Significance of upfront cytoreductive nephrectomy stratified by IMDC risk for metastatic renal cell carcinoma in targeted therapy era – a multi-institutional retrospective study

Background This retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria. Methods We reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method. Results Of 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29–0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11–0.59, p < 0.01). Conclusions Upfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.

Venetoclax Combined with Daunorubicin and Cytarabine (DAV) As Induction Therapy in De Novo Young Adult Acute Myeloid Leukemia

Background: Anthracycline and cytarabine ("3+7") have been the standard induction therapy for acute myeloid leukemia (AML) for almost 4 decades. Only 60%-70% patients can achieve complete remission (CR) with "3+7" induction treatment in de nove AML. The novel induction regimens with higher CR rate are urgent needed. Venetoclax, a b-cell lymphoma 2 (BCL-2) inhibitor combining with hypomethylation agents (HMA) or low dose cytarabine has showed a high response rate and safe in elder AML patients [Dinardo CD, N Engl J Med. 2020; Dinardo CD, Lancet Oncol 2018; Wei AH, J Clin Oncol 2019]. Recently, venetoclax combined with FLAG-IDA induction achieved 90% CR rate in newly diagnosed adult AML (Dinardo CD, J Clin Oncol. 2021). Whether venetoclax combined with standard 3+7 regimen (daunorubicin + cytarabine) as induction therapy can further improve the CR rate in adult AML patients need to be investigated in a well-designed trial. Objective: To evaluate the efficacy and safety of "3+7" (daunorubicin and cytarabine) combined with venetoclax induction regimen (DAV regimen) in young adult patients with de novo AML. Design, setting and participants: Single-arm, prospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (18-60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since December 25, 2020, with final follow-up in July 31,2021. Interventions: Patients were treated with daunorubicin 60mg/m 2 on days 1-3 (d1-3) and cytarabine 100 mg/m 2/d by continuous intravenous infusion daily on d1-7, combined with venetoclax (100mg d4, 200mg d5, 400mg d6-11). Main outcomes and measures: The primary endpoint was the percentage of patients who achieved CR/CR with incomplete count recovery (CRi) after once cycle of DAV regimen. Secondary endpoints included minimal residual disease (MRD), overall survival (OS), event-free survival (EFS) and adverse events. Results: Thirty-two patients were enrolled. Median age was 40 years old (range, 19-59), with poor-risk in 25% (8/32) of patients (European LeukemiaNet 2017 risk). Other characteristics of patients were listed in Table 1. The CR rate were 90.6% (29/32) (Table 1). Seven out eight (87.5%) patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 65.5% (19 out 29) of total patients achieved CR, and 71.4% (5 out 7) of poor-risk patients achieved CR (Table 1). Common adverse events (&gt;30%) included fatigue, nausea, bleeding, febrile neutropenia, infection, neutropenia, anemia and thrombocytopenia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were infection (81.3%), bleeding (28.1%) and mucositis (3.1%) (Table 1). No tumor lysis syndrome was observed. After a median follow-up of 118.5 days, no patient relapsed or died, and 24.1% (7/29) received allogeneic hematopoietic stem-cell transplantation in CR1. Conclusions: The novel combination of "3+7" (daunorubicin and cytarabine) with venetoclax (DAV regimen) was effective and well tolerated in young adult patients with de novo AML, with high CR rate and deep remission. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR2000041509. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Prognosis of Intermediate- and High-Risk Young AML Patients Who Did Not Receive Allo-HSCT Treated with Intensive Chemotherapy Is Not Superior to That of Elderly AML Patients Treated with the D-CAG Regimen

