Poor Risk Group Research Articles

International Metabolic Prognostic Index Is Superior to Other Metabolic Tumor Volume-Based Prognostication Methods in a Real-Life Cohort of Diffuse Large B-Cell Lymphoma.

Baseline metabolic tumor volume (MTV) is a promising prognostic marker in diffuse large B-cell lymphoma (DLBCL). We assessed the prognostic value of 4 novel metabolic risk scores in a real-life DLBCL cohort and compared them with the revised international prognostic index (IPI). Methods: We included a consecutive series of untreated DLBCL, not otherwise specified cases that were diagnosed in our hospital from 2008 to 2021 with available baseline [18F]FDG PET/CT. Clinical data were collected retrospectively, including the individual components of the revised IPI. MTV and other radiomic features, including lesion dissemination and tumor volume surface ratio, were calculated. Four novel metabolic risk scores including the international metabolic prognostic index (IMPI), the MTV/World Health Organization performance status, the MTV/standardized maximum distance, and clinical PET models were used to calculate the risk of progression using predefined cutoffs. Survival outcomes considered were 3-y progression free survival (PFS), 3-y time to progression (TTP), and 3-y overall survival (OS). The Harrell C-index was used to assess the discriminative performance of the risk scores. A multivariable model was built. Results: We included 355 DLBCL, not otherwise specified cases with a median MTV of 219 cm3 (range, 0-5,656 cm3). The IMPI had the highest C-index for 3-y PFS, 3-y TTP, and 3-y OS among the 4 metabolic risk scores (0.674, 0.696, and 0.677, respectively). For the 3-y TTP, the IMPI outperformed the strongest clinical risk score, the IPI, although the difference in the Harrell C-indices was small (0.696 vs. 0.693). Regarding the 3-y PFS and 3-y OS, the IPI has the highest C-index of all risk scores (0.696 and 0.693). The IMPI, the MTV/World Health Organization performance status, and the IPI score can recognize a poor risk group with a 3-y OS below 50% (43%, 32%, and 39%, respectively). In multivariable analysis, the IMPI remains an independent prognostic factor (P = 0.0089; hazard ratio, 1.207; 95% CI, 1.048-1.389). MTV and standardized maximum distance have the strongest prognostic values when used as a continuous variable. The tumor volume surface ratio has no significant prognostic value in our analysis. Conclusion: The IMPI has the strongest prognostic performance compared with the other 3 novel metabolic risk scores. However, in our real-world dataset, the IMPI could not replace the IPI, and further prospective trials are needed to compare their performance.

Efficacy and safety of lenvatinib and pembrolizumab as first-line treatment for advanced renal cell carcinoma patients: real-world experience in Japan.

Combined treatment with lenvatinib and pembrolizumab is currently regarded as one of the standard first-line therapies for advanced renal cell carcinoma (aRCC) patients. The objective of this study was to assess the efficacy and safety of this combined regimen in treatment-naïve Japanese aRCC patients. This study included a total of 50 consecutive aRCC patients receiving combined lenvatinib plus pembrolizumab in routine clinical practice in Japan, and comprehensively analyzed clinical outcomes of this treatment. Of these 50, 7 (14.0%), 23 (46.0%) and 20 (40.0%) were classified into favorable, intermediate and poor risk groups, respectively, according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) system. Responses to this combined therapy in the 50 patients were as follows: complete response, 7 (14.0%); partial response, 26 (52.0%); stable disease, 15 (30%) and progressive disease, 2 (4%); thus, the objective response rate (ORR) was 66%. ORRs in favorable, intermediate and poor risk groups were 57.1, 69.6 and 65.0%, respectively. During the observation period, disease progression and death occurred in 14 (28.0%) and 6 (12.0%) patients, respectively, and neither the median PFS nor OS was reached. Adverse events and those corresponding to grade ≥ 3 were observed in all (100%) and 33 (66.0%) patients, respectively. To our knowledge, this is the first study focusing on real-world outcomes of lenvatinib and pembrolizumab for treatment-naïve aRCC patients, showing that the efficacy and safety of this combined regimen are similar to those noted in randomized clinical trial.

Scoring System to Personalize Management of Emphysematous Pyelonephritis.

Emphysematous pyelonephritis (EPN) is a life-threatening condition that requires prompt diagnosis and treatment. The prognosis of EPN is variable, and there is no single treatment that is universally effective. In this study, we developed a scoring system to predict the prognosis of EPN and to guide management. The scoring system was developed based on a retrospective analysis of 91 patients with EPN. Nineteen risk factors for emphysematous pyelonephritis were assessed with univariate and multivariate analysis. Seven factors were found significant on analysis. The scoring system was developed by including these 7 risk factors: renal stone disease, leukocytosis, raised creatinine, EPN grade, and septic shock. The score ranged from 1 to 18, with a higher score indicating a worse prognosis. The scoring system was able to stratify patients into three risk groups: good risk, intermediate risk, and poor risk. The scoring system can be used to personalize the management of EPN. Patients in the good-risk group may be managed with conservative treatment, while patients in the intermediate-risk and poor-risk groups may require intervention, such as DJ stenting, percutaneous nephrolithotomy or nephrectomy. The scoring system is a valuable tool for predicting the prognosis of EPN and guiding management. It can help clinicians to tailor treatment to the individual patient and to improve outcomes. The prognostic score helps identify patients who are at high risk. This score helps in the selection of appropriate management options.

Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy.

