stem Cell ◽  
Deleterious Effect ◽  
Hla Class I ◽  
Class I ◽  
Amino Acid Substitutions ◽  
Hematopoietic Stem ◽  
Clinical Variables

Abstract Abstract 3050 Approximately 30% of Caucasian and 70% of African-American hematopoietic stem cell transplant (HCT) patients are unable to find an 8/8 HLA matched unrelated donor. Mismatches at HLA-A, B, C, or DRB1 alleles reduce survival. Therefore, identification and avoidance of high-risk allele combinations and the associated amino acid substitutions (AAS) that negatively impact HCT outcomes may increase access to this treatment option and allow safer utilization of HLA mismatched donors. Using random forest (RF) analysis, our group has previously reported the AAS associated with 100 day survival (D100S) in single HLA class I mismatched, DRB1 matched recipient-donor pairs. We now extend that analysis to one year outcomes of overall survival (1y OS), disease free survival (1y DFS), transplant related mortality (1y TRM), and acute graft-versus-host disease (aGvHD) grades III-IV using the same clinical variables (recipient age, disease type, disease status, and gender match) and 389 AAS position and types (AASPT). The AASPT were defined by the HLA locus, amino acid position in the HLA class I protein and the actual AAS, e.g. locus: HLA-C, position: 97, type: tryptophan to arginine = C97_WR. Patients (n=2107) received myeloablative (99%) HCT as treatment for ALL, AML, CML, and MDS in early and intermediate stage of disease between 1988 and 2003. RF analysis, a tree-based method for classification was used to assign an importance score (IS), reflecting the association of each potential predictor variable with the outcome of interest. Logistic regression analyses were performed to determine the magnitude of the effect of each individual AASPT (n=600) relative to 8/8 matched cases (n=1507), adjusted for the four clinical variables. Using the criteria of n≥10, a relatively high IS (≥5) and a highly statistically significant odds ratio (p<0.01), C 97_WR has a deleterious effect on all outcomes. HLA-C156_RW has a deleterious effect on all outcomes except on 1y DFS. HLA-C80_NK and C77_SN affects 1y OS and 1y DFS; HLA-C11_SA, C116_YS, and C24_AS affect 1y TRM and aGvHD III-IV. Eighteen additional AASPT were associated with a single outcome each. No AASPT at the HLA -B loci met the above criteria, which could be due to the small number of HLA-B mismatched cases (n=88) compared to HLA-A (n=179) and HLA-C (n=333) mismatched cases. Other AASPT conferred high point estimates of relative risk but the number of patients with a mismatch was too small to yield statistical significance. The most common alleles associated with all of the AASPT listed above are: HLA-C*01:02/02:02; 01:02/15:02; 02:02/01:02; 03:03/04:01; 04:01/16:01; 14:02/15:02; and HLA-A*02:01/02:05; 24:02/24:03; 29:02/30:01; 30:01/30:02; 30:01/32:01. To understand the potential biological significance of mismatched allele pairs in the molecular context of peptide antigen binding, computational models were constructed for the 10 most important AASPT. In silico screening of ∼500 unique peptides was conducted against each pair to determine differences in the peptide repertoire capable of binding to each mismatched molecule. We found that the mismatched pairs identified by RF as less permissive displayed greater loss in their ability to bind identical peptides compared to other mismatches in the binding groove predicted to be more permissive by RF analysis. Overall, the computational modeling suggests a different affinity and peptide binding repertoire between mismatched HLA molecules. Results from these analyses indicate that only a small number (6.4%) of AASPT clearly confer adverse outcomes in HCT patients with single HLA class I mismatched unrelated donors, and it is likely that these AASPT are responsible for differential binding of immunogenic peptides. Validation studies in an independent dataset are in progress. Additional prospective studies should be performed to refine HLA matching algorithms in the mismatched setting that may increase donor availability and minimize the adverse effects of donor HLA mismatching. Disclosures: No relevant conflicts of interest to declare.