Introduction: AML is an extremely heterogenous disease which poses fundamental challenges in developing effective treatment regimens, while simultaneously highlighting the critical need for more personalized therapy. This investigation explores AML patients who would benefit the most from the relatively low intensive regimen D-CAG or intensive therapy. Methods: A total of 331 patients with AML who were treated with intensive chemotherapy (young patients, n=179) or D-CAG regimen (older patients, n=152) were enrolled in this study.The young patients received IA regimen (idarubicin 10-12 mg/m 2 on days 1 to 3 and cytarabine 100 mg/m 2/d on days 1 to 7) as induction. A total of 37 patients were recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 27 patients were recipients of autologous HSCT. Patients who were unsuitable for HSCT were subjected to post-remission therapy consisting of 2-4 courses of intermediate to high dose cytarabine (cytarabine 2-3 g/m 2 twice daily on days 1-3). The D-CAG regimen (decitabine 15 mg/m 2 intravenously on days 1-5, cytarabine 10 mg/m 2 subcutaneous injection twice daily on days 3-9, aclarubicin 8-10 mg/m 2/d on days 3-6, and G-CSF 300 μg/d for priming until white blood cell count was &gt;20×10 9/L) was given to the older patients. An additional 4-6 cycles of D-CAG were administered to those who achieved CR. Those who failed to obtain CR after two cycles of D-CAG were given the option of palliative care or alternative treatments. None of the patients in this subgroup received allo- or auto-HSCT.Clinical outcomes were retrospectively analyzed for patients belonging to the two treatment arms. Results: The median age was 67 (range, 60 to 86 years) and 36 years (range, 14 to 59 years) in D-CAG and IA cohort, respectively. In the D-CAG cohort, there were significantly more patients demonstrating an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2-3 in contrast to the IA cohort (17.1% vs. 2.2%, P&lt; 0.0001). Conventional cytogenetic examination was conducted in all patients. However, sufficient metaphase data was not available for 15 of these patients. Based on the 2017 ELN cytogenetic risk classification, patients were risk stratified based on the presence of molecular and cytogenetic aberrances upon diagnosis. A total of 114 patients (34.4%) were determined to possess favorable-risk, 106 patients (32.0%) were intermediate-risk and 96 patients (29.0%) were poor-risk. There were significantly more patients in the favorable-risk category and less in the poor-risk category in the IA cohort as in contrast to the D-CAG cohort (favorable-risk: 47.5% vs. 19.1%, P&lt; 0.0001; poor-risk: 21.2% vs. 38.2%, P=0.001). Older patients harbored significantly more complex, monosomal karyotypes and abnormalities in chromosomes 5 and/or 7 (-5/5q- and/or -7/7q-) in comparison to young patients. Clinical features of gender, white blood cell (WBC), hemoglobin and platelet count at diagnosis as well as percentage of blasts in bone marrow, were similar between the two cohorts. Our data revealed that the young patients had significantly better complete remission (CR) rate (80.4% vs.67.1%, P=0.0051) and median overall survival (OS) (38 vs. 15 months, P&lt;0.0001) compared to older patients. However, the objective response rate (ORR) and median OS of the intermediate- and high-risk groups was comparable between older and young patients who were not recipients of allo-HSCT. The median OS was comparable between D-CAG-treated patients with or without FLT3-ITD, DNMT3A, IDH2, TP53 and as well as DNA methylation associated gene mutations, whereas patients treated with intensive therapy who bore these mutations demonstrated markedly lower median OS in contrast to those bore wild-type genes. Individuals with biallelic CEBPA and NRAS mutations were more likely to benefit from intensive chemotherapy regimens. Conclusions: Intensive chemotherapy had little effect on the prognosis of intermediate- or high-risk young patients who did not undergo allo-HSCT. Patients harboring FLT3-ITD, DNMT3A, IDH2, TP53 and DNA methylation associated mutations were found to benefit more from the D-CAG regimen in comparison to intensive chemotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

Introduction A standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range. Methods We performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift. The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients. Results From July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk. For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3]. Conclusions HiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of "fitness," limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Safety and Short-Term Efficacy of Venetoclax Combined with Azacitidine in Acute Myeloid Leukemia: A Single Institution Experience