To develop and validate a prognostic risk model for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with upfront abiraterone acetate (ABI). This retrospective multicenter study involved 233 high-risk mHSPC patients who received upfront ABI, developed by three academic centers. The model was externally validated with an independent cohort of 282 patients. To identify independent prognostic factors for second progression-free survival (PFS2) and develop the best-fitted model, Cox proportional hazards regression, followed by the Akaike information criterion, was used. Patients were categorized into three groups based on their risk scores. PFS2 and overall survival (OS) were evaluated according to the risk groups in the discovery and validation cohorts. The median age was 72 (range 51-89) years, with a median follow-up duration of 27 months. Independent factors linked to PFS2 included an Eastern Cooperative Oncology Group performance status ≥2, a primary Gleason score of 5, an extent of disease score of ≥3 or liver metastasis, and lactate dehydrogenase >220 U/L. Median PFS2 for favorable-, intermediate-, and poor-risk groups were not reached, 43 months, and 16 months, respectively. The median OS was 29 months in the poor-risk group, whereas it was not reached in the favorable- and intermediate-risk groups. The 2-year OS rates in the favorable-, intermediate- and poor-risk groups were 94.5%, 80.1%, and 60.3%, respectively. The validation cohort confirmed the risk model's relationship with PFS2 and OS. The median PFS2 and OS in the high-risk group were 21 months and 32 months, respectively. Our prognostic model, including five clinical factors, is useful for patient care and treatment selection in high-risk mHSPC patients treated with ADT plus ABI. The developed model could provide more accurate information, guide treatment decisions, or classify patients in future clinical trials.

Comparison of the efficacy of sunitinib and pazopanib in patients with advanced non-clear renal cell carcinoma

Non-clear cell renal cell carcinoma (non-ccRCC) is a highly heterogeneous disease group, accounting for approximately 25% of all RCC cases. Due to its rarity and especially heterogeneity, phase III trial data is limited and treatment options generally follow those of clear cell RCC. In the literature, there exists a number of studies with sunitinib, cabozantinib, and everolimus, but data on the efficacy of pazopanib are limited. Our aim in this study was to compare the efficacy of pazopanib and sunitinib, in a multicenter retrospective cohort of non-ccRCC patients. Our study included patients diagnosed with non-ccRCC who received pazopanib or sunitinib treatment as first-line therapy from 22 tertiary hospitals. We compared the progression-free survival (PFS), overall survival (OS), and response rates of pazopanib and sunitinib treatments. Additionally, we investigated prognostic factors in non-ccRCC. PFS and response rates of sunitinib and pazopanib were found to be similar, while a numerical difference was observed in OS. Being 65 years and older, being in the intermediate or poor risk group according to the International Metastatic Renal Cell Carcinoma Database Consortium, having liver metastases, presence of a sarcomatoid component, and having de novo metastatic disease were found to be significantly associated with shorter PFS. Pazopanib treatment appears to have similar efficacy in the treatment of non-ccRCC compared to sunitinib. Though randomized controlled trials are lacking and will probably be never be available, we suggest that pazopanib could be a preferred agent like sunitinib and cabozantinib.

1711P Real-word data challenging the treatment paradigm in metastatic renal cancer: Time to separate IMDC intermediate / poor risk groups?

1711P Real-word data challenging the treatment paradigm in metastatic renal cancer: Time to separate IMDC intermediate / poor risk groups?

CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib

AbstractAchieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month BCR::ABL1% (PR-1), or high CD302 expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; P < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; P = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle–related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34+CD302+ and CD14+CD302+ cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data

BackgroundTo date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy. Patients and MethodsPatients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs). ResultsForty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0–16.0) with cabozantinib and 9.5 months (6.0–13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P = .091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P = .202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P = .033). ConclusionThe efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC.

The outcome in pediatric acute myeloblastic leukemia; results of the first-line treatment and contribution of hematopoietic stem cell transplantation to survival of relapsed patients.

To analyze the long-term outcome of pediatric patients with acute myeloblastic leukemia. Data from 69 patients 0-18 years of age diagnosed between December 2001 and October 2019 were analyzed in April 2023. Patients received MRC-AML10 chemotherapy (2ADE+MACE+MidAC). No maintenance chemotherapy or preventive cranial radiotherapy was administered. Twelve patients with Down syndrome and 15 patients with promyelocytic leukemia were in the cohort. Patients with Down syndrome received reduced chemotherapy (cumulative anthracycline 420 mg/m2, cytarabine 3.4 g/m2, etoposide 1400 mg/m2). ATRA was added to chemotherapy in promyelocytic leukemia. Four patients (5.8%) died in the induction (two typhlitis, one intracranial hemorrhage, and one resistant disease). The complete remission rate of 66 patients was 87.8%. There was one death due to cardiotoxicity. Total infection-related deaths were 7.2%. Seven patients with high-risk criteria and one with resistant disease underwent hematopoietic stem cell transplantation (HSCT) following the first-line treatment. All seven patients in remission were alive and disease-free. The relapse rate was 34.4% (n = 21). Four patients developing marrow relapse were disease-free in the second remission after salvage and maintenance chemotherapy. Thirteen patients (18.84%) underwent HSCT in the second remission and 8 are alive and disease-free. The mean follow-up period of patients from diagnosis was 185 ± 13 months. Thirty-four patients (49.2%) were alive and disease-free in the first remission whereas another two patients in the first remission developed secondary malignancy. In good, standard, and poor risk groups, event-free survival (EFS) rates were 68.2%, 52.9%, and 10%, and overall survival (OS) rates were 86.4%, 79.4%, and 20%, respectively. Fifteen years of EFS and OS of the whole cohort were 49.3% and 69.6%, respectively. When compared with national data and multicenter studies of developed countries, survival rates were acceptable.