scholarly journals LINC-28. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF CHILDREN WITH MEDULLOBLASTOMA TREATED AT THE NATIONAL CANCER INSTITUTE (INCA) IN RIO DE JANEIRO, BRAZIL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii383-iii384
Author(s):  
Gabriela Oigman ◽  
Diana Osorio ◽  
Joseph Stanek ◽  
Jonathan Finlay ◽  
Denizar Vianna ◽  
...  
Keyword(s):  
High Risk ◽  
Maternal Education ◽  
Survival Outcomes ◽  
Middle Income ◽  
Female Ratio ◽  
High Risk Patients ◽  
Presenting Symptoms ◽  
Risk Patients ◽  
Epidemiological Characteristics ◽  
Standard Risk

Abstract BACKGROUND Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according to World Bank, with features of LMIC and HIC. METHODS We conducted a retrospective review of 126 children (0–18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively; overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS The male/female ratio was 1.42 and the median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting (75%) were the most common presenting symptoms. The median time from onset of symptoms to surgery was 50 days. The OS for standard-risk patients was 69% and 53% for high-risk patients. Patients initiating radiation therapy within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived &gt;40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS These findings suggest that socioeconomic factors, education, early diagnosis and continuous data collection, besides oncological treatment must be adressed to improve the survival of children with MB.

scholarly journals 658 An Audit of Frequency of Cancer Genetics Referral in Patients with a Family History of Colorectal Cancer

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
M Abbakar ◽  
T James ◽  
P Boxall ◽  
M Lim
Keyword(s):  
Family History ◽  
High Risk ◽  
Hereditary Cancer ◽  
Risk Category ◽  
Average Risk ◽  
Insufficient Data ◽  
High Risk Patients ◽  
Amsterdam Criteria ◽  
Family History Questionnaire ◽  
Risk Patients

Abstract Introduction Guidelines on the management of hereditary colorectal cancers were updated in 2019. In this study, data from patients within the colonoscopy surveillance programme for hereditary cancer at York Teaching Hospitals Trust were analysed to assess category of risk and appropriateness of referrals to regional geneticists. Method After examination of electronic records and clinical notes, patients were assigned a risk category of average, moderate or high according to the Amsterdam criteria and latest BSG/ACPGBI/UKCGG guidelines. Patients were then assessed to see if a concurrent referral had been made to the regional cancer genetic services. Results There were 228 patients. 72(31.6%) patients were in the average, 81(35.5%) in the moderate and 41(18%) were in the high-risk category. 34 (14.9%) patients with insufficient data and/or assessments were in the indeterminate category. 18 of 72 (25%) patients with average risk were unnecessarily referred to the regional genetics team, while 5/41(12%) of high-risk patients were not. A large proportion of patients with insufficient data (19/34, 55.8%) were rightly or wrongly, referred to the regional genetics team. Conclusions Assessment of hereditary cancer risk is difficult in the absence of good quality information. Risk assessment may be improved with use of a dedicated family history questionnaire/template - this facilitates identification of high-risk patients that benefit most from referral to geneticists.

scholarly journals A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2107-2107
Author(s):  
Christopher R. D'Angelo ◽  
Aric C. Hall ◽  
Kyungmann Kim ◽  
Ryan J. Mattison ◽  
Walter L. Longo ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

Prospective Evaluation of Allogeneic Hematopoietic Stem-Cell Transplantation From Matched Related and Matched Unrelated Donors in Younger Adults With High-Risk Acute Myeloid Leukemia: German-Austrian Trial AMLHD98A

2010 ◽  
Vol 28 (30) ◽  
pp. 4642-4648 ◽  
Author(s):  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
Silja Mack ◽  
Michael Stoppel ◽  
Franz Király ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Younger Adults ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Risk Patients ◽  
Unrelated Donors ◽  
Acute Myeloid

Purpose To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. Results Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. Conclusion Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.

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