Introduction The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor (venetoclax) combined with hypomethylating agents (azacitidine) has shown promising activity in patients with acute myeloid leukemia (AML). However, there are no single center real-world research results with relatively large sample size in China. The purpose of this study is to explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven + AZA) in previously untreated patients who were ineligible for standard chemotherapy and patients with relapsed/refractory (R/R) AML in China. Methods A retrospective study was conducted on 60 previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML who received Ven + AZA (venetoclax，100mg D1、200mg D2、400mg D3-28；azacitidine, 75mg/m2 D1-7) in the Peking University Institute of Hematology from March 15, 2019 to May 20, 2021. The incidence of adverse events (AE), complete remission (CR)/CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) and minimal residual disease (MRD) status in patients with different risk stratification and different gene subtypes were analyzed. Results Patient Characteristics The median age was 54 (18-77) years, 33 males (55.0%), and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients who were ineligible for standard chemotherapy and 36 (60.0%) were R/R patients. The median cycles of Ven + AZA in the two groups were both 1 (1-5). The median follow-up time of them were 2.9 (1.5-13.2) and 118 (1.4-26.3) months, respectively. In the previously untreated patients who were ineligible for standard chemotherapy, 2 were over 75 years old, 16 cases were diagnosed with active infection, 6 had organ dysfunction. According to the risk stratification of NCCN, it was divided into 8 cases of favorable-risk, 2 cases of intermediate-risk and 14 cases of poor-risk. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 cases in the poor-risk group (CR to hematological recurrence &lt;18 months, no remission after 1 cycle of therapy, no remission after ≥2 cycles of therapy). Efficacy In the previously untreated patients who were ineligible for standard chemotherapy, after the first cycle of Ven + AZA treatment, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) cases achieved partial remission (PR), and the ORR was 83.3%. Among the CR/CRi patients, 8/17 (47.1%) achieved MRD negative after 2 cycles of therapy. Four patients achieved CR/CRi after the first cycle of Ven + AZA, ineligible factors (active infection) were eliminated, followed by chemotherapy, and MRD achieved negative after 1-2 cycles of consolidation therapy. The median duration of induction therapy in R/R group was 28 (14-28) days, and the total CR/CRi rate was 58.3%. 11/24 (45.8%) cases achieved CR/CRi after one cycle of Ven + AZA in the poor-risk R/R group, and 10/12 (83.3%) cases achieved CR/CRi in the favorable-risk R/R group, which was significantly superior than that in the poor-risk group (P = 0.031). The efficacy in patients with different risk stratification and gene subtypes are displayed in Table. Safety The incidence of hematological AEs was 100%, and the incidence of neutropenic fever was 40.0% (24/60). The incidence of grade 3-4 leukopenia was 86.7% (52/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 leukopenia caused by therapy was 26.7% (16/60). The incidence of grade 3-4 anemia was 71.7% (43/60), of which 51.7% (31/60) occurred before therapy, and the incidence of grade 3-4 anemia caused by therapy was 20.0% (12/60). The incidence of grade 3-4 thrombocytopenia was 76.7% (46/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 thrombocytopenia caused by therapy was 16.7%. The most common non hematological AE was infection, followed by gastrointestinal AE. Infection mainly included pneumonia (13.3%) and soft tissue infection (6.7%), both of which were grade 3-4. Conclusion Ven + AZA has acceptable safety in previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML, can achieve a high response rate, and some patients can achieve MRD negative in China. It is effective in patients with NPM1, IDH1/IDH2 and TP53 positive. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Epidemiologic and Clinical Analysis of Tumor Mutational Burden (TMB) in Acute Myeloid Leukemia (AML): Exome Sequencing Study of the Mayo Clinic AML Epidemiology Cohort (MCAEC)