Survival and Prognosis of Patients with Acute Myeloid Leukemia with Myelodysplasia-Related Changes Transformed from Myelodysplastic Syndrome

To explore the risk factors affecting the survival and efficacy of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) transformed from myelodysplastic syndrome (MDS). The clinical data of 60 patients with AML-MRC transformed from MDS who hospitalized in The Third Affiliated Hospital of Soochow University from January 2010 to December 2021 were retrospectively analyzed. The demographic data and laboratory parameters, cytogenetic karyotypes, target genes of AML detected by next generation sequence, risk stratification, treatment regimen, therapeutic efficacy and survival outcome were documented. Rank sum test and Chi-square test or Fisher exact test were used to compare the survival and efficacy. The effects of clinical parameters, risk stratification and treatment regimens on the survival and efficacy of the AML-MRC patients were analyzed by univariate and multivariate analysis. The median overall survival (OS) of the AML-MRC patients was 4.5 months, the 1-year OS rate was 28.3%, and the complete remission (CR) rate after treatment was 33.3%. The univariate analysis showed that age≥60 years, leukocytosis, severe thrombocytopenia, poor-risk group and only accepted hypomethylating agents(HMAs) or supportive therapy were the risk factors affecting OS. COX multivariate analysis showed that thrombocytopenia ( HR=4.46), HMAs therapy (compared to transplantation, HR=10.47), supportive therapy (compared to transplantation, HR=25.80) and poor-risk group (compared to medium-risk group, HR=13.86) were independent hazard factors for median OS of patients with AML-MRC. The univariate analysis showed that the risk factors affecting 1-year OS in patients with AML-MRC were age≥60 years, thrombocytopenia, time of transformation from MDS to AML (TTA)≥3 months, fibrinogen-albumin ratio index (FARI)≥0.07, CONUT score≥5, poor-risk group and supportive therapy. Binary logistic regression analysis showed that the independent risk factors for 1-year OS in AML-MRC patients were age≥60 years ( HR=11.23), thrombocytopenia ( HR=8.71), FARI≥0.07 ( HR=5.19) and poor-risk group ( HR=14.00). The risk factors affecting CR of AML-MRC patients in univariate analysis were age≥60 years, thrombocytopenia, FARI≥0.1, CONUT score≥5, poor-risk group and supportive therapy, while binary logistic regression analysis showed that age≥60 years( HR=7.35), CONUT score≥5 ( HR=9.60), thrombocytopenia ( HR=12.05) and poor-risk group ( HR=32.5) were independent risk factors affecting CR of the patients. The OS of AML-MRC patients is poor, old age(≥60 years old), supportive therapy, HMA therapy, poor-risk, thrombocytopenia, FARI≥0.07 and CONUT score≥5 may be associated with poor prognosis.

Abstract 928: Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC)

Abstract Multiple regimens are available for management of mccRCC including either immuno-oncology doublet (IO/IO) or combinations of IO and tyrosine kinase inhibitors (TKI). Clinical trials have compared these regimens to sunitinib, with no direct comparison between them. As such, there is ambiguity among physicians about preferred first-line for mccRCC. We performed a single-institution retrospective study of adults treated in first-line for mccRCC between 1/1/2017 and 1/1/2023. Regimens included IO/IO (ipilimumab/nivolumab [I/N]) or IO/TKI (pembrolizumab/axitinib [P/A], nivolumab/cabozantinib [N/C], or pembrolizumab/lenvatinib [P/L]). We compared efficacy and toxicity endpoints, using Kruskal-Wallis test for medians and Chi-square for categorical variables. 42 patients with median age of 61 (range: 36-95) were included. Patient distribution in IO/IO vs IO/TKI group was 20.0% vs 30.8% in International Metastatic Database Consortium (IMDC) favorable risk, 46.7% vs 38.5% in intermediate-risk, and 33.3% vs 30.8% in poor-risk group. 78.6% vs 66.6% of patients had WHO grade 3/4 ccRCC, 18.8% vs 15.4% had sarcomatoid features in the IO/IO vs IO/TKI, respectively. 38% (16/42) received I/N, 7% (3/42) N/C, 52% (22/42) P/A, and 2% (1/42) P/L. Median follow-up was 109 weeks. Table-1 compares the efficacy of IO/IO vs IO/TKI. IO-related toxicity, TKI-related toxicity, treatment interruptions, dose reductions, and need for steroids were not significantly different between IO/IO and IO/TKI (p= 0.240, p=0.372, p=0.923, p=1.00, and p=0.248, respectively). Genomic characteristics will be reported in poster. Despite small sample size, our real-world data showed that patients treated with IO/IO had significantly worse outcomes compared to those treated with IO/TKI. While this difference may stem from a more aggressive disease in IO/IO group but further insights needs to be obtained through future prospective studies comparing IO/IO and IO/TKI regimens. Variable IO/IO IO/TKI p-value Median treatment duration (weeks) 8.3 59.4 &amp;lt;0.001 Disease control rate (complete response + partial response + stable disease) (%) 50.0 91.7 0.024 Time from 1st line to 2nd line therapy (weeks) 14.6 57.1 0.001 Median overall survival (weeks) 63.6 Not reached 0.001 Citation Format: Omid Yazdanpanah, Sami Dwabe, Garrett Harada, Steven Seyedin, Nataliya Mar. Real-world comparison of first-line treatments for metastatic clear cell renal cell carcinoma (mccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 928.

Abstract 6954: Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway

Abstract Glycine decarboxylase (GLDC) is a mitochondrial enzyme of glycine cleavage system which catalyzes glycine to donate for one-carbon metabolism. It is implicated as a tumor suppressor in hepatocellular carcinoma but as an oncogene in lung cancer. Although GLDC expression in the kidney is second highest next to the liver, the role of GLDC in the kidney remains unclear. Thus, this study was designed to determine the role of GLDC in renal carcinoma. We found markedly increased expressions of GLDC in patients with renal cell carcinoma (RCC) classified as poor-risk group based on the Memorial Sloan Kettering Cancer Center prognostic model. In vitro studies revealed that cellular proliferation, colony formation was decreased in GLDC-deficient renal carcinoma cells. Additionally in vivo xenograft studies with GLDC-deficient and -overexpressing cells also revealed that tumor sizes were noticeably decreased in GLDC-deficient cell-injected mice while those were increased in GLDC-overexpressing cell-injected mice. Mechanistically, we found GLDC regulates renal carcinoma progression via interferon (IFN) stimulated gene factor 3 (ISGF3)-mediated pathway. Expressions of IRF9 and STAT2 were increased in GLDC-deficient cells while those were decreased in GLDC-overexpressing cells. Upon inducing expression of ISGF3 subunits, GLDC deletion elevated DNA damage, mitotic catastrophe, mitochondrial deficiency induced by chemotherapy. Finally, GLDC knockdown diminished pyrimidine synthesis to impair renal cancer progression. In summary, our finding reveals that GLDC regulates renal carcinoma progression and DNA damage response via ISFG3-medated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of renal carcinoma. Citation Format: Jin Young Kim, Byung Hoon Kim, Misun Choe, Thi Tuyet Mai Pham, Mikyung Kim, Ji Hae Seo, So Jin Shin. Glycine decarboxylase regulates renal carcinoma progression and DNA damage response via interferon stimulated gene factor 3-mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6954.