TMB is used to guide PD-1-directed immunotherapy in solid tumor Oncology. However, it has not been systematically studied in AML, where the focus has been on cytogenetic risk and individual driver gene mutations (GM's). TMB contribution to AML epidemiology is also uncertain. We therefore studied its association with epidemiologic risk factors; driver GM's and somatic mutations (SM's) in AML risk genes which we recently demonstrated (ABCB1; CYP1A1; CYP2B6; EPHX1; ERCC1,2,& 5; MEFV; MTRR; and TERT); clinical and cytogenetic features; and outcome after therapy in the MCAEC, a highly annotated clinical epidemiology cohort of consecutive AML pts [Finn, Cancer Epidemiol 39:1084, 2015]. Methods: We obtained somatic leukemia DNA from remnant diagnostic cytogenetic pellets in 98 MCAEC patients (pts), as previously described [Foran, Blood (2017) 130:570a]. Whole exome sequencing (WES) was performed at depth of ~100 million paired end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Reads were mapped to human genome build hg19 using BWA-MEM. Single nucleotide variants (SNVs) and small INDELs were identified using Mayo Clinic (MC) analytic pipeline GenomeGPS 4.0.1 following Broad GATK variant discovery best practices of alignment, realignment and recalibration, and multi-sample joint genotyping; and filtered using both germline whole exome and genome sequencing of ~1200 MC Biobank samples and public germline variant databases of 1000 genome project, 6500 individuals in exome sequencing project, and HapMap phase 3. Remaining variants were annotated using ANNOVAR, and functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. TMB was defined as the number of functional mutations per Mb of coding region, heterozygous or homozygous. TMB associations with epidemiologic risk, clinical characteristics, and SM's in AML risk genes (listed above) or driver GM's (occurring in 5 or more pts: ASXL1, BCOR, CEBPA, DNMT3A, FLT3, IDH2, KRAS, MLL2-5, NF1, NPM1, NRAS, PHF6, RUNX1, SF3B1, STAG2, TET2, TP53, U2AF1) were evaluated using linear regression models; a rank transformation of TMB was utilized due to its skewed distribution. Multivariable analysis (MVA) models were adjusted for variables with p-value &lt;0.05 in unadjusted analysis. Regression coefficients ("β") were estimated, interpreted as change in mean TMB rank for specified variables or characteristic. Associations with outcomes were examined using logistic regression or Cox proportional hazards regression models. All statistical tests were two-sided (version 3.6.2; R Foundation for Statistical Computing, Vienna, Austria). Results Median age at AML diagnosis was 70 yrs (Range: 19-94 yrs), and 67 pts were male. Cytogenetic risk group was favorable (7%), intermediate-normal (46%) or abnormal (20%), and poor risk (27%). 40/61 pts (66%) achieved complete remission (CR). With a median follow-up of 8.0 months (Range: 0.1 - 186), 80 pts (82%) died and 20 (20%) underwent allogeneic transplantation (AlloBMT). Median TMB was 18.2 (Range: 15.0-70.1). In MVA, significant associations with increased TMB were observed in pts with history of prior immunosuppressive therapy or solid organ transplantation (β=19.48, P=0.015), and with FLT3 (β=21.12, P=0.015), MLL2 (β=20.91, P=0.001), and MLL3 (β=11.31, P=0.031) GM's. A borderline association was observed for U2AF1 (β=16.14, P=0.057). TMB was also associated with SM's in TERT (β=25.13, P=0.028); a borderline association with SM's in ABCB1 was not confirmed in MVA (β=-17.98, P=0.069). Additionally, cytogenetic risk group was associated with TMB in MVA (P=0.005), being highest in intermediate-normal and lowest in poor risk groups. Body Mass Index was inversely associated with TMB (unadjusted β=-16.99, P=0.005), but unconfirmed in MVA (β=-8.29, P=0.12). There was no association with CR (OR=0.93, P=0.46), use of (HR=0.96, P=0.64) or relapse risk (HR=1.00, P=0.98) following AlloBMT, or survival (HR=0.97, P=0.56) (Figure). Conclusions Measurement of TMB is feasible in this AML epidemiologic cohort, and we observed important associations with AML risk factors, risk gene SM's, cytogenetic risk group, and driver GM's. We acknowledge the relatively small sample size and possibility of type II error, and therefore these observations require validation in a large prospective cohort which is planned. Figure 1 Figure 1. Disclosures Foran: OncLive: Honoraria; certara: Honoraria; actinium: Research Funding; boehringer ingelheim: Research Funding; novartis: Honoraria; abbvie: Research Funding; servier: Honoraria; taiho: Honoraria; pfizer: Honoraria; revolution medicine: Honoraria; gamida: Honoraria; takeda: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; syros: Honoraria; aptose: Research Funding; bms: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Genentech: Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration.

Impact of p53 Disruption on AML & HR-MDS Treatment out-Come. a Single Centre Experience

Introduction: Acute myeloid leukaemia (AML) is a heterogeneous disorder that arises from clonal expansion of malignant hematopoietic precursor cells. Somatic mutations of the p53 gene have been reported in 5-10% of AML, with a higher incidence therapy-related disease and elderly patients. Alteration or loss of p53 is one of the most powerful independent indicators of poor outcome. Methods: This is a retrospective analysis of AML & high risk-Myelodysplastic syndrome (HR-MDS) patients treated over the study period (2006-2020). Informed consent was obtained. Initial presentation, treatment response, and survival were analysed. Percentage of p53 expression (a surrogate marker for TP53 mutations) by immunohistochemistry (IHC) (&gt;30% cut-off) on BM trephines was analysed and its impact on treatment outcome was evaluated. Results: We identified 114 patients (AML=104 & HR-MDS=10), the median age was 70 years (Range 36-85) with male predominance (M=73 vs. F=41). The AML group included, 57 patients (50%) with Denovo AML and 47 patients (41%) with Secondary AML (MDS=27, MPN=12 / JAKII mutation =7, t-AML=8). The median age was 70 years (Range 36-85) and the median blast count was 70% (Range 25-95%). Cytogenetic analysis reports were available on 78 patients (75%)(Poor risk=40 vs. Intermediate risk=38). NPM1 (22 patients) and FLT3 mutations analysis (33 patients )were available and reported as positive in 4(18%) and 5(15%) patients respectively. The HR-MDS is defined by patients who fall into higher-risk group categories in the original or revised IPSS (N=10), the median age was 74 years (Range 63-83) with male predominance (M=7 vs. F=3). The median blast count was 15% (Range 11-18%). Cytogenetic risk prognostic subgroup results were available on 6 patients (60%), 2 patients (2%) had intermediate-risk and 4 patients (4%) had poor-risk. Ninety-nine patients (87%) were eligible for treatment, 48 patients (42%) were treated with intensive induction chemotherapy, and 51 patients (45%) received less intensive therapy (HMA / LD-Ara C). Five patients (4%) consolidated with allogeneic stem cell transplant (Allo-SCT) post-induction therapy. The remaining (15 patients) were on supportive care. Forty-one AML patients (36%) relapsed post CR1, 3 patients had Allo-SCT in CR2. Table 1 At the time of study analysis (31/01/2021), 25 patients (22%) are still alive including 23 patients (20%) with AML (Denovo AML=18 & Sec AML=5) and 2 patients (4%) with HR-MDS. The median age of the survival group was 69 years (Range 51-83). The whole study cohort median OS was 12 months. (Figure. 1) The median OS & PFS for AML patients were 15 & 13 months respectively. According to AML sub-type, t-AML associated with shortest median OS of 2.5 months (P.value 0.0190). (Figure. 2) The median OS was more favourable for intermediate-risk than the high-risk cytogenetic AML, 24 and 10 months respectively (P&lt;00016).(Figure. 3) The HR-MDS group median OS was 22 months. One hundred and four patient's BM trephines (91%) were available and screened for p53 IHC expression (AML= 96 & HR-MDS =8). Eight samples (8%) showed p53 over-expression, all these samples with underlying AML diagnosis. The remaining 96 samples (92%) were negative for high p53 expression. The majority of p53 over-expressed AML harboured complex cytogenetics, 4 patients with Sec AML, 3 patients with Denovo AML, and 1 patient with t-AML. Most of the patients (5 patients) in this sub-set had a refractory disease to induction therapy, of whom 2 patients (25%) had Allo-SCT consolidation in CR2. Only one patient (12%) is still alive in this sub-group. The median OS & PFS in p53 wild-type AML cohort was 16 & 13 months respectively, which compared favourably to 12 & 8 months in those with p53 disruptions. The P. values were 0.134 & 0.193, respectively. The impact of the p53 alterations was more pronounced on the AML sub-group treated with intensive chemotherapy (42%), the median OS & PFS in wild-type p53 AML were 24 & 20 months, while in p53 disrupted cohort were 12 & 10 months respectively (P= 0.030)(95%CI of ratio 0.1755 to 1.425) & (P=0.049)( 95%CI of ratio 0.7015 to 5.702).(Figure.4) Conclusion: In this study we demonstrated the potential role for p53 expression by IHC, which is readily available in routine practice, in assessing AML prognosis. Our real-life data confirms the dismal prognosis of p53 alterations in this disease. Participation in clinical trials based on genetic risk stratification is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