Pembrolizumab plus lenvatinib (P+L) versus alternative therapies in first-line (1L) advanced renal cell carcinoma (aRCC) by IMDC risk status: A network meta-analysis (NMA).

421 Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria is a widely used prognostic model in advanced RCC. Pembrolizumab plus lenvatinib (P+L) demonstrated a significant improvement in ORR, PFS, and OS versus sunitinib in subjects with cc aRCC in the KEYNOTE-581/CLEAR trial. This NMA indirectly compared the efficacy of P+L to other therapies in 1L aRCC subjects within IMDC risk groups using data from randomized clinical trials (RCTs). Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. Trials reporting results for IMDC favorable risk and/or intermediate+poor risk groups were included. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). The NMAs assuming constant hazard ratios (HRs) for OS and PFS were performed for all IMDC risk group categories. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: For the IMDC favorable risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + ipilimumab (N+I) (OR=5.35; 95% CrI: 2.59, 11.41) and nivolumab (OR=8.41; 95% CrI: 1.84, 43.77). For PFS, P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.31, 95% CrI: 0.17-0.56). For OS, no significant differences were observed compared to other alternatives in the network. For the IMDC intermediate+poor risk subgroup, P+L demonstrated statistically significant increase in ORR compared to nivolumab + cabozantinib (N+C) (OR=1.77; 95% CrI: 1.02, 3.10), N+I (OR=3.15; 95% CrI: 1.94, 5.10), and nivolumab + ipilimumab + cabozantinib (N+I+C) (OR=2.34; 95% CrI: 1.34, 4.12), pembrolizumab + axitinib (P+A) (OR=2.65; 95% CrI: 1.57, 4.44) and nivolumab (OR=4.68; 95% CrI: 1.84, 12.02). For PFS, P+L resulted in a statistically significant improvement compared to N+I (HR=0.59; 95% CrI: 0.41, 0.84) (P+A) (HR=0.64; 95% CrI: 0.44, 0.93), and avelumab + axitinib (A+A) (HR=0.65; 95% CrI: 0.46, 0.93). For OS, no significant differences were observed compared to other alternatives in the network. Conclusions: PFS analysis favored P+L over all alternative therapies in the network in favorable or intermediate+poor IMDC risk groups. ORR analysis favored P+L over all alternative therapies in the network in intermediate+poor IMDC risk groups. No significant difference in OS was observed between P+L and other alternative therapies in the network.

Potential Predictive Biomarkers for the Development and Outcomes of Inhibitors in Hemophilia A Patients

Introduction Inhibitor development poses a significant challenge in the treatment of hemophilia A (HA). Approximately 30% of HA patients develop inhibitors in response to FVIII infusion therapy. While the risk is highest early in treatment days, patients are at risk throughout their lifetime. Regardless of certain known risk factors, the lack of biomarkers for inhibitor development hampers efforts to prevent their occurrence. Since inflammation is a well-known risk factor, one of our goals is to identify potential biomarkers among inflammatory cytokines. Another focus is glycosylation-related biomarkers, which has drawn great attention in biomarker discovery of various diseases including cancers. By analyzing the association of cytokines and plasma glycosylation with inhibitor formation, this research aims to provide valuable references for clinical care. Methods Plasma samples from 60 HA patients, and 23 healthy donors were analyzed to detect the levels of G-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL12p70, IP-10 and TNF. The HA samples were divided into inhibitor negative (InhNeg, BU &amp;lt; 0.6, n = 26) and inhibitor positive (InhPos, BU ≥ 0.6, n = 34) groups. A predictive model of inhibitor development was established using logistic regression analysis. To investigate the correlation between cytokine levels and high inhibitor titers, the inhibitor-positive samples were further categorized into good risk (&amp;lt; 10 BU, n = 14) and poor risk (≥ 10 BU, n = 20) groups based on immune tolerance induction therapy prognosis. Total plasma N-glycans were released, methylated, and analyzed by using MALDI-TOF MS/MS. A synthesized N-glycan was spiked in to quantify each glycoform. The study evaluated the correlation between HA sample groups and various glycosylation ratios, including for sialylation, core-fucosylation, galactosylation and galactose. The cut-off value of each glycosylation ratio was based on the median of the inhibitor-negative group. Results The adjusted odds ratio of inhibitor development for elevated G-CSF, IL-6 and decreased IL-10 were 2.84 (95% CI: 1.45-8.48; p = 0.021), 1.50 (95% CI: 1.14-2.42; p = 0.069), and 0.28 (95% CI: 0.10-0.61; p = 0.006), respectively in HA patients. Among InhPos HA patients, the levels of G-CSF, IL-2, IL-6, IL-8, and IL-10 in poor risk group were significantly higher than in good risk group (p-value &amp;lt; 0.05, ANOVA). Since aging also causes glycosylation changes, we analyzed adult (≥ 18 years old, n = 31) and pediatric (&amp;lt; 18 years old, n = 17) HA patients separately. Among analyzed glycan ratios, 80% of adult HA patients with inhibitors had a higher core-fucosylation ratio. All pediatric patients with inhibitors had significant lower sialylation and higher galactosylation ratios. Strikingly, pediatric patients with inhibitors exhibited around 2-fold higher core-fucosylation than those without inhibitor. Conclusion Our finding of elevated levels of G-CSF and IL-6 along with decreased levels of IL-10 associated with the presence of inhibitors, suggests the potential for prediction of inhibitor development. Moreover, high levels of G-CSF, IL-2, IL-6, IL-8 and IL-10 in patients with high inhibitor titers (≥ 10 BU, poor risk group) but not in good risk group imply they could be explored in future studies as prognostic factors in immune tolerance therapy. Glycan ratios can also hold promise as biomarkers including higher core-fucosylation in adult patients. Additionally, significant lower sialyation, higher galactosylation and core-fucosylation ratios indicate higher possibility of inhibitor development in pediatric patients.

Disparities in Genetic Profiles, Risk Stratification and Outcomes in Adults with Acute Myeloid Leukemia Comparing Patients of Hispanic and Non-Hispanic Ethnicity in Central California

Acute myeloid Leukemia (AML) is the most common type of acute leukemia in adults. Ethnic disparities due to distinct biology and socioeconomic status have been described in AML. Prior studies indicated Hispanic AML patients had a younger age at presentation, more frequent high-risk mutations, and worse survival compared with non-Hispanics. We conducted a retrospective study to investigate the differences in AML risk stratification, mutational profiles and outcomes between Hispanic and non-Hispanic AML patients treated at Community Medical Centers (CMC) in Central California. Methods: We retrospectively analyzed patients ≥ 18 years diagnosed with AML between January 2016-December 2022 and treated at CMC in Fresno, CA. Patients with Acute promyelocytic leukemia and patients without complete cytogenetic and molecular data were excluded. The clinical data including age, sex, ethnicity, race, zip code, WBC on diagnosis, cytogenetics, molecular data and treatment regimens were reviewed. Molecular profiling was performed by next generation sequencing using established myeloid panels by NeoGenomics (NeoTYPE comprising of 63 genes) or Foundation One Heme laboratory (406 genes). Risk groups were identified based on the European Leukemia Network (ELN) 2022 criteria. RedCap data collection tool was used for data collection. A comparison of patient characteristics and rate of genetic alterations between Hispanic and Non-Hispanic patients was done using the Fisher exact test or Chi-square test. Kaplan-Meier Curve with log-rank test was used for evaluation of overall survival (OS) and progression-free survival (PFS). Results: 201 patients met the study criteria, 30 of them did not receive treatment and were included for their diagnostic data only but excluded from the survival analysis. The mean age at diagnosis was 65.6. 58.5% were males and 30% were Hispanic. Hispanic patients were younger than non-Hispanics (57.6 vs 64.6 years, p=0.01). Hispanic patients were also more likely to live in the relatively low Socioeconomic status (SES) neighborhoods (i.e., living in zip codes with the 1st or 2nd quartile of median income level) p=0. 007. More Hispanic patients needed interpreter P&amp;lt;0.001. However, Hispanics were more likely to experience favorable risk AML (8.4 % vs 0.7%, p=0.012), while non-Hispanics had higher rate of poor risk disease (63.8 Vs 55.9%, p=0.012).). There was no significant difference between Hispanics and non-Hispanics in terms of sex, de novo versus secondary AML, WBC at time of diagnosis, Extramedullary or Central nervous system (CNS) involvement, type of induction regimen or rate of consolidative or subsequent allogeneic stem cell transplant. Median OS in Hispanics was 17.3 months compared to 10.28 months for non-Hispanics, p=0.117.and median PFS for Hispanics was 9.17months compared to non-Hispanics at 6.04 months P=0.034 (Figure 1). In univariate analysis PFS and OS were better in patients with normal cytogenetics compared to those with abnormal cytogenetics (15.3 vs 3.52 months and 20.4 vs 7.69 months respectively, p &amp;lt; 0.001) and in patients with favorable compared to intermediate risk and poor risk groups (84.5 vs 11.4 vs 4.1 months for PFS and Non reached vs 18.1 vs 7.8 months for OS, p&amp;lt; 0.001). There was no significant effect of income level in terms of OS or PFS. The most common genetic mutations in our patients were NPM1, FLT3-ITD, DNMT3A, TET2 and TP53. However, there were differences in the rates between Hispanics and non-Hispanics. 5q deletion and STAG2 were more common in non-Hispanics while KMT2C was detected more in Hispanics (table 1). Conclusion: Our study identified biologic differences between Hispanic and non-Hispanic AML patients with heterogeneity in genetic mutations. While Hispanic patients had lower income, they were younger at diagnosis and more likely to have favorable risk AML. Hispanic patients had better PFS and a trend towards improvement in OS. Further studies on larger patient population are warranted to evaluate the effect of ethnicity and SES on outcomes of AML patients.

Prognostic Impact of Conditioning Intensity on Outcomes after Allogeneic Transplantation for MDS with Low Blasts