AN ASSESSMENT OF PERCEPTION OF WASTE-PICKERS AND RISK-PROTECTIVE BEHAVIOUR FROM SELECTED DUMPSITES IN OGUN STATE NIGERIA

Waste-pickers experience situations which place them at high risk of developing morbidities mainly external and internal injuries. The present study investigated the waste-pickers perception of waste-handling and risk-protective behavior from chosen dumpsites in Ogun State, Nigeria. This study adopted a cross-sectional design and a multi-stage sampling technique, this was used to choose 60 waste-pickers. A structured and validated questionnaire was used for data collection. Data was analyzed using descriptive statistics. Educated waste-pickers had elementary education. The time interval of waste-picking ranged from 1 to 15 years. The majority of the waste-pickers had a poor perception of waste-handling. The majority of the waste-pickers had poor risk-protective behavior. Only 9(15%) reported using personal protective gears every time. The waste-pickers reported that they used the following PPEs; long sleeve shirt 46(22.0%) and trousers 51(24.4%). However, few used trousers 51(24.4%); boot/shoe 43(20.6%) and cap 24(11.5%). Fifty percent of the waste-pickers reported that they washed up after the day’s job. In conclusion, the waste-pickers had poor perception and poor risk-protective behavior. This study recommends that policy makers and charity organizations should educate waste-pickers on the importance of using protective gears and proper waste-handling.

Three-Tier Prognostic Index in Young Adults With Advanced Gastric Cancer

PurposeTo characterize clinical features and identify baseline prognostic factors for survival in young adults with advanced gastric cancer (YAAGC).Materials and MethodsA total of 220 young inpatients (age less than or equal to 40 years) with an initial diagnosis of advanced gastric cancer were retrospectively enrolled in this study.ResultsOf a consecutive cohort of 220 patients with YAAGC, the median overall survival (OS) time was 16.3 months. One-year survival rate was 43.6% (95% CI: 36.5 to 50.7). In this cohort, a female (71.4%, n = 157) predominance and a number of patients with poorly differentiated tumors (95.9%, n = 211) were observed. In the univariate analysis, OS was significantly associated with neutrophil–lymphocyte ratio (NLR) (≥3.12), hypoproteinemia (&lt;40 g/L), presence of peritoneal or bone metastases, and previous gastrectomy of primary tumor or radical gastrectomy. In multivariate Cox regression analysis, hypoproteinemia [hazard ratio (HR) 1.522, 95% CI 1.085 to 2.137, p = 0.015] and high NLR level (HR 1.446, 95% CI 1.022 to 2.047, p = 0.021) were two independent poor prognostic factors, while previous radical gastrectomy was associated with a favorable OS (HR 0.345, 95% CI 0.205 to 0.583, p = 0.000). A three-tier prognostic index was constructed dividing patients into good-, intermediate-, or poor-risk groups. Median OS for good-, intermediate-, and poor-risk groups was 36.43, 17.87, and 11.27 months, respectively.ConclusionsThree prognostic factors were identified, and a three-tier prognostic index was devised. The reported prognostic index may aid clinical decision-making, patient risk stratification, and planning of future clinical studies on YAAGC.