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). The blast percentage in MDS is one of the important factors to utilize allo-HSCT, and the other disease-related factors, such as transfusion dependency and chromosomal risk, are crucial to consider whether patients harboring MDS with less than 5% of marrow blasts (MDS-Lo) undergo to allo-HSCT. However, the prognostic impacts of conditioning intensity in MDS-Lo patients are still unclear. We here conducted a nationwide retrospective study to clarify the prognostic factor and investigate the optimal conditioning intensity for MDS-Lo. Methods In this study, patients diagnosed as the other than refractory anemia with excess blasts (RAEB)-1 and -2 according to the WHO classification (marrow blasts &amp;lt;5% and peripheral blood blasts &amp;lt;1%) were considered to be MDS-Lo. The clinical data of 1,229 de novo MDS-Lo patients (i) who had stayed MDS-Lo from diagnosis to transplantation and (ii) who underwent their initial allo-HSCT between January 2001 and December 2020 were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In a total of 1,229 patients, 651, 397, and 181 patients received myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and non-myeloablative conditioning (NMAC) groups, respectively. The estimated 3-year OS rates were 63.3%, 61.0%, and 69.7% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CRFS rates were 41.1%, 43.9%, and 47.2% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year GRFS rates were 27.5%, 33.4%, and 35.4% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CIR were 11.9%, 14.2%, and 16.0% in MAC, RIC, and NMAC groups, respectively; and the estimated 3-year NRM were 29.8%, 31.0%, and 24.7% in MAC, RIC, and NMAC groups, respectively. The multivariate analyses revealed four factors affecting lower OS: older recipient's age (Hazard ratio (HR) [95% confidential interval], 1.70 [1.28-2.24]; P&amp;lt;0.001 for 40-59 years)(HR, 2.32 [1.71-3.15]; P&amp;lt;0.001 for 60 years or older), performance status 2-4 at HSCT (HR, 1.84 [1.32-2.57]; P&amp;lt;0.001), the history of infection before HSCT (HR, 2.12 [1.55-2.89]; P&amp;lt;0.001), and high number of red blood cell (RBC) transfusion before HSCT (HR, 1.65 [1.35-2.02]; P&amp;lt;0.001). These factors also negatively affected CRFS, GRFS, and NRM. In addition, poor cytogenetic risk group was associated with worse OS (HR, 1.66 [1.32-2.09]; P&amp;lt;0.001), CRFS (HR, 1.48 [1.22-1.80]; P&amp;lt;0.001), and GRFS (HR, 1.36 [1.14-1.64]; P=0.001) but not CIR. There was no significant difference of OS, CRFS, GRFS, CIR, and NRM in either RIC or NMAC group compared to MAC group. We next performed the subgroups analysis based on the prognostic factors. The subgroup analysis for the comparison between MAC and RIC regimens showed the better OS of MAC regimen among patients with low number of RBC transfusion (HR, 1.33 [1.01-1,75]; P=0.039). The subgroup analysis for the comparison between RIC and NMAC regimens revealed the better OS of NAMC regimen among patients aged &amp;lt;40 years (HR, 0.43 [0.19-0.96]; P=0.038), no history of infection (HR, 0.67 [0.50-0.91]; P=0.009), and good cytogenetic risk (HR, 0.54 [0.38-0.83]; P=0.004). Conclusion This study showed the prognostic factors on the post-transplant outcomes among MDS-Lo patients, and no significant difference of conditioning intensity in the entire population. Furthermore, we found the factors (the number of RBC transfusion, patient's age, the history of infection, and cytogenetic risk) potentially affecting the selection of conditioning intensity. These findings would improve the management for transplant candidates with MDS-Lo.

Comparison of Safety and Efficacy between Venetoclax Combined with CAG (cytarabine, aclarubicin, G-CSF) Regimen and CAG Regimen Alone in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have dismal outcomes, representing an urgent unmet need. The BCL2 inhibitor venetoclax has exhibit encouraging anti-tumor activity in AML. The clinical efficacy of the CAG regimen in patients with R/R AML has been confirmed in previous studies. The aim of this study was to retrospectively compare the safety and efficacy of the combination of venetoclax with CAG regimen and CAG alone in patients with R/R AML. Patients and methods: We retrospectively reviewed and compared the efficacy and safety of venetoclax combined with the CAG regimen (Ven-CAG group, n=37) and CAG regimen alone (CAG group, n=37) for 74 patients with R/R AML treated at our institution between August, 2016 and March 2023. The patients included those who were refractory to at least one cycle of induction chemotherapy, and patients with relapsed leukemia. According to the duration from complete remission (CR) to relapse, the relapsed patients were further divided into two subgroups, the favorable-risk relapsed group (the duration≥12 months) and the poor-risk relapsed group (the duration&amp;lt;12 months). The incidence of composite complete remission (CCR), minimal residual disease (MRD) status, one-year overall survival (OS), and adverse events (AEs) were analyzed and compared in two groups. Results: Patient age, sex, ELN risk stratification, disease status, risk stratification according to the duration from CR to relapse were comparable between two groups (Table 1). The CCR of Ven-CAG group was 78.4% (29/37)，which was superior to 56.8% (21/37) of CAG group (P=0.047) . Furthermore, the rate of MRD elimination in patients who achieved CCR in Ven-CAG group was significantly higher than that in CAG group [44.8% (13/29) vs. 9.5% (2/21), P= 0.007] (Table 2). The rate of MRD elimination in favorable-risk relapsed group (CR to hematological relapse ≥12 months) was higher in Ven-CAG group [100% (5/5) vs. 25% (1/4), P= 0.048]. The one-year OS were 78.4% (95% CI, 62.3%-94.5%) and 66.7% (95% CI, 51.2%-82.2%) in Ven-CAG and CAG group (P=0.225), respectively. The incidences of grade 3-4 hematologic AEs in Ven-CAG group and CAG group were 100% (37/37) and 97.3% (36/37), respectively (P=1.000). The incidences of febrile neutropenia were 67.6% (25/37) and 62.2% (23/37), respectively (P=0.626). Among patients who achieved CCR, the median time for neutrophil recovery in the Ven-CAG group and CAG group were 8 (3-30) days and 9.5 (3-31) days (P=0.781), while the median time for platelet recovery was 9 (3-28) days and 8 (3-19) days (P=0.708). The incidences of grade 3-4 non-hematologic AEs were comparable in Ven-CAG and CAG group (32.4% vs. 35.1%, P=0.806). The most common nonhematologic AEs were infections, with the incidences of 18.9% and 27%, respectively (P=0.407). No patients died within 4 weeks after initiating the induction course in Ven-CAG group. There was one case of early death during induction in CAG group due to cerebral hemorrhage. Conclusions: Venetoclax added to CAG regimen was safe and active in patients with R/R AML, producing higher CCR and MRD-negative remissions than CAG regimen alone. These results highlight the incremental benefit of venetoclax added to CAG regimen. This requires further verification through prospective, larger size clinical trials.

Only FLT3-ITD Mutation Did Not Have a Deleterious Effect on Acute Myeloid Leukemia Patients with NPM1 Mutation, but Concomitant with DNMT3A Mutation or a＜3log Reduction of MRD2 Predicted Poor Survival

Background Co-occurring mutations were observed in NPM1-mutated acute myeloid leukemia (AML) frequently, and the measurable residual disease (MRD) for NPM1 is effective for the prognosis of NPM1-mutated AML. However, the combined effects of co-occurring gene mutation at the baseline and MRD on survival are unclear. We investigated the impact of gene mutation status and NPM1 MRD on predictive value of AML patients with NPM1 mutation. Methord A single-center, retrospective cohort study was carried out in patients diagnosed as AML with NPM1 mutation in Peking University Peoples'hospital. Patients were treated by an anthracycline and cytarabine-based or homoharringtonine and cytarabine-based induction chemotherapy regimen and followed by high dose cytarabine as consolidation therapy. Patients who had the indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) underwent allo-HSCT. A small part of patients with FLT3-ITD mutation received FLT3 inhibitor. Targeted next-generation sequencing (NGS) were analyzed at diagnosis, and quantitative NPM1 mutation (A, B, and D type) were detected at diagnosis and each end of chemotherapy cycle. As MRD for NPM1 rare type (NPM1 RT) was not available, MRD, relapse free survival (RFS) or overall survival (OS) analysis were conducted in patients received chemotherapy only (NGS chemo), excluding harboring NPM1 RT. Results A total of 234 patients, with NGS results, diagnosed as NPM1-mutated AML were included. 68.4% (160/234) patients including 17 patients with NPM1 RT received chemotherapy only, and NGS chemo patients were 143. After chemotherapy, 31.6% (74/234) patients underwent allo-HSCT. 1.7% (4/234) patients died of infection or hemorrhage during induction therapy. 15.8% (37/234) patients received FLT3 inhibitor，and 92.2% (212/230) patients achieved complete remission rate (CR) or incomplete hematologic recovery (CRi). During median follow-up time of 24.9 [interquartile range (IQR) 11.6-47.8] months, 40.6% (95/234) patients died. Median transcription of NPM1 at diagnosis was 31.13 (IQR 17.23-56.91)%, and would take a median time of 4.1 (IQR 2.6-5.6) months to converted to negativity.Reduction of MRD at the end of second cycle of consolidation (MRD2) ≥3log associated with higher RFS (3-year RFS rate 66.3% vs. 11.1%, p＜0.001) and OS (3-year OS rate 78.4% vs. 32.4%, p＜0.001) than reduction＜3log, and consistent negativity of MRD also predicted higher RFS (3-year RFS rate, 98.1% vs. 42.3%, p＜0.001) and OS (3-year OS rate, 100% vs. 67.7%, p＜0.001) than those whose MRD turned from negativity to positivity. 9 genes were mutated in＞10% in 234 patients, and DNMT3A and FLT3-ITD were the most prevalence (Figure 1). Univariate analysis showed FLT3-ITD, DNMT3A and reduction of MRD2＜3log were associated with poorer RFS and OS in 143 NGS chemo patients. But In multivariate analysis, only DNMT3A mutation [RFS, hazard ratio (HR)=1.9, p =0.023; OS, HR=2.1, p =0.032] and reduction of MRD2 ≥3log（RFS, HR=0.1; OS, HR =1.9, both p＜0.001）were independent prognostic factors for survival. Four subgroups were divided by different status of DNMT3A and FLT3-ITD, that were both FLT3-ITD and DNMT3A negative, FLT3-ITD positive and DNMT3A negative, FLT3-ITD negative and DNMT3A positive, and both FLT3-ITD and DNMT3A positive. The concurrence of FLT3-ITD and DNMT3A was associated with lowest RFS and OS (3-year RFS rate 29.2%, p＜0.001; 3-year OS rate 53.5%, p＜0.001). However, patients with only FLT3-ITD mutation did not contribute to poor survival compared with patients without FLT3-ITD mutation (3-year RFS rate 71.4% vs. 74.4%, p＜0.843; 3-year OS rate 74.5% vs.75.8%, p = 0.759). Three risk group were re-stratified by the gene mutation and gene reduction of MRD2 (Figure2), and the RFS and OS of the poor risk group, defined by patients with ＜3log reduction of MRD2, or with both FLT3-ITD and DNMT3A mutation, could be improved by allo-HSCT(3-year RFS rate, 56.4% vs. 29.2%, p = 0.015; 3-year OS rate, 72.0% vs. 31.6%, p = 0.001). Conclusion In AML patients with NPM1 mutation, the deleterious effect of FLT3-ITD could be pronounced in patients concomitant with DNMT3A mutation. A＜3log reduction of MRD2 was also another independent poor prognostic factor for survival, which could be improved by allo-HSCT. Meanwhile, the conversion of MRD for NPM1 from negative to positive might be a poor prognostic factor, but it requires to be validated by multivariate analysis.

Prospective Real-World Outcomes of Acute Myeloid Leukemia

Background: It is evident that treatment outcomes improve with the clinical studies, in this study we aimed to investigate the demographics and treatment modalities of the acute myeloid leukemia (AML) patients in a large population-based cohort who were diagnosed and followed up in Turkey as a real-world data. Methods: All AML adult patients who were recorded on the database of Turkish AML Registry project from 25 sites were included in this study if they were diagnosed before 1st of June 2022. Study approved by ethics committee and Ministry of Health of Turkey. Demographics and disease related parameters both at the time of diagnosis and at the follow up and treatment outcomes were presented. Results: A total of 906 patients were included in the study, 891 patients data accepted as adequate and underwent further evaluation. Median follow-up period was 12.0 (SD:26.6) months and 45.4% of the patients were female. Median age at the time of diagnosis was 58 (18-91). According to the FAB classification most common subtypes were M4 (23.6%), M2 (21.6%), M5 (16.8%) and M1 (13.5%) and AML, NOS (36.9%) is the most common type according to the WHO classification. Of the patients 60.8%, 24.7%, 14.5%, was intermediate, favorable and poor respectively considering AML risk stratification (ELN 2017) by genetics. Only 4.4% of the patients had extramedullary involvement. For the first induction 70.8% of the patients had received intensive regimens composing anthracyclines and ARA-C and for the first relapse 71.8%. ARA-C (71.7%) backbone and Azacitidine alone (13.4%) are the most used regimens, 10.5% and 22.5% underwent allo-HCT during the first and second induction respectively. Response rates obtained by the induction therapies were as follows; 61.7% CR (including 9.3% MLFS), 14.2% PR, 8.6% SD, 15.5% PD, the ratio was 59.7% and 24.3% for CR2 and PD respectively. Median overall survival has not been reached for the favorable risk group, were 16.2 months for the intermediate risk and 14.1 months for the poor risk group (p&amp;lt;0.001) and 22.7 months for the entire population. Median progression free survival were 32.6 months for the favorable risk group, 12.7 months for the intermediate risk and 9.4 months for the poor risk group (p&amp;lt;0.001) and 15.2 months for the entire population (Figure 1). COX regression analysis were performed for the prognostic factors of OS, univariate analysis performed with the parameters; age (&amp;lt;60 and ≥60), FAB classification, ECOG, FLT3, NMP1, HCT were accepted as clinically significant covariates. First univariate then with the significant parameters (p&amp;lt;0.05) multivariate COX regression analysis were perfomed. With the multivariate analysis age (p:0.005, HR:2.140, 95% CI: 1.254-3.653), FAB classification (favorable were reference, intermediate p:0.045, HR: 2.269, 95% CI: 1.017-5.064, poor p:0.217, HR: 2.105, 95% CI: 6.858) and HCT (p:0.034, HR:2.618, 95% CI: 1.073-6.387) were found as significant. Conclusion: Progression free survival obtained after induction therapy and overall survival were relatively shorter than the ones which were presented by other real-world registries. Lack of early access to the targeted and novel agents, like Flt3 inhibitors, Venetoclax, IDH1 and 2 inhibitors, CPX351 and Glasdegib should be a potential explanation to this relatively short PFS and OS. We have also been aware of un-ideal access to well established and nation wide cytogenetic laboratory service to induce early integration of targeted agents to the treatment and better risk stratification to determine the patients who should obtain the best prolonged survival via allo-HCT.

Assessment of T-Cell Receptor (TCR) Mediated T-Cell Activation in Acute Myeloid Leukemia at Diagnosis Has Implications for Risk Stratification and Response to Immune Checkpoint Inhibitors

Background Relapse in patients with acute myeloid leukemia (AML) has been, in part, attributed to the ability of leukemic blasts to escape immune surveillance through mechanisms such as MHC class II antigen modulation, alteration of the cytokine milieu, and upregulation of inhibitory and immune checkpoint ligands that promote T-cell suppression. Yet, immune checkpoint inhibitors (ICI) used in AML have yielded variable and unpredictable results. Moreover, evaluation of T-cell function is not part of the diagnostic assessment of patients with AML. Methods To better characterize the T-cell dysfunction in AML, we conducted a prospective study on freshly harvested, bone marrow aspirates from patients with AML at presentation, collected under an Institutional IRB-approved banking protocol over the past two years. Using a multiparameter flow cytometry-based assay, we analyzed T-cell activation potential in response to CD3/CD28 (bead-based), T-cell receptor (TCR) stimulation, both alone (n= 40 AMLs and 10 healthy donors) or in combination with a library of ICI (n=15 AML and 5 healthy donors). We selected OX40 (CD134/TNFRSF4) and ICOS (Inducible T-cell costimulator) as surrogate markers for T-cell activation based on their expression pattern post bead-based stimulation in healthy donors' bone marrows. The ICI library comprised 31 therapeutic antibody inhibitors of known immune checkpoints, signaling pathways, and chemokines reported to be implicated in T-cell suppression in AML and other solid tumors. Results Healthy T-cells displayed the highest surface expression of OX40 and ICOS at 5 days post-bead-stimulation, which was selected as the endpoint for our in vitro analyses. We found that bone marrow-derived T-cells from healthy donors upregulated the expression of the markers ICOS and/or OX40 in at least 20% of T-cells post-stimulation (n= 10, ICOS: median 36.9%, range 20-72%; OX40: median 59.3%, range 21.4 -83%). Overall, AML samples displayed a lower degree of ICOS and OX40 T-cell expression in response to TCR stimulation (n=40, ICOS: median 20.5%, range 4-65%; OX-40: median 30.3%, range 0.3-80%). Based on this result, T-cell activation was defined as &amp;gt;20% CD3+ cells ICOS+/OX-40+ with stimulation, with greater than 2-fold changes from baseline ICOS and OX40 expression. Using this criterion, patients with AML were then classified as activators or non-activators. T-cell activation status correlated with ELN 2022 risk (1) (Figure 1A). For the intermediate risk group, we observed that the activators group had a significantly longer relapse-free survival when compared to the non-activators (Figure 1B, n=10, Mantel-Cox log-rank = 0.02, follow up 400 days at the time of writing). While a similar trend was observed in the favorable and the poor risk groups, it did not reach significance in these ELN categories. To assess if the T-cell activation could be rescued or augmented upon immune checkpoint inhibition, we tested the effect of each of the 31 compounds of the ICI library on the degree of T-cell activation in diagnosis bone marrow aspirates of 15 patients (7 activators and 8 non activators) and in 5 healthy donors. Matched peripheral blood (PB) samples were available for 5 of the 15 patients with AML. All tested normal donors reached the threshold for T-cell activation, which was not significantly affected by ICI treatment. The 7 AML activators behaved similarly to the healthy donors. In 2 of the 8 AML non-activators, selected ICI rescued T-cell activation in absence of TCR stimulation, while in the remaining 6 cases, T-cell activation was not achieved under any condition. Similar, but overall dampened activation trends, were observed in PB samples. Conclusions Consistent with the findings of our previous retrospective study (2), the ongoing prospective analysis of T-cell activation of diagnosis bone marrows of patients with AML suggests that testing TCR-mediated T-cell activation potential at diagnosis may help refine risk stratification of the heterogenous ELN intermediate risk group. AML immune suppression seems to be reversible in a minority of cases with the use of selected ICI inhibitors.